WO2026003582A2 - Lipides et nanoparticules lipidiques - Google Patents

Lipides et nanoparticules lipidiques

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Publication number
WO2026003582A2
WO2026003582A2 PCT/IB2025/000348 IB2025000348W WO2026003582A2 WO 2026003582 A2 WO2026003582 A2 WO 2026003582A2 IB 2025000348 W IB2025000348 W IB 2025000348W WO 2026003582 A2 WO2026003582 A2 WO 2026003582A2
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WIPO (PCT)
Prior art keywords
alkylene
compound
optionally substituted
cpr
independently selected
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/IB2025/000348
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English (en)
Other versions
WO2026003582A3 (fr
Inventor
Mark Cornebise
Kerry E. BENENATO
Örn ALMARSSON
Yan Xia
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Axelyf Ehf
Original Assignee
Axelyf Ehf
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Publication of WO2026003582A2 publication Critical patent/WO2026003582A2/fr
Publication of WO2026003582A3 publication Critical patent/WO2026003582A3/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C219/06—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having the hydroxy groups esterified by carboxylic acids having the esterifying carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms of an acyclic saturated carbon skeleton
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
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    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
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    • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C219/14—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the hydroxy groups esterified by a carboxylic acid having the esterifying carboxyl group bound to a carbon atom of a six-membered aromatic ring
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    • C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C219/16—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the hydroxy groups esterified by an inorganic acid or a derivative thereof
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    • C07C229/12—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of acyclic carbon skeletons
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    • C07C229/60—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in meta- or para- positions
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    • C07C233/00—Carboxylic acid amides
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    • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/35—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/36—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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    • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/35—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/40—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being unsaturated and containing rings other than six-membered aromatic rings
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    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/50—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
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    • C07C235/80—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms having carbon atoms of carboxamide groups and keto groups bound to the same carbon atom, e.g. acetoacetamides
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    • C07D211/40—Oxygen atoms
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    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
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Definitions

  • Lipid nanoparticles are a type of nanoscale delivery system composed of lipids that have gained significant attention and validation in the field of medicine. These particles have shown great potential for the delivery of various therapeutic agents, including but not limited to nucleic acids such as DNA, RNA, circRNA, self-amplifying RNA, small-activating RNA, and siRNA. LNPs offer several advantages over other delivery systems, including intracellular delivery of sensitive nucleic acids like mRNA, biocompatibility, biodegradability, and the ability to encapsulate hydrophobic and hydrophilic molecules.
  • LNPs as a drug delivery system
  • researchers recognized the potential of lipids to form stable nanoparticles and protect encapsulated molecules. While various molecules of different sizes and properties can be encapsulated in lipid particles, the focus of LNP research was on gene therapy, where the delivery of nucleic acids posed significant challenges due to their inherent instability and the need for efficient intracellular delivery. Over the years, advancements in lipid chemistry, formulation techniques, and manufacturing processes have contributed to the refinement of LNP-based delivery systems.
  • LNPs have shown tremendous promise in the field of medicine, particularly in the delivery of nucleic acid-based therapeutics. This includes the delivery of small interfering RNA (siRNA) for gene silencing, messenger RNA (mRNA) for protein synthesis, and gene editing tools such as CRISPR-Cas9. LNPs protect the encapsulated nucleic acids from degradation, enhance their cellular uptake, and facilitate their delivery and release at the target site, thereby improving therapeutic efficacy.
  • siRNA small interfering RNA
  • mRNA messenger RNA
  • CRISPR-Cas9 gene editing tools
  • LNP-based delivery systems face barriers such as uptake by the reticuloendothelial system (RES) and clearance by the liver and kidneys, which can limit their circulation time and reduce their therapeutic efficacy.
  • RES reticuloendothelial system
  • LNPs may induce an immune response due to their foreign nature and inherent adjuvant potential, leading to adverse reactions or decreased therapeutic outcomes.
  • LNPs pose significant challenges. Maintaining batch-to-batch consistency, controlling particle size, and optimizing production processes are crucial for the successful translation of LNPs from the laboratory to large-scale manufacturing.
  • the present invention provides for lipids that may be formulated in a delivery vehicle to facilitate the encapsulation of a wide range of single or multiple payloads including therapeutic, theragnostic, preventive, prophylactic, pre-emptive, and diagnostic agents, such as, without limitation, nucleic acids (e.g., RNA or DNA), proteins, peptides, and small molecule active pharmaceutical ingredients (APIs).
  • nucleic acids e.g., RNA or DNA
  • proteins e.g., peptides
  • APIs small molecule active pharmaceutical ingredients
  • the lipid compounds of the present invention can be used in combination with other lipid components, such as neutral lipids, sterols and polymer conjugated lipids, to form lipid nanoparticles for delivery of payloads both in vitro and in vivo, for therapeutic or prophylactic purposes, including vaccination.
  • the present invention further provides for lipid nanoparticles (LNPs) comprising said lipids as well as methods of administering LNPs to a subject, e.g., delivering an mRNA and achieving prolonged expression of a desired polypeptide in the animal or human subject.
  • LNPs lipid nanoparticles
  • the invention provides for a method of delivering and/or producing a polypeptide of interest in a cell.
  • administering refers to introducing a composition or agent of the present invention (e.g., an LNP comprising a nucleic acid payload) into a subject, organ, tissue or cells for theragnostic, preventive, prophylactic, pre-emptive therapeutic, pharmacokinetic, diagnostic, and theragnostic purposes, or companion medicine and research purposes.
  • administering includes in vivo, in vitro, ex vivo and in utero administration. The introduction of a composition or agent into a subject is by any route of administration that is suitable for the specific composition or agent.
  • Routes of administration include, but not limited to, oral, pulmonary, intranasal, parenteral (e.g., intravenous, intramuscular, intraperitoneal, or subcutaneous), rectally, intravesical, intranodal, intralymphatical, intratumoral, regional, local and topical administration.
  • parenteral e.g., intravenous, intramuscular, intraperitoneal, or subcutaneous
  • rectally e.g., intravesical, intranodal, intralymphatical, intratumoral, regional, local and topical administration.
  • “Cationic lipid” refers to any lipid that is or can be positively charged.
  • the cationic lipid is an ionizable lipid, i.e., an ionizable cationic lipid, which is predominantly protonated and positively charged at a pH that exceeds about 2 units of the pKa value, known as the negative Iog(10) value of the apparent acid dissociation constant (Ka) of the protonated, positively charged form of the lipid in the LNP assembly context.
  • Cationic and cationic ionizable lipids are highly waterinsoluble, even when charged, due to the lipophilic nature of the overall molecule.
  • thermodynamic pKa of an ionizable lipid is generally not measured but is estimated or calculated, and the measurement of pKa is instead done at the particle level by a TNS method (Heyes J et al., J Control Release 2005, pp. 276-287).
  • the pKa' is about 2 to 4 units lower than the pKa, based on estimation methodology proposed for correlating the pKa and pKa' (e.g. Carrasco et al., Comm Biol, 2021, vol 4:956).
  • pKa' for the purposes of relating functional aspects of ionizable lipids and their LNPs we use pKa' in the following sections.
  • ionizable lipids are to facilitate endosomal release, by changing LNP structure via interaction with the endosomal membrane of LNPs within endosomes. This occurs about pH 5.5 and below.
  • ionizable cationic lipid in an LNP is predominantly neutral at physiological pH (pH 7.4) and is ionized and positively charged in the same LNP at a pH that is below physiological pH (e.g., between pH 4-5, preferably about pH 4.5).
  • the ionizable cationic lipid is about neutral at physiological pH (7.4 pH) and becomes protonated when introduced to an environment where the pH is about 4.5 or the pH inside of endosomes.
  • ionizable cationic lipids have a pKa' in the range of about 4 to about 7 as measured in the particle context (TNS assay).
  • ionizable lipid may include "cleavable lipid" or "SS-cleavable lipid”.
  • lipid refers to any lipid that is negatively charged at pH 7.4 (physiological pH). These lipids include, but are not limited to, phosphatidylglycerols, cardiolipins, diacylphosphatidylserines, diacylphosphatidic acids, N-dodecanoyl phosphatidylethanolamines, N-succinyl phosphatidylethanolamines, N-glutarylphosphatidylethanolamines, lysylphosphatidylglycerols, palmitoyloleyolphosphatidylglycerol (POPG), and other anionic modifying groups joined to neutral lipids.
  • phosphatidylglycerols cardiolipins
  • diacylphosphatidylserines diacylphosphatidic acids
  • N-dodecanoyl phosphatidylethanolamines N-succinyl phosphatidylethanolamines
  • Hydrocarbon refers to a group formed by removing two hydrogen atoms from a hydrocarbon, the free valencies of which are not engaged in a double bond.
  • Hydrophilic lipid refers to compounds having a polar group(s) that include, but are not limited to, long-chain saturated and unsaturated aliphatic hydrocarbon groups and such groups optionally substituted by one or more aromatic, cycloaliphatic, or heterocyclic group(s). Suitable examples include, but are not limited to, diacylglycerol, dialkylglycerol, N,N-dialkylamino, l,2-diacyloxy-3- aminopropane, and l,2-dialkyl-3-aminopropane.
  • Hydroalkyl means a linear monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical, substituted with one or two hydroxy groups, provided that if two hydroxy groups are present, they are not on the same carbon atom.
  • Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, l-(hydroxymethyl)-2- methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1- (hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2- (hydroxymethyl)-3- hydroxypropyl, preferably 2- hydroxyethyl, 2,3-dihydroxypropyl, and 1- (hydroxymethyl)-2- hydroxyethyl.
  • Ci-Cg hydroxyalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with either one hydroxy group or two hydroxy groups on different carbon atoms. Where the alkyl is substituted with an alkene, the group is a "hydroxyalkenyl" group.
  • bonds encompasses chemical conjugation, adsorption (physisorption and/or chemisorption).
  • bonds encompassed by the term “linked” are covalent interactions and noncovalent interactions (e.g., hydrogen bonds, ionic bonds, van der Waal bonds, and hydrophobic bonds).
  • Neutral lipid refers to a lipid that exist either in an uncharged or neutral zwitterionic form in a pH range comprising pH 4 - 7.4. At physiological pH, such lipids include, for example, diacylphosphatidylcholine, diacylphosphatidylethanolamine, ceramide, sphingomyelin, cephalin, cholesterol, cerebrosides, and diacylglycerols.
  • non-fusogenic cationic lipid is meant a cationic lipid that can condense and/or encapsulate the nucleic acid cargo, such as mRNA, but does not have, or negligible, fusogenic activity with a cell plasma membrane.
  • cleavable lipid or "SS-cleavable lipid” refers to a lipid comprising a disulfide bond cleavable unit.
  • Cleavable lipids may include cleavable disulfide bond ("SS") containing lipid-like materials that comprise a pH-sensitive tertiary amine and self-degradable phenyl ester.
  • SS cleavable disulfide bond
  • a SS-cleavable lipid can be an SS-OP lipid (COATSOME* SS-OP), an SS-M lipid (COATSOME* SS-M), an SS-E lipid (COATSOME* SS-E), an SS-EC lipid (COATSOME* SS-EC), an SS-LC lipid (COATSOME* SS-LC), an SS-OC lipid (COATSOME* SS-OC), and an SS-PalmE lipid (see, for example, Formulae l-l V), or a lipid described in Togashi R, et al. J Control Release 2018 Jun 10;279:262-270, US Patent 9,708,628, or US Patent 10,385,030.
  • non-cationic lipid refers to a neutral lipid or anionic lipid.
  • nucleic acid refers to a polymer containing at least two nucleotides (i.e., deoxyribonucleotides or ribonucleotides) in either single- or double-stranded form and includes DNA, RNA, DNA-RNA hybrids, as well as analogs and modified forms thereof.
  • DNA may be in the form of, e.g., antisense molecules, plasmid DNA, DNA-DNA duplexes, pre-condensed DNA, PCR products, vectors (PI, PAC, BAC, YAC, artificial chromosomes), expression cassettes, chimeric sequences, chromosomal DNA, or derivatives and combinations of these groups.
  • DNA may be in the form of minicircle, plasmid, bacmid, minigene, ministring DNA (linear covalently closed DNA vector), closed- ended linear duplex DNA (CELiD or ceDNA), doggyboneTM DNA, dumbbell shaped DNA, minimalistic immunological-defined gene expression (MIDGE)-vector, viral vector or nonviral vectors.
  • RNA may be in the form of small interfering RNA (siRNA), dicer-substrate dsRNA, small hairpin RNA (shRNA), asymmetrical interfering RNA (aiRNA), circRNA, self-amplifying RNA, small-activating RNA, long nocoding RNA, short non-coding RNA, microRNA (miRNA), mRNA, rRNA, tRNA, gRNA, viral RNA (vRNA), and combinations thereof.
  • Nucleic acids include nucleic acids containing known nucleotide analogs or modified backbone residues or linkages, which are synthetic, naturally occurring, and non-naturally occurring, and which have similar binding properties as the reference nucleic acid.
  • analogs and/or modified residues include, without limitation, phosphorothioates, phosphorodiamidate morpholino oligomer (morpholino), phosphoramidates, methyl phosphonates, chiral-methyl phosphonates, 2'-O-methyl ribonucleotides, locked nucleic acid (LNATM), and peptide nucleic acids (PNAs).
  • morpholino phosphorodiamidate morpholino oligomer
  • phosphoramidates phosphoramidates
  • methyl phosphonates chiral-methyl phosphonates
  • 2'-O-methyl ribonucleotides locked nucleic acid (LNATM)
  • PNAs peptide nucleic acids
  • the term encompasses nucleic acids containing known analogues of natural nucleotides that have similar binding properties as the reference nucleic acid.
  • nucleic acid sequence also implicitly encompasses conservatively modified variants thereof (e.g., degenerate codon substitutions), alleles, orthologs, SNPs, and complementary sequences as well as the sequence explicitly indicated.
  • nucleic acid therapeutic refers to any modality of therapeutic using a nucleic acid as an active pharmaceutical ingredient of therapeutic agent to treat a disease or disorder.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” includes any of the standard pharmaceutical carriers/excipients, such as a phosphate buffered saline solution, TRIS/sucrose buffer, water, emulsions such as an oil/water or water/oil, and various types of wetting agents.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” includes any of the standard pharmaceutical carriers/excipients, such as a phosphate buffered saline solution, TRIS/sucrose buffer, water, emulsions such as an oil/water or water/oil, and various types of wetting agents.
  • the term also encompasses any of the agents approved by a regulatory agency of the US Federal government or listed in the US Pharmacopeia for use in animals, including humans, as well as any carrier or diluent that does not cause significant irritation to a subject and does not abrogate the biological activity and properties of the administered compound.
  • subject refers to a human or animal, to whom treatment, including prophylactic treatment, with the therapeutic nucleic acid according to the present disclosure, is provided.
  • Animals include mammals, birds and fish.
  • the animal is a mammal, e.g., primate, rodent, lagomorph, companion animal or livestock.
  • Primates include humans, chimpanzees, cynomolgus monkeys, spider monkeys, and macaques, e.g., rhesus macaque.
  • Rodents include mice, rats, and hamsters.
  • Livestock include cows, horses, pigs, sheep and goats.
  • the subject is a human.
  • a human subject can be of any age, gender, race or ethnic group.
  • terapéuticaally effective amount of an active agent (e.g., a TNA described herein) are used interchangeably to refer to an amount that is sufficient to produce a desired effect, e.g., expression or inhibition of a target gene/sequence or disease modification.
  • an “effective amount” may be an amount sufficient to produce an increase in expression of a target polypeptide in comparison to the normal expression level, if any, detected in the absence of the messenger RNA.
  • Suitable assays for measuring expression of a target gene or target sequence include, examination of protein or RNA levels using techniques known to those of skill in the art such as dot blots, northern blots, in situ hybridization, FISH, RNAscopeTM, ELISA, immunoprecipitation, enzyme function, fluorescence or luminescence of suitable reporter proteins, as well as phenotypic assays.
  • the terms include prophylactic or preventative amounts of an active agent is an amount sufficient to eliminate or reduce the risk, lessen the severity, or delay the onset of a disease, disorder or condition.
  • dose and “dosage” is the amount of an active agent administered at any given time. Dosage levels are based on a variety of factors, including the specific disease or disorder, the age, weight, sex, medical condition of the patient, the severity of the condition, the route of administration, and the particular active agent or agents employed. The dosage regimen can be determined routinely by a physician using standard methods.
  • therapeutic effect refers to a consequence of treatment, the results of which are judged to be desirable, safely achieved, and beneficial.
  • a therapeutic effect can include, directly or indirectly, the arrest, reduction, or elimination of a disease manifestation or progression.
  • treat may be therapeutic, prophylactic or palliative, and include abrogating, inhibiting, delaying, slowing or reversing the progression of a disease, disorder or condition; ameliorating clinical symptoms of a disease, disorder or condition; or preventing or reducing the appearance of clinical symptoms of a disease, disorder or condition.
  • Amine or “amino” as used herein interchangeably refers to a functional group that contains a basic nitrogen atom with a lone pair.
  • Aryl refers to a monovalent aromatic group derived from an arene by removal of a hydrogen atom from a ring carbon atom.
  • aryl includes substituted or unsubstituted single-ring aromatic groups and polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings, wherein at least one of the rings is aromatic.
  • a “carboaryl” refer to an aryl group containing only carbon and hydrogen atoms.
  • Arylene or "arenediyl” refers to a bivalent aromatic group derived from an arene by removal of a hydrogen atom from two different ring carbon atoms, forming a group with two attachment points. In multi-ring systems, the two hydrogens may be removed from the same ring or different rings.
  • Alkyl refers any alkyl group (as defined herein) in which one or more hydrogen atoms have been substituted by the same number of like and/or different aryl (as defined herein) groups.
  • arenyl means any aryl group (as defined herein) in which one or more hydrogen atoms have been substituted by the same number of like and/or different alkyl groups (as defined herein).
  • alkene refers to a group consisting of at least two carbon atoms and at least one carboncarbon double bond
  • alkyne refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond.
  • the alkyl moiety, whether saturated or unsaturated, may be branched, straight chain, or cyclic.
  • Alkenyl refers to a hydrocarbon monovalent radical with one or more carbon-carbon double bonds, including radicals having "cis” and “trans” orientations, or by an alternative nomenclature, "E” and “Z” orientations. Alkenyls may be linear or branched and may be optionally substituted.
  • Examples include C2-20 alkenyl groups, such as, C2-20 alkenyl, C2-18 alkenyl, C2-16 alkenyl, C2-14 alkenyl, C2-12 alkenyl, C2-10 alkenyl, C2-9 alkenyl, C2-8 alkenyl, C2-7 alkenyl, C2-6 alkenyl, C2-5 alkenyl, C2-4 alkenyl, and C2-3 alkenyl.
  • C2-20 alkenyl groups such as, C2-20 alkenyl, C2-18 alkenyl, C2-16 alkenyl, C2-14 alkenyl, C2-12 alkenyl, C2-10 alkenyl, C2-9 alkenyl, C2-8 alkenyl, C2-7 alkenyl, C2-6 alkenyl, C2-5 alkenyl, C2-4 alkenyl, and C2-3 alkenyl.
  • Alkenylene refers to an aliphatic bivalent hydrocarbon radical with one or more carbon-carbon double bonds (i.e., a group derived from an alkene with two attachment points), including radicals having "cis” and “trans” orientations, or by an alternative nomenclature, "Z” and “E” orientations, respectively. Alkenylenes may be linear or branched and may be optionally substituted.
  • Examples include C2-20 alkenylene groups, such as, C2-20 alkenylene, C2-18 alkenylene, C2-16 alkenylene, C2-14 alkenylene, C2-12 alkenylene, C2-10 alkenylene, C2-9 alkenylene, C2-8 alkenylene, C2-7 alkenylene, C2-6 alkenylene, C2-5 alkenylene, C2-4 alkenylene, and C2-3 alkenylene.
  • “Internal alkenylene” refers to an alkenylene group where the carbon-carbon double bond is not at an end of the carbon chain, i.e., the terminal carbon atoms are not double bonded.
  • Alkynyl refers to a hydrocarbon monovalent radical with one or more carbon-carbon triple bonds.
  • Alkynylene refers to a hydrocarbon bivalent radical with one or more carbon-carbon triple bonds (i.e., a group derived from an alkyne with two attachment points).
  • Internal alkynylene refers to an alkynylene group where the carbon-carbon triple bond is not at an end of the carbon chain, i.e., the terminal carbon atoms are not triple bonded.
  • Cyclic groups of the present invention include monocyclic and bicyclic groups (bridged or fused).
  • Alkyl refers to saturated monovalent hydrocarbon radical. Alkyls may be linear or branched and may be optionally substituted. Examples include Ci. 2O alkyl, Ci-i 8 alkyl, Ci-i 6 alkyl, C1.14 alkyl, Ci-i 2 alkyl, CMO alkyl, Ci-9 alkyl, Ci.g alkyl, C1-7 alkyl, Ci.g alkyl, C1-5 alkyl, C1-4 alkyl, and C1.C 3 alkyl.
  • Examples further include methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-l-propyl, 2-butyl, 2-methyl-2-propyl, 1- pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-l-butyl, 2-methyl-l-butyl, 1- hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, 1-heptyl, 1-octyl, and the like.
  • Alkylene refers to a saturated bivalent hydrocarbon radical (a group derived from an alkane with two attachment points). Alkylenes may be linear or branched and may be optionally substituted. Examples include Ci- 2 o alkylene groups, such as Ci- 2 o alkylene, Ci-ig alkylene, CUB alkylene, C1-14 alkylene, Ci-i 2 alkylene, C1-10 alkylene, C1-9 alkylene, Ci-g alkylene, C1-7 alkylene, CI-B alkylene, C1-5 alkylene, C1-4 alkylene, and C1.C3 alkylene.
  • Ci- 2 o alkylene groups such as Ci- 2 o alkylene, Ci-ig alkylene, CUB alkylene, C1-14 alkylene, Ci-i 2 alkylene, C1-10 alkylene, C1-9 alkylene, Ci-g alkylene, C1-7 alkylene, CI-B alkylene, C1-5 alkylene, C1-4
  • Bivalent refers a functional group with two attachment points. Bivalent groups are formed by the loss of a hydrogen atom from two different atoms of a parent compound and are named using the suffixes -diyl or -ylene.
  • Carbocycle and “carbocyclic” refers to a C3-C 2 o monocyclic or polycyclic (e.g., bicyclic or tricyclic), saturated, partially saturated or unsaturated ring(s), in which all the atoms composing the ring are carbon atoms. Ring moieties include fused, spirocyclic and bridged bicyclic rings. Saturated carbocyclic rings include, for example, "cycloalkyl” rings, e.g., cyclopropyl, cyclobutyl, etc.
  • Carbocyclyl is a monovalent radical of a carbocycle, i.e., a carbocycle functional group with one attachment point.
  • Carbocyclediyl or carbocyclene is a bivalent radical of a carbocycle, i.e., a carbocycle functional group with two attachment points.
  • Cycloalkyl refers to a monovalent saturated carbocyclic ring radical. Cycloalkyls may be optionally substituted. Cycloalkyl groups include groups having from 3 to 18 ring atoms. Cycloalkyl groups include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl or norbornyl.
  • Cycloalkylene refers to a bivalent, saturated, 3-18-membered carbocyclic ring radical with two attachment points.
  • Specific monocyclic cycloalkylene groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclooctylene, cyclononylene, cyclodecylene, cycloundecylene, cyclododecylene, and the like.
  • the cycloalkylene is cyclopropylene.
  • Halogen or halo refers to F, Cl, Br or I.
  • Heterocycle “heterocyclic” and “heterocyclic ring” are used interchangeably and refer to 5-20 aromatic or 3-20 aliphatic cyclic group having at least one ring heteroatom and at least one ring carbon atom.
  • the heteroatom is oxygen, sulfur, or nitrogen.
  • a heterocycle containing more than one heteroatom may contain different heteroatoms.
  • Heterocyclyl is a monovalent radical of a heterocycle and have one attachment point.
  • An aromatic heterocyclyl is also referred to a "heteroaryl”.
  • Heterocyclene or heterocyclediyl refers to a bivalent heterocycle group with two attachment points.
  • Heterocyclyl and heterocyclene moieties include both monocyclic and multicyclic (e.g., bicyclic or tricyclic) ring moieties.
  • Ring moieties include fused, spirocyclic and bridged bicyclic rings and may comprise one or more heteroatoms in one or more of the rings.
  • Either ring of a bicyclic heterocycle may be saturated, partially unsaturated or aromatic.
  • the heterocycle may be attached to the rest of the molecule via a ring carbon atom or a ring nitrogen atom.
  • heterocyclic functional groups include aziridinyl, diaziridinyl, thiaziridinyl, azetidinyl, diazetidinyl, triazetidinyl, thiadiazetidinyl, thiazetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl, isothiazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, azepanyl, and azocanyl.
  • Heteroaryl refers to a monovalent group with one attachment point derived from heteroarene by removal of a hydrogen atom from a ring atom.
  • Heteroarylene or “heteroarenediyl” refers to a bivalent group derived from a heteroarene by removal of a hydrogen atom from two different ring atoms, forming a group with two attachment points. The hydrogens may independently be removed from either a carbon or nitrogen atom (as available).
  • Heteroaryls of the present invention include 5-18- membered aromatic radicals (e.g., C5-C13 heteroaryl), preferably 5-10-membered aromatic groups, that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur, and which may be a monocyclic or polycyclic (e.g., a bicyclic, tricyclic or tetracyclic ring system).
  • a polycyclic heteroaryl group may be fused or non-fused.
  • the heteroatom(s) in the heteroaryl radical are optionally oxidized.
  • One or more nitrogen atoms, if present, are optionally quaternized.
  • “Pharmaceutically acceptable salt” as used herein refers to pharmaceutically acceptable organic or inorganic salts of an ionizable lipid of the disclosure.
  • Spirocycle and “spiroheterocycle” refer is a 5- to 20-membered bicyclic ring system functional group, including spiro[cycloalkyl] and spiro[cycloalkenyl] with both rings connected through a carbon single atom.
  • a spirocycle/spiroheterocycle can be fully saturated or can be partially unsaturated.
  • the rings can be different in size and nature, or identical in size and nature. Examples include spiropentanyl, spriohexanyl, spiroheptanyl, spirooctanyl, spirononanyl, or spirodecanyl.
  • a (C5-C14) spirocycloalkyl e.g., is a spirocycle containing between 5 and 14 carbon atoms.
  • “Spiroheterocycloalkyl” or “spiroheterocyclyl” is understood to mean a spirocyclyl as defined above wherein at least one of the rings is a heterocycle, i.e., a ring containing a heteroatom.
  • the heteroatom is oxygen, sulfur, or nitrogen. Ranges set forth herein are inclusive of the end values.
  • Hydrogen atoms connected to carbons may be substituted with deuterium ( 2 H) atoms.
  • the invention provides for a lipid as disclosed herein.
  • the lipid may be used, e.g., in a lipid vesicle including liposomes, in a lipid film, and lipid nanoparticles (LNPs).
  • the lipid may be a cationic lipid.
  • the lipid may further be an ionizable cationic lipid.
  • the invention provides for a lipid nanoparticle (LNP) comprising a lipid of the present invention.
  • LNP lipid nanoparticle
  • the present disclosure provides for a LNP composition comprising a plurality of LNPs and at least one pharmaceutically acceptable carrier, diluent or excipient.
  • LNPs of the invention are lipid vesicles with a diameter that is typically in the range of 25-1000 nm.
  • LNPs of the invention comprise multiple lipids, at least one of which is positively charged (cationic) at low pH (enabling RNA complexation and endosomal escape).
  • the cationic lipid is preferably an ionizable cationic lipid that is substantially in the neutral form in an LNP at physiological pH.
  • the LNP may further comprises a non-cationic, structural/helper lipid, a sterol (to provide membrane fluidity) and a polymer conjugated lipid (to prevent aggregation).
  • LNPs of the invention may comprise a targeting moiety, such as a protein or peptide or a cluster of peptides and/or small molecule targeting ligands, and modified version of the above with lipid and/or carbohydrate groups or other functionalization.
  • a targeting moiety such as a protein or peptide or a cluster of peptides and/or small molecule targeting ligands, and modified version of the above with lipid and/or carbohydrate groups or other functionalization.
  • LNPs of the invention may comprise a labelling moiety, such as a fluorophore small molecule (BODIPY and the like) for tracking purposes with confocal microscopy and fluorescence imaging methods.
  • LNPs of the invention may further comprise a diagnostic or therapeutic agent and be used to deliver the agent, such as TNA, to a cell, tissue or organ.
  • the LNP comprises a therapeutic agent such as a TNA (e.g., mRNA), protein, peptide or other sensitive cargo encapsulated or contained in the lipid portion of the particle, thereby protecting it from enzymatic degradation, excretion or immunogenic or other reaction.
  • TNA can be a single kind or multiple types in the same particle system.
  • the lipid particles of the disclosure have a mean diameter of: from about 40 nm to about 45 nm, from about 45 nm to about 50 nm, from about 50 nm to about 55 nm, from about 55 nm to about 60 nm, from about 60 nm to about 65 nm, from about 65 nm to about 70 nm, from about 70 nm to about 75 nm, from about 75 nm to about 80 nm, from about 80 nm to about 85 nm, from about 85 nm to about 90 nm, from about 90 nm to about 95 nm, from about 95 nm to about 100 nm, from about 100 nm to about 105 nm, from about 105 nm to about 110 nm, from about 110 nm to about 115 nm, from about 115 nm to about 120 nm, from about 25 nm to about 125 nm, from 25 nm to about 100 nm to about 100
  • Lipid particle size can be determined, e.g., by quasielastic light scattering using a Malvern Zetasizer Nano ZS (Malvern, UK) or Wyatt Dynapro DLS (Wyatt Technologies, Santa Barbara CA).
  • the LNPs may be relatively homogenous.
  • a polydispersity index may be used to indicate the homogeneity of the LNPs.
  • a small, for example less than 0.3 or less than 0.2, polydispersity index generally indicates a narrow particle size distribution.
  • a composition of the LNPs described herein may have a polydispersity index from about 0 to about 0.25 or to about 0.30, such as 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29 or 0.30.
  • the polydispersity index of the LNP composition may be from about 0 to about 0.30 or 0.05 to 0.20.
  • the LNP comprises: a (ionizable) cationic lipid, a sterol or a derivative thereof, a noncationic lipid, and a polymer-conjugated lipid.
  • the LNP comprises more than one (ionizable) cationic lipid, more than one sterol or a derivative thereof, more than one non-cationic lipid, and/or more than one polymer-conjugated lipid.
  • the lipid particle e.g., lipid nanoparticle
  • the cationic lipid, non-cationic phospholipid, cholesterol and a PEGylated lipid are present in a molar ratio of about 50:7:40:3 or 50: 10:38.5: 1.5, respectively.
  • the LNP comprises about: 40- 50 mol%, 45-50 mol%, 50-55 mol%, 45-46 mol%, 46-47 mol%, 47-48 mol%, 48-49 mol%, or 49-50 mol%, 45 mol%, 45.5 mol%, 46 mol%, 46.5 mol%, 47 mol%, 47.5 mol%, 48 mol%, 48.5 mol%, 49 mol%, or 49.5 mol% (ionizable) cationic lipid.
  • the LNP comprises about: 5-25 mol%, 5-15 mol%, 10-12 mol%, 5-6 mol%, 6-7 mol%, 7-8 mol%, 8-9 mol%, 9-10 mol%, 10- 11 mol%, 11-12 mol%, 12-13 mol%, 13-14 mol%, or 14-15 mol% non-cationic lipid.
  • the LNP comprises about: 25-55 mol%, 30-45 mol%, 35-40 mol%, 30-31 mol%, 31-32 mol%, 32-33 mol%, 33-34 mol%, 35-35 mol%, 35-36 mol%, 36-37 mol%, 38-38 mol%, 38- 39 mol%, or 39-40 mol% sterol.
  • the LNP comprises about: 0.5-15 mol%, 1-5 mol%, 1-3 mol%, 1.5-2.5 mol%, 1-2 mol%, 2-3 mol%, 3-4 mol%, or 4-5 mol% polymer conjugated lipid, e.g., PEGylated lipid.
  • the lipid nanoparticle comprises a total lipid content that is 20-60 mol% (ionizable) cationic lipid, 5-25 mol% non-cationic lipid, 25-55 mol% sterol, and 0.5-15 mol% polymer conjugated lipid, e.g., PEGylated lipid.
  • the lipid nanoparticle comprises a total lipid content that is 40-50 mol% (ionizable) cationic lipid, 5-15 mol% non-cationic lipid, 30-45 mol% sterol, and 1-5 mol% polymer conjugated lipid, e.g., PEGylated lipid. In one embodiment, the lipid nanoparticle comprises a total lipid content that is 45-50 mol% (ionizable) cationic lipid, 10-12 mol% non-cationic lipid, 35-40 mol% sterol, and 1-3 mol% polymer conjugated lipid, e.g., PEGylated lipid.
  • the lipid nanoparticle comprises a total lipid content that is 45-50 mol% (ionizable) cationic lipid, 10-12 mol% non-cationic lipid, 35-40 mol% sterol, and 1.5-2.5 mol% polymer conjugated lipid, e.g., PEGylated lipid conjugate.
  • Cationic and ionizable lipids are examples of Cationic and ionizable lipids.
  • the lipid nanoparticle of the present invention comprises a cationic lipid.
  • the cationic lipid is an ionizable cationic lipid.
  • the ionizable cationic lipid is positively charged at low pH, which facilitates association with the negatively charged nucleic acid.
  • the ionizable lipid is neutral at physiological pH (pH 7.4). The ability of these lipids to ionize at low pH is believed to aid in endosomal escape of the nucleic acid into the cytoplasm.
  • the invention provides for a pharmaceutical composition
  • a pharmaceutical composition comprising a lipid nanoparticle, wherein the lipid nanoparticle comprises a cationic lipid.
  • the cationic lipid is an ionizable cationic lipid.
  • LNPs can be used to deliver a diagnostic or therapeutic agent to a target cell, tissue or organ in a subject.
  • Exemplary ionizable lipids that may be used with a composition of the present invention are described in International PCT patent publications WO 2025/119217, WO 2025/113654, WO 2025/113662, WO
  • WO2024/205657 WO2024/198497, WO2024/195922, WO2024/192528, WO2024/192277, W02024/184500, WO2024/183821, WO2024/177426, WO2024/177424, WO2024/177282, WO2024/173307, WO2024/165974, WO2024/165973, WO2024/156291, WO2024/152512, WO2024/150222, W02024/147060, W02024/144009, WO2024/138134, WO2024/138034, WO2024/136309, WO2024/136254, WO2024/135604, WO2024/130421, W02024/130086,
  • WO2013/148541 WO2013/126803, WO2013/116126, W02013/089151, WO2013/086373,
  • W02011/038160 W02011/022460, W02011/000107, W02011/000106, W02010/144740,
  • Further examples include 3-(didodecylamino)-Nl,Nl,4-tridodecyl-l-piperazineethanamine (KL10), Nl- [2-(didodecylamino)ethyl]-Nl,N4,N4-tridodecyl-l,4- piperazinediethanamine (KL22), 14,25-ditridecyl- 15, 18,21 ,24-tetraaza-octatriacontane (KL25), 1.2-dilinoleyloxy-N,N-dimethylaminopropane (DLin- DMA), 2,2-dilinoleyl-4-dimethylaminomethyl-[l,3]-dioxolane (DLin-K-DMA), (6Z,9Z,28Z,31Z)- heptatriacont-6,9,28,31-tetraene-19-yl 4-(dimethylamino)butano
  • the ionizable cationic lipid or cationic lipid is represented by a structural formula selected from: wherein,
  • R1 is selected from the group consisting of:
  • R19 for each occurrence is independently
  • R20 is R19 or R24
  • R116 is -H, -D, -CD 3 or C1-3 alkyl
  • R146 is an optionally substituted group selected from: 3-7 membered carbocyclylene or 3-7 membered heterocyclylene;
  • R114 for each occurrence, is independently selected from: -H, -CH 2 (halo), -CH(halo) 2 , -C(halo) 3 , -F, - CF 3 , -Cl, -Br, -I, -OH, or an optionally substituted, linear or branched, group selected from C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl;
  • R23 is an optionally substituted group selected from: a 3-18-membered saturated or partially unsaturated carbocyclyl, a 5-18-membered unsaturated carbocyclyl, a 3-18-membered saturated or partially unsaturated heterocyclyl, or 5-18-membered unsaturated heterocyclyl; wherein said heterocyclyl contains one or more of heteroatoms independently selected from N, O or S as a ring atom;
  • R2 is a bond, or a linear, branched or optionally substituted group selected from: -C1-C15 acyclic hydrocarbylene-, Ci-C 8 alkylene, C 2 -C 8 alkenylene, C 2 -C 8 alkynylene, -C 0 -C 8 acyclic hydrocarbylene- R148-CO-C 8 acyclic hydrocarbylene-, 3-7 membered carbocyclylene or 3-7 membered heterocyclylene;
  • R148 is selected from: R47, R143, R146, -CH(R147)-, -O-, -S-, -S-S- or -N(R114)-;
  • R47 for each occurrence, is independently selected from: a bond, an optionally substituted 3-14- membered saturated, partially unsaturated or unsaturated carbocyclene or an optionally substituted 3-14-membered saturated, partially unsaturated or unsaturated heterocyclene;
  • R147 for each occurrence, is an optionally substituted group selected from: 3-7 membered carbocyclyl or 3-7 membered heterocyclyl; each R50 is independently selected from:
  • R26 and R27 are each independently selected from: a bond, or an optionally substituted, linear or branched, C1-C10 alkylene, C1-C10 alkenylene or C1-C10 alkynylene;
  • R13, R14, R61, R73 and R107 are each independently selected from:
  • R60 is selected from: is absent (i.e., an unbonded pair of electrons on N), -H, -D -CD 3 or optionally substituted C1-C6 alkyl; wherein, when R60 is -H or optionally substituted C1-C6 alkyl, R60 is bound directly to a nitrogen atom with a +1 charge.
  • the +1 charge may be counterbalanced with anion from a pharmaceutically acceptable acid;
  • R15, R16, R17 and R18 are each independently selected from: -H, -D; an optionally substituted linear or branched, -R26-Ci-Cio alkylene-R28, -R26-C2-C10 alkenylene-R28, or -R26-C2-C10 alkynylene-R28; an optionally substituted, R26-R149, R26-R23, -R26-C 3 -C 7 cycloalkylene-R28, -R26-C 3 -C 7 cycloalkylene- R26-C 3 -C 7 cycloalkylene- R26-C 3 -C 7 cycloalkylene-R28 -R26-C 3 -C 7 cycloalkenylene-R28, -R26-C 5 -Ci5-spirocycloalkylene-R28, - R26-C 3 -Ci5-carbocyclylene-R28, -R
  • R28 is selected from: -H, -D, -CDs, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl;
  • R149 is: ; wherein, each R155 is each independently selected from: -H, -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl or optionally substituted C1-C6 alkoxy;
  • R191 is selected from: is a bond or optionally substituted, linear or branched C1-C6 alkylene, -C0-C3- alkylene-C3-Cio-carbocyclylene-Co-C 3 -alkylene- or -Co-C3-alkylene-C 3 -Cio-heterocyclylene-Co-C3- alkylene-; each R137 is independently selected from: ein each variable is defined above or for any aspect or embodiment herein.
  • R1 or R19 is selected from:
  • Rl is selected from:
  • one R33 is -R22-R21- and each remaining R33 group is independently selected from: -H, -D, -F, -Cl, -Br, or -OH.
  • R1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • At least one R33 is -F; at least one R33 is -Cl; at least one R33 is -Br; at least two R33 are -F; at least two R33 are -Cl; at least two R33 are -Br; at least one R33 is -OH; at least two R33 are -OH; at least one R33 is -F -Cl or -Br and at least one R33 is -OH; at least two R33 is independently selected from -F, -Cl or -Br and at least one R33 is -OH; at least two R33 is -F and at least one R33 is -OH; at least two R33 are -Cl and at least one R33 is -OH; at least two R33 are -Br and at least one R33 is -OH; at least two R33 is independently selected from -F, -Cl or -Br and at least one R33 is -OH; at least two R33 are -Cl and at least
  • the R1 is bound to an R2 selected from: C1-C6 alkylene, C1-C6 alkenylene, C1-C6 alkynylene, -(CH2)O-B-0-(CH2)O-6-, -(CH2)O-B-0- (CH 2 )I-6-, (subscripts in the foregoing allowing a range of CH 2 ), -(CH 2 )2-, -(CH 2 )3-, -(CH2)2-O-(CH 2 )3- or - CH2-O-(CH 2 ) 3 -.
  • R1 is wherein,
  • R141 is any remaining variables are as defined above or for any other embodiment herein.
  • one R140 is R141 and each remaining R140 is independently R33.
  • the R1 is bound to an R2 selected frormC1-C6 alkylene, C1-C6 alkenylene, C1-C6 alkynylene, -(CH2)O-B-0-(CH2)O-6-, -(CH2)O-6-0-(CH2)I-6-, (subscripts in the foregoing allowing a range of CH 2 ), -(CH 2 )2-, -(CH 2 )3-, -(CH2)2-O-(CH 2 )3- or -CH 2 -O- (CH 2 ) 3 -.
  • Rl or R19 are selected from:
  • each L-2. is independently selected from a single or double bond, wherein selection of said single or double bond maintains proper valency, i.e., does not cause a valency violation such as a carbon, nitrogen or oxygen atom violating the octet rule.
  • R21, R22, R25 and any remaining variables are as defined above or for any other embodiment herein; and each — is independently selected from a single or double bond, wherein selection of said single or double bond maintains proper valency, i.e., does not cause a valency violation such as a carbon, nitrogen or oxygen atom violating the octet rule.
  • R1 or R19 is selected from:
  • R1 or R19 is selected from: or ; wherein
  • Each is independently selected from a single or double bond, wherein selection of said single or double bond maintains proper valency, i.e., does not cause a valency violation such as a carbon, nitrogen or oxygen atom violating the octet rule.
  • Rl or R19 is a bicyclic aromatic or hetero-aromatic group.
  • R23 is an optionally substituted group selected from: a 3-18-membered saturated or partially unsaturated carboaryl, a 5-18-membered unsaturated carboaryl, a 3-18- membered saturated or partially unsaturated heteroaryl, or 5-18-membered unsaturated heteroaryl; wherein said heteroaryl contains one or more of heteroatoms independently selected from N, O or S as a ring atom.
  • the carboaryl or heteroaryl is a 5-10 membered carboaryl or heteroaryl.
  • the carboaryl or heteroaryl is a 5-10, 5-9, 5, 6 or 7 membered carboaryl or heteroaryl.
  • R23 is an optionally substituted group selected from: a 3-14-membered saturated or partially unsaturated carbocyclyl, a 5-14-membered unsaturated carbocyclyl, a 3-14- membered saturated or partially unsaturated heterocyclyl, or 5-14-membered unsaturated heterocyclyl; wherein said heterocyclyl contains one or more of heteroatoms independently selected from N, O or S as a ring atom.
  • R23 is independently substituted with at least one group selected from: -F, -Cl and -Br.
  • each R144 is independently selected from: -F, -Cl, -Br, -OCH 3 or -OH.
  • each R144 is independently selected from: -F, -Cl and -Br.
  • the R23 is a 3-14- membered saturated or partially unsaturated carbocyclyl, a 5-14-membered unsaturated carbocyclyl, a 3-14-membered saturated or partially unsaturated heterocyclyl, or 5-14-membered unsaturated heterocyclyl; wherein said heterocyclyl contains one or more of heteroatoms independently selected from N, O or S as a ring atom.
  • the carbocyclyl or heterocyclyl is idenpendently substituted with 1, 2, 3, 4 or 5 R144 groups.
  • each R144 is independently selected from: -OH, -OCH 3 , -F, Cl or Br.
  • At least one R144 is -F; at least one R144 is -Cl; at least one R144 is -Br; at least two R144 are -F; at least two R144 are -Cl; at least two R144 are -Br; at least one R144 is -OH; at least two R144 are -OH; at least one R144 is -OCH 3 ; at least two R144 are -OCH 3 ; at least one R144 is -F -Cl or -Br and at least one R144 is -OH or -OCH 3 ; at least two R144 is independently selected from -F, -Cl or -Br and at least one R144 is -OH or - OCH 3 ; at least two R144 is -F and at least one R144 is -OH or -OCH 3 ; at least two R144 are -Cl and at least one R144 is -OH or -OCH 3 ; at least two R144 are -
  • R23 is an optionally substituted with R147-R143-.
  • R147-R143- is an optionally substituted benzoyloxyphenyl-.
  • the benzoyloxyphenyl- is 4-(benzoyloxy)-phenyl.
  • the benzoyloxyphenyl- is substituted with one or more R144; wherein, R144 is independently selected from: -CH 3 , -CH 2 CH 3 ,- CH 2 (halo), -CH(halo) 2 , -C(halo) 3 , -F, -CF 3 , -Cl, -Br, -I, -CH 3 , -OCH 3 , -CD 3 , -OCD 3 , or -CH 2 OCH 3 .
  • R144 is independently selected from -F, -Cl, -Br, -OH or -OCH 3 , wherein R144 is independently substituted with at least one group selected from: -F, -Cl and -Br.
  • R23 is an optionally substituted group selected from: pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, bicyclo(l.l.l)pentanyl, coumarinyl, furanyl, tetrahydrofuranyl, thiophenyl, pyrrolyl, pyrrolidinyl, pyranyl, piperidinyl, piperazinyl, imidazolyl, thiazolyl, 1,2-thiazinyl, 1,3-thiazinyl, 1,4-thiazinyl, dioxanyl, morpholinyl, 1,2-oxathiolanyl, 1,2-oxazolyl, 1,3-oxazolyl, isoxazolyl, silolyl, indolyl (2,3-benzopyrrolyl), isoindolyl, indolizinyl, quinolinyl, isoquinolinyl,
  • R25 or R23 is an optionally substituted group selected from: 1-oxa-cyclobutan- 2-yl, tetrahydrofuran-3-yl, morpholin-4-yl, 2-thiacyclohex-l-yl, 2-oxo-2-thiacyclohex-l-yl, 2,2-dioxo-2- thiacyclohex-l-yl, 4-methyl-piperazin-2-yl, 2-hydroxy-aziridin-l-yl, 3-oxo-l-oxacyclobutan-2-yl, 2,2- dimethyl-tetrahydrofuran-3-yl, 3-carboxy-morpholin-4-yl, and l-cyclopropyl-4-methyl-piperazin-2-yl, oxetanyl, azetidinyl, thietanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydr
  • R23 or R25 is an optionally substituted cycloalkyl.
  • the optionally substituted cycloalkyl is selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and norbornyl.
  • R23 is an optionally substituted heteroaryl. In some further embodiments, R23 is an optionally substituted heteroaryl selected from: pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl or tetrazolyl.
  • R23 is an optionally substituted heteroaryl selected from: azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1,4- benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzofurazanyl, benzothiazolyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d
  • R23 is selected from: wherein:
  • R35 and R41 are each independently selected from:
  • R24 and R60 is as defined above or for any aspect or embodiment herein;
  • R35 is -CR24- or -CH(R24)-.
  • the 6- membered ring formed by R35 through R40 or the 5-membered ring formed by R41 through R45 is an aryl or heteroaryl group.
  • R23 is selected from: ; wherein
  • the 6-membered ring formed by R35 through R40 or the 5-membered ring formed by R41 through R45 is an aryl or heteroaryl.
  • R23 is selected from:
  • R25 for each occurrence is independently selected from: -H, -D or an optionally substituted group selected from: Ci-Cio alkyl, C2-C10 alkenyl, C2-C10 alkynyl, 3-14-membered cycloalkyl, 5-14-membered spirocycloalkyl or 3-14-membered heterocycloalkyl.
  • R25 for each occurrence is independently selected from: 3-10-membered cycloalkyl, 5-10-membered spirocycloalkyl or 3-10-membered heterocycloalkyl.
  • R114 for each occurrence, is independently selected from: -H, -D, -CD 3 or an optionally substituted, linear or branched, C1-C6 alkyl, C 3 -Cg alkenyl or C 3 -Cg alkynyl. In some embodiments, R114, for each occurrence, is independently selected from an optionally substituted, linear or branched: C 3 -C 3 alkyl, C 3 -Cg alkyl, C 3 -Cg alkenyl or C 3 -Cg alkynal.
  • R25 for each occurrence, is independently selected from: -H, -D, -CD 3 , -CH 3 , - CH2CH 3 , -F, -Cl, -Br, -I, -OCH 3 , -OCD 3 , -OH or -NH2.
  • the carbocyclyl or heterocyclyl is independently selected from a 5-10 membered carbocyclyl or heterocyclyl.
  • the carbocyclyl or heterocyclyl is a 5-10, 5-9, 5, 6 or 7 membered carbocyclyl or heterocyclyl.
  • the heterocyclyl contains one or more heteroatoms independently selected from N or O as a ring atom.
  • each ring heteroatom of the heterocyclyl is either N or O.
  • R25 is an optionally substituted C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl that is linear and in other embodiments, R25 is a C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl that is branched.
  • R25 is an optionally substituted group selected from: spiropentanyl, spriohexanyl, spiroheptanyl, spirooctanyl, spirononanyl, or spirodecanyl.
  • R145 is selected from: -H, -D, -CD3, -OCD3, methoxy, -OH, methyl, ethyl or propyl.
  • R22 is selected from: -CH 2 -, -[CH 2 ] 2 -, - NH-,
  • halo is independently selected from: -F, -Cl or -Br.
  • R24 is an optionally substituted, linear or branched group selected from: Ci-C 8 - alkyl, C2-C8 alkenyl, C 2 -C 8 alkynyl, C1-C6- alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C4- alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl.
  • the Co-Cg acyclic hydrocarbylene is a C 2 -C 8 acyclic hydrocarbylene, C2-C6 acyclic hydrocarbylene or C1-C3 acyclic hydrocarbylene.
  • R2 is a linear, branched or optionally substituted group selected from: Ci-Cg alkylene, C 2 -C 8 alkenylene, C 2 -C 8 alkynylene, C 2 -C 8 internal alkenylene, C 2 -C 8 internal alkynylene, -Ci- C 6 akylene-R47-C1-C6 akylene-, -C1-C6 akylene-R143-C1-C6 akylene-, -C1-C6 akylene-R146-C1-C6 akylene-, -C1-C6 akylene-CH(R147)-C1-C6 akylene-, -C1-C6 akylene-O-C1-C6 akylene-, -C1-C6 akylene-S- C1-C6 akylene-, -C1-C6 akylene-S- C1-C6 aky
  • alkylene, alkenylene or alkynylene is linear. In some further embodiments, the alkylene, alkenylene or alkynylene is unsubstituted. In some further embodiments, the alkylene, alkenylene or alkynylene is linear and unsubstituted.
  • R2 is a linear, branched or optionally substituted group selected from: C1-C6 alkylene, C1-C6 alkenylene, C1-C6 alkynylene, C1-C6 internal alkenylene, C1-C6 internal alkynylene, -C1-C3 alkylene-R47-C1-C3 alkylene-, -C1-C3 alkylene-R143-C1-C3 alkylene-, -C1-C3 alkylene-R146-C1-C3 alkylene- , -C1-C3 alkylene-CH(R147)-C1-C3 alkylene-, -C1-C3 alkylene-O-C1-C3 alkylene-, -C1-C3 alkylene-S-Ci-C 3 alkylene-, -C1-C3 alkylene-S-S-Ci-Cs alkylene-, -C1-C3
  • alkylene, alkenylene or alkynylene is linear. In some further embodiments, the alkylene, alkenylene or alkynylene is unsubstituted. In some further embodiments, the alkylene, alkenylene or alkynylene is linear and unsubstituted. In some further embodiments, R47 is a Cs-Cg heterocyclylene or C 3 -C 8 carbocyclylene.
  • R2 is selected frormC1-C6 alkylene, C1-C6 alkenylene, C1-C6 alkynylene, -(CH 2 )o- 6 -0-(CH 2 )O- 6 -, -(CH 2 )O- 6 -0-(CH 2 )I. 6 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 2 -O-(CH 2 ) 3 - or -CH 2 -O-(CH 2 ) 3 -.
  • R2 is selected from: -[CH 2 ]o-6-0-[CH 2 ]o-6- or -[CH 2 ]O-6-0-[CH 2 ]I. 6 -, -[CH 2 ]I. 6 -O- [CH 2 ]O-6- , -l,4-piperazin-l,4-diyl-, -l,3-piperazin-l,3-diyl- or -l,4-diazepan-l,4-diyl.
  • R2 or R146 is selected from: C3-C7 cycloakylene or C3-C7 cycloakenylene. In some embodiments, R2 or R146 is cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cyclopropendiyl, cyclobutendiyl, cyclopentendiyl or cyclohexendiyl.
  • R2 is R29-O-R30 or R29-R47-R30, wherein R29 and R30 are each independently an optionally substituted, straight or branched C1-C6 alkylene, C1-C6 alkenylene, C1-C6 alkynylene, and R47 is defined above or for any aspect/embodiment herein.
  • R29 and R30 are each independently an optionally substituted, straight or branched C1-C6 alkylene.
  • R29 and R30 are different.
  • R29 and R30 are each independently -[CH 2 ]O-6-.
  • R29 is -CH 2 - and R30 is -[CH 2 ] 2 _6-. In some embodiments, R29 is - [CH 2 ] 2 - and R30 is -CH 2 - or -[CH 2 ]3-6-. In some embodiments, R29 is -[CH 2 ]3- and R30 is -[CH 2 ]I. 2 - or - [CH 2 ] 4 -6--- In some embodiments, R29 is -[CH 2 ] 4 - and R30 is -[CH 2 ]I-3- or -[CH 2 ] 5 -6-.
  • R29 is -[CH 2 ] 4 - and R30 is -[CH 2 ]I-3- or -[CH 2 ] 5 -6-. In some embodiments, R29 is -[CH 2 ] 5 - and R30 is - [CH 2 ]I. 4 - or -[CH 2 ] 6 -. In some embodiments, R29 is -[CH 2 ]g- and R30 is -[CH 2 ]I_ 5 -.
  • R2 is selected frormC1-C6 alkylene, C1-C6 alkenylene, Ci-Cg alkynylene, -[CH 2 ]o-6-0-[CH 2 ]o-6-, -[CH 2 ]o-6-0- [CH 2 ]I-6-, -[CH 2 ] 2 -, -[CH 2 ] 3 -, -[CH 2 ] 2 -O-[CH 2 ] 3 - or -CH 2 -O-[CH 2 ]3-.
  • R2 is -0-[CH 2 ]O-B- .
  • R2 is -O-[CH 2 ]I. 6 -.
  • R2 is -O-[CH 2 ] 2.6 -. In some embodiments, R2 is -[CH 2 ] 2 -, -[CH 2 ]3-, -[CH 2 ] 2 -O-[CH 2 ]3- or -CH 2 -O-[CH 2 ]3-. In some embodiments, R29 is -[CH 2 ] 2 .6- and R30 is -CH 2 -. In some embodiments, R29 is -CH 2 - or -[CH 2 ]3-6- and R30 is -[CH 2 ] 2 -. In some embodiments, R29 is -[CH 2 ]I.
  • R29 is - [CH 2 ]I-3- or -[CH 2 ] 5 -6-. and R30 is -[CH 2 ] 4 -. In some embodiments, R29 is -[CH 2 ]I. 4 - or -[CH 2 ]g and -R30 is -[CH 2 ] 5 -. In some embodiments, R29 is -[CH 2 ]I_ 5 - and R30 is -[CH 2 ]g-.
  • R29 and R30 are each independently selected from: methylene, ethylene, propylene, isopropylene, butylene, isobutylene, tert-butylene, pentylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene, 1- methylbutylene, 2-methylbutylene, 3-methylbutylene, 1-ethylpropylene, 1,2-dimethylpropylene or hexylene.
  • R47 for each occurrence, is independently a 3-10-membered group independently selected from: cycloalkylene, cycloalkenylene, saturated heterocyclene or partially unsaturated heterocyclene.
  • R47, for each occurrence,' is independently selected from: an optionally substituted 3-8-membered saturated, partially unsaturated or unsaturated carbocyclene or an optionally substituted 3-8-membered saturated, partially unsaturated or unsaturated heterocyclene.
  • R47, for each occurrence is independently a 3-7-membered group independently selected from: cycloalkylene, cycloalkenylene, saturated heterocyclene or partially unsaturated heterocyclene.
  • R47, for each occurrence is independently selected from: cPr, cBu or cHx.
  • R147 is selected from C3-C7 cycloakyl or C3-C7 heterocycloakyl.
  • R147 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1,3-cyclohexadienyl or 1,4-cyclohexadienyl.
  • each R50 is independently selected from:
  • -R67-R125-R68-R126-R69-R70-R71 wherein said group has: a) a total number of carbon atoms selected from: 10-24, 12-22, 14-22, 16-20, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 carbon atoms; or b) a longest linear chain (i.e., excluding side groups) with a total number of carbon atoms or total number of atoms (i.e., carbon and heteroatoms) that is selected from: 10-24, 12-22, 14-22, 16-20, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 carbon atoms.
  • an R50 or R137 has a longest linear chain (i.e., excluding side groups) with a total number of carbon atoms that is selected from: 16, 17, 18, 19, 20, 21 or 22. In some further embodiments, an R50 or R137 has a longest linear chain (i.e., excluding side groups) with a total number of atoms that is selected from: 16, 17, 18, 19 or 20. In some further embodiments, an R50 or R137 has a longest linear chain (i.e., excluding side groups) with a total number of atoms that is selected from: 18, 19, 20, 21 or 22 carbon atoms.
  • the "longest liner chain” refers only to those atoms that directly form the chain, such that no bond between any two chain atoms can be broken without breaking the chain.
  • R3, R4, Rll and R12 are each independently selected from: a bond, -R26-C1- C10 alkylene-R27-, -R26-C 2 -CIO alkenylene-R27-, -R26-C 2 -CIO alkynylene-R27-, -R26-C3-C10 carbocyclylene-R27-, -R26-C3-C10 heterocyclylene-R27-; wherein, R26 and R27 are each independently selected from: a bond, or an optionally substituted C1-C6 alkylene, C 2 -C 6 alkenylene or C 2 -C 6 alkynylene.
  • R26 and R27 are each independently selected from: a bond, or an optionally substituted C1-C3 alkylene, C 2 -Cs alkenylene or C 2 -Cs alkynylene.
  • R3, R4, Rll and R12 are each independently selected from: C1-C10 alkylene, C2-C10 alkenylene or C2-C10 alkynylene, C3-C10 carbocyclylene or C3-C10 heterocyclylene.
  • R3, R4, Rll and R12 are each independently selected from: a bond, C1-C10 alkylene, C2-C10 alkenylene or C2-C10 alkynylene.
  • each cPr has a cis configuration. In some further embodiments, each double bond has a cis configuration.
  • R26 and R27 are each independently selected from: a bond, C1-C6 alkylene, C 2 - Cg alkenylene or C2-C6 alkynylene. In some further embodiments, R26 and R27 are each independently selected from: a bond, C1-C3 alkylene, C2-C3 alkenylene or C2-C3 alkynylene.
  • R5, R6, R9 and RIO are each independently selected from the group consisting of: -O-CH2-, -O-CH(OH) 2 -, -N(OH)-, -NH- or -C(NH[OH])-.
  • R7 and R8 are each independently selected from R3.
  • R115 for each occurrence, is each independently an optionally substituted group selected from: linear or branched Ci-Cg alkylene, C2-C8 alkenylene or C2-C8 alkynylene; -R26-C3- C10 heterocyclylene-R27- or -R26-C3-C10 carbocyclylene-R27-; -R26-C3-Cg-carbocyclylene-R27-, -R26-C3- C6-heterocyclylene-R27-; wherein, R26 and R27 are defined above or for any aspect or embodiment herein.
  • R115 is -R26-C3-Cg-cycloakylene-R27-; wherein R26 and R27 are defined above or for any aspect or embodiment herein.
  • R26 and R27 are each independently selected from: a bond, C1-C3 alkylene, C2-C3 alkenylene or C2-C3 alkynylene.
  • each double bond or cPr has a cis configuration.
  • each double bond or -cPr- has a cis configuration.
  • R15, R16, R17 and R18 are each independently selected from: -H, -D -CD 3 ; an optionally substituted linear or branched, C1-C6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; an optionally substituted, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkenyl, C 5 - Cio-spirocycloalkyl, C3-C 7 -carbocyclyl, C3-C 7 -heterocyclyl, phenyl, or 5-7 membered heteroaryl.
  • each R26 is independently selected from: a bond or linear or branched C1-C6 alkylene, C1-C6 alkenylene or C1-C6 alkynylene, and R28 is selected from: -H, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl.
  • each R26 is independently selected from: a bond, Ci- C3 alkylene, C2-C3 alkenylene or C2-C3 alkynylene.
  • R28 is selected from: -H, C1-C3 alkyl, C2-C4 alkenyl or C2-C4 alkynyl.
  • each double bond has a cis configuration.
  • each double bond or -cPr- has a cis configuration.
  • each R26 is independently selected from: a bond or linear or branched C1-C6 alkylene, C1-C6 alkenylene or C1-C6 alkynylene, and R28 is selected from: -H, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl.
  • each R26 is independently selected from: a bond, C1-C3 alkylene, C 2 -C 3 alkenylene or C 2 -C 3 alkynylene.
  • R28 is selected from: -H, C1-C3 alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl.
  • R149 is:
  • R123, R124, R125, R126, R127, R128, R132 and R133, R164 for each occurrence, is independently selected from: -H or optionally substituted, linear or branched C1-C3 alkyl; and R191 is selected from: is a bond or optionally substituted, linear or branched C1-C3 alkylene, -Co-C 3 -alkylene-C 3 -C 7 - carbocyclylene-Co-C 3 -alkylene- or -Co-C 3 -alkylene-C 3 -C 7 -heterocyclylene-Co-C 3 -alkylene-.
  • each of said halo is independently selected from -F, -Cl or -Br, and in further embodiments, -Br or -Cl.
  • said carbocyclyl or heterocyclyl is independently an optionally substituted group selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclobutadienyl, cyclopentadienyl, cyclohexadienyl, cycloheptadienyl or cycloheptatrienyl.
  • said carbocyclyl or heterocyclyl is independently an optionally substituted group selected from: lH-pyrrolizidinyl, 1,2-dihydroquinolinyl, 1,5-naphthyridinyl, 1,8-naphthyridinyl, IH-indazolyl, lH-isochromenyl, IH-pyrrolizidinyl, 1-naphthyl, 2H-benzo[b][l,4]oxazinyl, 2H- benzo[e][l,2]oxazinyl, 2h-chromenyl, 2-naphthyl, 4H-quinolizinyl, adeninyl, azaindazolyl, azaindolyl, benzimidazolyl, benzo
  • said carbocyclyl or heterocyclyl is independently an optionally substituted group selected from: furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridazinyl, pyridyl (pyridinyl), pyrimidinyl, thiadiazolyl, thienyl, tetrazolyl, thiazolyl, triazolyl, 1,2- thiazinyl, 1,3-thiazinyl, 1,4-thiazinyl, azepinyl, azetidinyl, dioxothiomorpholinyl, imidazolidinyl, morpholinyl, oxanyl, ox
  • said carbocyclyl or heterocyclyl is independently an optionally substituted group selected from: adamantanyl, azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.1]heptanyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 6- oxa-3-azabicyclo[3.1.1]heptanyl, 8-Methyl-8-azabicyclo[3.2.1]octanyl, 8-oxa-3- azabicyclo[3.2.1]octanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, tricyclo[2.2.1.0(2,6)]hept
  • said carbocyclyl or heterocyclyl is independently an optionally substituted group selected from:
  • said carbocyclylene or heterocyclylene is independently an optionally substituted group selected from: 1,2-dihydroquinolinediyl, 1,5-naphthyridinediyl, 1,8-naphthyridinediyl, lH-indazolediyl, 1H- isochromenediyl, lH-pyrrolizidinediyl, 1-naphthalenediyl, 2H-benzo[b][l,4]oxazined
  • said carbocyclylene or heterocyclylene is independently an optionally substituted group selected from: cyclopropylene (cyclopropanediyl), cyclobutylene (cyclobutanediyl), cyclopentylene (cylcopentanediyl), cyclohexylene (cyclohexenediyl), cycloheptylene (cycloheptanediyl), cyclopropenediyl, cyclobutenylenediyl,
  • said carbocyclylene or heterocyclylene is independently an optionally substituted group selected from: adamantanediyl, azabicyclo[3.1.0]hexanediyl, 3- azabicyclo[3.1.1]heptanediyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 3-oxa- 8-azabicyclo[3.2.1]octanediyl, 6-oxa-3-azabicyclo[3.1.1] heptanediyl
  • said carbocyclylene is independently an optionaly substituted group selected from:
  • each R33 is independently selected from -H, -CH 2 (halo), -CH(halo) 2 , -C(halo)3, -F, -Cl, -Br, -I, -CH3, -OH, -OCH3, -CD3 or -OCD3.
  • each R33 is independently selected from -H, -CH 2 (halo), -CH(halo) 2 , -C(halo) 3 , -F, -Cl, - Br, -or -OH.
  • said carbocyclylene or heterocyclylene is independently an optionally substituted group selected from: In some embodiments, -R3-R5-R7-R9-R11-R13-R15, -R3-R5-R7-R9-R11-R13-R17, -R4-R6-R8-R10-R12- R14-R16, and -R4-R6-R8-R10-R12-R14-R18, each independently, have a total number of carbon atoms that is selected from: 16-22, inclusive, 16-20, inclusive, 17, 18 or 19 carbon atoms.
  • -R3-R5-R7-R9-R11-R13-R15, -R3-R5-R7-R9-R11-R13-R17, -R4-R6-R8-R10-R12-R14-R16, and -R4-R6-R8-R10-R12-R14-R18 each independently, have a longest linear chain (i.e., excluding side groups) with a total number of carbon atoms that is selected from: 16-22, 16-20, 17, 18 or 19 carbon atoms.
  • R13, R14, R61, R73 and R107 are each independently selected from: for R13, a bond labelled 2 or 4 is attached to R15 or R62 and a bond labelled 3 is attached to R3, R17 or R67; for R14, a bond labelled 2 or 4 is attached to R16 and a bond labelled 3 is attached to R18; for R61, a bond labelled 2 or 4 is attached to R3, R13, R62 and a bond labelled 3 is attached to R4, 67; for R73, a bond labelled 2 or 4 is attached to R74 and a bond labelled 3 is attached to R76; and for R107, a bond labelled 2 or 4 is attached to R108 and a bond labelled 3 is attached to R110.
  • the ionizable cationic lipid has a structural formula represented by (7)
  • the ionizable cationic lipid has a structural formula represented by (8):
  • each of R2 through R18 and R25 is independently as described above or for any aspect or embodiment herein.
  • the ionizable cationic lipid has a structural formula represented by (9):
  • each of R3 through R18 and R25 is independently as described above or for any aspect or embodiment herein.
  • the ionizable cationic lipid has a structural formula represented by (10): wherein, each of Rll through R18 and R25 is independently as described above or for any aspect or embodiment herein.
  • the ionizable cationic lipid has a structural formula represented by (11): wherein each occurrence of R2 through R18 is independently as described above or for any aspect or embodiment herein.
  • the ionizable cationic lipid or cationic lipid has is represented by a structural formula selected from: wherein: R142 is selected from: -N(R31)(R32), R58, R119 or R32;
  • R31 and R32 are each independently selected from: -H, -D, -CDs, or an optionally substituted group selected from: linear or branched Ci-io alkyl, CMO hydroxyalkyl, Ci-io alkoxyalkyl, linear or branched Ci- 10 alkenyl, linear or branched CMO alkynyl, 3-14 membered carbocyclyl, 3-14 membered heterocyclyl, 5-10 membered spirocyclyl, 5-10 membered spiroheterocyclyl, 3-7 membered carbocyclyl-Ci.g alkyl-, 3-7 membered heterocyclyl-Ci.g alkyl-, 5-10 membered spirocyclyl-Ci.g alkyl-, 5-10 membered spiroheterocyclyl-Ci.
  • R34 is selected from a bond, -N(R116)-, -O-, -S-, -S(R46);
  • R116 is -H, -D, -CD 3 , or C1-3 alkyl
  • R47 is selected from: a bond, an optionally substituted 3-14-membered saturated, partially unsaturated or unsaturated carbocyclene or an optionally substituted 3-14-membered saturated, partially unsaturated or unsaturated heterocyclene;
  • R48 is selected from: a bond or an optionally substituted group selected from: CMO alkylene, Ci-w internal alkenylene, C1-10 internal alkynylene, -Co-C 3 alkyl-3-6-membered cycloalkylene-Co-C 3 alkyl-, - Co-C 3 alkyl-4-6-membered cycloalkenylene- Co-C 3 alkyl-, -Co-C 3 alkyl-phenylene- Co-C 3 alkyl-, -Co-C 3 alkyl-3-6-membered heterocycloalkylene-Co-C 3 alkyl-, -Co-C 3 alkyl-4-6-membered heterocycloalkenylene- Co-C 3 alkyl-, -Co-C 3 alkyl-5-6-membered heteroarylene- Co-C 3 alkyl-;
  • R121 is selected from: R134-R135-R136;
  • R134 and R136 are independently selected from: a bond or an optionally substituted group selected from C1-C10 alkylene, C2-C10 alkenylene or C2-C10 alkynylene;
  • R138 is selected from: R50, R51 or R137. each R50 and R137 are each independently defined above or for any aspect or embodiment herein.
  • R51 is selected from:
  • R3-R18, R22, R62 through R71, R73 through R79, R105 through R113, R123 through R128, R132, R133, and any remaining variables are as defined above or for any aspect or embodiment herein;
  • R55 is selected from: a bond, or C1-C4 alkylene;
  • R57 is a bond, C1-C6 alkylene, -C1-C6 alkylene-O-C1-C6 alkylene-;
  • R58 is selected from:
  • R60 is selected from: is absent (i.e., an unbonded pair of electrons on N), -H, -D, -CD3 or optionally substituted C1-C6 alkyl; wherein, when R60 is -H or -D, -CD 3 , or optionally substituted C1-C6 alkyl, R60 is bound directly to a nitrogen atom with a +1 charge.
  • each R139 is independently selected from: -H, -D, -CD 3 , -OH or C1-C4 alkyl; each R59 is independently selected from: -H, -D, -CD 3 , C1-C4 alkyl, C1-C4 cycloalkyl, -(CH2)I-4-CI-C4 cycloalkyl or R31; and, R119 is a 4-7-member heterocyclyl, wherein: one ring atom is a nitrogen atom (nitrogen ring atom) and each remaining ring atom is a carbon atom (carbon ring atom); each carbon ring atom adjacent to the nitrogen ring atom is substituted with R31 to form -CH(R31)-; each carbon ring atom that is non- adjacent to the nitrogen ring atom is unsubstituted; said heterocyclyl has a ring with 0 or 1 carbon- carbon
  • the ionizable cationic lipid or cationic lipid is represented by a structural formula of a compound selected from: wherein each of the variables are described above or for any aspect or embodiment herein.
  • R22 is selected from: a bond, optionally substituted Ci- 5 alkylene, optionally substituted -C1-C6 alkylenediyl-O-, -CH2-, -[CHzh-, -[Cl-bh-, isopropylene, butylene, isobutylene, -NH-, - N(R116)-, -O- or -S-.
  • R22 is -Ci-Cg alkanediyl-O-.
  • R22 is -C1-C3 alkanediyl-O-.
  • R22 is selected from: -CH2-O-, -[CHzh-O-, -[CHzh-O-.
  • R31 and R32 are each independently an optionally substituted group selected from: -CD3, C1-5 alkyl, C1-5 hydroxyalkyl, C1-5 alkoxyalkyl, C1-5 alkenyl, C1-5 alkynyl, or R31 and R32, together with the nitrogen atom to which they are attached, form an optionally substituted aziridinyl, azetidinyl, pyrrolidinyl or piperidinyl group.
  • R31 and R32 are each independently selected from: -CD3, C1-C4 alkyl, methyl, ethyl, propyl, 2-propyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, n-butyl, n-pentyl, n-hexyl, hydroxymethyl, 2-hydroxyethyl, 2- hydroxypropyl, 2-hydroxybutyl, 2-hydroxypentyl, 2-hydroxyhexyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl, 6-hydroxyhexyl, 2,3-dihydroxypropyl, l,3-dihydroxy-2-propyl, 2,4-dihydroxy-butyl, 2,3,4-trihydroxy-butyl.
  • R31 and R32 are each independently selected from: 3-7 membered- cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl.
  • R31 and R32 are each independently selected from: 3-7 membered- cycloalkyl- C1-C4 alkyl-, 3-7 membered-cycloalkenyl-Ci-C4 alkyl-, 3-7 membered-heterocycloalkyl-Ci-C4 alkyl-, 3-7 membered- heterocycloalkenyl.
  • R31 and R32 are each independently selected from: -CD3, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl or hydroxypropyl.
  • R31 is Ph3C-0-[CH2]o-2CH2- (Ph refers to phenyl).
  • R31 is hydroxyethyl and R32 is methyl, ethyl or hydroxyethyl.
  • R31 and R32 are the same.
  • R34 is selected from: a bond, -N(R116)- or -O-. In some embodiments, R34 is -O- or -N(R116)-. In some embodiments, R34 is -O- or -NH-.
  • R47 is an optionally substituted group selected from: 1,2-dihydroquinolindiyl, 1,5-naphthyridindiyl, 1,8-naphthyridindiyl, lH-indazoldiyl, lH-isochromendiyl, lH-pyrrolizidindiyl, 1- naphthalendiyl, 2H-benzo[b][l,4]oxazindiyl, 2H-benzo[e][l,2]oxazindiyl, 2h-chromendiyl, 2- naphthalendiyl, 4H-quinolizindiyl, adenindiyl, azaindazoldiyl, azaindoldiyl, benzimidazoldiyl, benzo[b]thiophendiyl, benzo[c][l,2,5]thiadiazoldiyl, benzo[c]isothiazoldi
  • R47 is an optionally substituted group selected from: furandiyl, imidazoldiyl, isothiazoldiyl, isoxazoldiyl, oxadiazoldiyl, oxazoldiyl, pyrazoldiyl, pyrroldiyl, pyridazindiyl, pyridindiyl, pyrimidindiyl, thiadiazoldiyl, thiendiyl, tetrazoldiyl, thiazoldiyl, triazoldiyl, azepindiyl, azetidindiyl, dioxothiomorpholindiyl, imidazolidindiyl, morpholindiyl, oxandiyl, oxazindiyl, oxazolidindiyl, oxepindiyl, oxetandiyl, piperazindiyl
  • R47 is an optionally substituted group selected from: cyclopropylene (cyclopropandiyl), cyclobutylene (cyclobutandiyl), cyclopentylene (cylcopentandiyl), cyclohexylene (cyclohexendiyl), cycloheptylene (cycloheptandiyl), cyclopropendiyl, cyclobutenylendiyl, cyclopentenylendiyl, cyclohexendiyl, cycloheptendiyl, cyclobutadiendiyl, cyclopentadiendiyl, cyclohexadiendiyl or cycloheptadiendiyl or cycloheptatriendiyl.
  • R47 is an optionally substituted group selected from: adamantandiyl, azabicyclo[3.1.0]hexandiyl, 3-azabicyclo[3.1.1]heptandiyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 3-oxa-8-azabicyclo[3.2.1]octandiyl, 6-oxa-3-azabicyclo[3.1.1]heptandiyl, 8- oxa-3-azabicyclo[3.2.1]octandiyl, 3-oxa-6-azabicyclo[3.1.1]heptandiyl, tricyclo[2.2.1.0(2,6)]heptanyl, 6,6-dimethylbicyclo[3.1.1]heptyl, or 2,6,6-trimethylbicyclo[3.1.1]heptyl, 5-azaspiro[2.3]hexandiyl, 2- azas
  • R47 is an optionally substituted group selected from:
  • stereochemical relationship of the substituent groups on each ring can be cis or trans.
  • R47 is an optionally substituted group selected from:
  • R47 is an optionally substituted group selected from:
  • R47 is an optionally substituted phenylene.
  • R47 is an optionally substituted group selected from:
  • At least one R144 is -F; at least one R144 is -Cl; at least one R144 is -Br; at least two R144 are -F; at least two R144 are -Cl; at least two R144 are -Br; at least one R144 is -OH; at least two R144 are -OH; at least one R144 is -F -Cl or -Br and at least one R144 is -OH or - OCH 3 ; at least two R144 is independently selected from -F, -Cl or -Br and at least one R144 is -OH or - OCH 3 ; at least two R144 is -F and at least one R144 is -OH; at least two R144 are -Cl and at least one R144 is -OH or -OCH 3 ; at least two R144 are -Br and at least one R144 is -OH; at least two R144 is independently selected from -F, -Cl or -
  • R48 is an optionally substituted group selected from: Ci-Cg alkylene, C2-C8 internal alkenylene, C2-C8 internal alkynylene, -Co-C 3 alkyl-3-6-membered cycloalkylene-Co-C 3 alkyl-, - C 0 -C 3 alkyl-4-6-membered cycloalkenylene- C 0 -C 3 alkyl-.
  • R48 is an optionally substituted group selected from: methylene, ethylene, propylene, C 3 -Cg branched alkylene, -Co-C 3 alkylene-3-6-membered cycloalkylene-Co-C 3 alkylene- or Co-C 3 alkylene-4-6-membered cycloalkenylene- Co-C 3 alkylene-.
  • R48 is -Co-C 3 alkylene-3-6-membered cycloalkylene-Co-C 3 alkylene-, wherein said 3-6-membered cycloalkylene is selected from cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene.
  • R48 is an optionally substituted group selected from: methylene, ethylene, propylene, isopropylene, butylene or isobutylene.
  • R57 is selected from: methylene, ethylene or propylene. In some embodiments, R57 is -[CH 2 ]I.5-O-[CH 2 ]I. 5 -. In some embodiments, R57 is -[CH 2 ]I. 3 -O-[CH 2 ]I. 3 -. In some embodiments, R57 is selected from: -[CH 2 ] 2 -O-[CH 2 ] 3 - or -[CH 2 ] 3 -O-[CH 2 ] 2 -.
  • R119 is a heterocycloalkyl. In some embodiments, R119 is heterocyclyl selected from azetidinyl, pyrrolidinyl, piperindinyl or azepanyl.
  • R119 is selected from:
  • R59 is -H, -D, -CD3, or C1-C4 alkyl. In some further embodiments, R59 is selected from: -H, -D, -CD 3 , methyl, ethyl, propyl, isopropyl, or cyclopropylmethyl. In some further embodiments, R59 is selected from: -H, -D, -CD3, -OH, methyl or -[CHjh-j-OH.
  • R31 and/or R32 are each independently substituted with one or more substituents each independently selected from: R15 or R24; wherein R15 and R24, for each occurrence, is independently as described above or for any aspect or embodiment herein.
  • R134 and R136 are independently selected from: a bond or an optionally substituted group selected from: C1-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene. In some embodiments, R134 and R136 are independently selected from: a bond or an optionally substituted group selected from: C1-C3 alkylene, C 2 -C 3 alkenylene or C 2 -C 3 alkynylene. In some embodiments, R134 and R136 are independently selected from: methylene, ethylene or propylene. In some embodiments, R134 and R136 are independently selected from: methylene or ethylene.
  • R134 and R136 are independently selected from: a bond or an optionally substituted group selected from C1-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene. In some embodiments, R134 and R136 are independently selected from: a bond or an optionally substituted group selected from C1-C6 alkylene. In some embodiments, R134 and R136 are independently Ci-C 3 alkylene.
  • the ionizable cationic lipid or cationic lipid represented by any one of structural formulas (12)-(20), (21) (23), (24), (27), (29), (30) or (31) wherein (as present):
  • R31 and R32 are ethyl, R31 is hydroxyethyl and R32 is -CD 3 or methyl, or R31 is Ph 3 C-O-CH 2 -CH 2 - and R32 is -CD 3 or methyl;
  • R48 is propylene or butylene
  • R34 is -O- or -NH-
  • R47 is benzene-l,3-diyl or benzene-l,4-diyl
  • R22 is methoxy
  • the ionizable cationic lipid or cationic lipid represented by any one of structural formulas (15), (19), (24), (30), (31) wherein:
  • R32 is Ci-io hydroxyalkyl
  • ionizable cationic lipid or cationic lipid is represented by structural formula (20)
  • R31 and R32 are each independently selected from: -CDs, Ci to C3 alkyl, cyclopropylmethyl, 2- hydroxyethyl, 2-hydroxypropyl, or 3-hydroxypropyl;
  • R48 is selected from: a bond, or Ci to C 6 alkylene
  • R34 is selected from: a bond, -O-, -NH-, or -S-;
  • R22 is selected from: a bond, substituted Ci to C 3 alkylene, -CH2-O-, -[Cl-bh-O-, -[CH2] 3 -O-, -CH2-S-, - [CH 2 ] 2 -S-, or -[CH 2 ] 3 -S-.
  • ionizable cationic lipid or cationic lipid is represented by structural formula (24)
  • R31 and R32 are each independently selected from: -CD 3 , Cito C 3 alkyl, hydroxymethyl, 2- hydroxyethyl, 3-hydroxypropyl, or Ph 3 C-0-[CH2]o-2CH2- (Ph refers to phenyl);
  • R48 is selected from Ci to C 7 alkylene
  • R22 is selected from Ci to C 3 alkylene;
  • R31 is selected from -CD 3 or Ci to C 3 alkyl
  • R32 is selected from 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, cyclopropylmethyl or PhsC- 0-[CH 2 ]O- 2 CH 2 - (Ph refers to phenyl),
  • R48 is selected from C 2 to C 5 alkylene
  • R22 is selected from -CD3 or Ci to C3 alkylene.
  • ionizable cationic lipid or cationic lipid is represented by structural formula (25): wherein,
  • R58 is selected from
  • R57 is selected from a bond, -CD 3 or Ci to C 5 alkylene
  • R59 and R139 are each independently selected from: -H, -D, -CD 3 , C1-C3 alkyl or C1-C3 alkylene-OH; and
  • R60 is -H or -D.
  • ionizable cationic lipid or cationic lipid is represented by structural formula (26):
  • R59 and R139 are each independently selected from: -H, -D, -CD3, C1-C3 alkyl or C1-C3 alkylene-OH;
  • R60 is -H or -D.
  • ionizable cationic lipid or cationic lipid is represented by structural formula (29)
  • R31 and R32 are each independently selected from: -CD 3 , Ci to C 4 alkyl, cyclopropylmethyl, 2- hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, or 4-hydroxybutyl;
  • R48 is selected from a bond, or Ci to C 6 alkylene
  • R120, R47, and R22 are each a bond
  • R23 is selected from: f
  • R22 is selected from: Ci to C 3 alkylene, hydroxymethyl, 1-hydroxyethyl, or 1-hydroxypropyl;
  • R62 is selected from Ci to Cg alkylene.
  • R62 is selected from: a bond or Ci to Cg alkylene.
  • ionizable cationic lipid or cationic lipid is represented by structural formula (35):
  • R 23 is selected from:
  • R22 is selected from: a bond, C1-C3 alkylene, hydroxymethyl, 1-hydroxyethyl, or 1-hydroxypropyl;
  • R62 is selected from: a bond, Ci to C 5 alkylene;
  • R67 is selected from Ci to Cg alkylene.
  • ionizable cationic lipid or cationic lipid is represented by structural formula (36)
  • R25 is selected from: branched or linear Ci to Cg alkyl, -CD 3 , cyclopropyl, cyclobutyl, or branched or linear hydroxy-Ci-C 8 alkyl-;
  • R21 is a bond.
  • each R50, R51, R138 and R137 (where applicable) is represented by a structural formula independently selected from:
  • each R50, R51, R138 and R137 (where applicable) is represented by a structural formula independently selected from:
  • R61 is defined above or for any aspect or embodiment herein.
  • R61 is selected from:
  • each R50, R51, R138 and R137 (where applicable) is represented by a structural formula independently selected from:
  • the ionizable cationic lipid or cationic lipid has a structural or chemical formula of a compound of Table 1., wherein R138 is selected from R50, R51 or R137, wherein each R50, R51 and R137 are defined above or for any aspect or embodiment herein. In some embodiments, R138 is R50. In some embodiments R138 is R51. In some embodiments R148 is R137.
  • the ionizable cationic lipid has a structural formula selected from a compound in Table 2.
  • the invention provides for a cationic lipid with a structural formula of a compound in Table 3.
  • the cationic lipid is a non-fusogenic lipid.
  • a non-fusogenic lipid is meant a cationic lipid that can condense and/or encapsulate a payload, e.g., a therapeutic nucleic acid, but has insufficient fusogenic activity to effectively delivery the payload across cellular membranes.
  • the lipid nanoparticles have mean diameter of 20-75 nm or 30-100 nm.
  • the pKa' i.e., the apparent pKa, of formulated cationic lipids in particles, can be correlated with the effectiveness of the LNPs for intracellular delivery of nucleic acids.
  • the pKa' of a cationic lipid can be determined in lipid nanoparticles, e.g., using an assay based on fluorescence of 2-(p-toluidino)-6- napthalene sulfonic acid (TNS).
  • TNS 2-(p-toluidino)-6- napthalene sulfonic acid
  • Lipid nanoparticles in phosphate-buffered saline (PBS), at a concentration of 0.4 mM total lipids, are prepared using standard methods.
  • TNS can be prepared as a 100 mM stock solution in distilled water and mixed into buffers of different pH values.
  • Vesicles can be diluted to 24 mM lipid in 2 mL of buffered solutions containing, 10 mM HEPES, 10 mM MES, 10 mM ammonium acetate, 130 mM NaCI, where the pH ranges from 2.5 to 11.
  • An aliquot of the TNS solution can be added to give a final concentration of 1 mM and, after vortex mixing, the fluorescence intensity is measured at room temperature in a SLM Aminco Series 2 Luminescence Spectrophotometer using excitation and emission wavelengths of 321 nm and 445 nm.
  • a sigmoidal non-linear least-squares fit analysis can be applied to the fluorescence data and the pKa' is measured as the pH giving rise to half-maximal fluorescence intensity.
  • the LNP comprises about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, about 30% to about 50%, or about 30% to about 40%, about 40% to about 80%, about 30% to about 70%, about 40% to about 60%, about 40% to about 50%, about 50% to about 80%, about 50% to about 70%, 50% to about 60%, about 60% to about 80%, or about 70% to about 80% (ionizable) cationic lipid.
  • the lipid particles can further comprise a component, such as a sterol, to provide membrane integrity and stability of the lipid particle.
  • a component such as a sterol
  • an exemplary sterol that can be used in the lipid particle is cholesterol, or a derivative thereof.
  • Nonlimiting examples of cholesterol derivatives include 5-a-cholestanol (5a-Cholestan-3p-ol), 5-p- coprostanol, cholesteryl-(2' -hydroxy)-ethyl ether, cholesteryl-( 4' -hydroxy)-butyl ether, and 6- ketocholestanol, 5a-cholestane, cholestenone, 5-a-cholestanone, 5 p-cholestanone, allocholesterol, epi-allocholesterol and cholesteryl decanoate, and mixtures thereof.
  • the cholesterol derivative is a polar analogue such as cholesteryl-(4'-hydroxy)-butyl ether.
  • cholesterol derivative is cholesteryl hemisuccinate.
  • the sterol is a sea cucumber sulphated sterol, e.g., cholest-5-en-3P-yl hydrogen sulfate or 24-methylene- cholesterol sulfate (J. Oleo Sci. 71, (3) 401-410 (2022)).
  • the lipid is fecosterol, sitosterol, campesterol, stigmasterol, brassicasterol, ergosterol, tomatidine, tomatine, ursolic acid or alpha-tocopherol.
  • Exemplary cholesterol derivatives are described in International Patent Application Publication No. W02009/127060 and U.S. Patent Application Publication No. US2010/0130588.
  • the component providing membrane integrity can comprise 0- 50% (mol) of total lipids present in the lipid particle (e.g., lipid nanoparticle). In some embodiments, such a component is 20-50% (mol) of total lipids present in the lipid particle (e.g., lipid nanoparticle). In some embodiments, such a component is 30-40% (mol) of total lipids present in the lipid particle (e.g., lipid nanoparticle). In some embodiments, such a component is 35-45% (mol) of total lipids present in the lipid particle (e.g., lipid nanoparticle). In some embodiments, such a component is 38- 42% (mol) of total lipid present in the lipid particle (e.g., lipid nanoparticle).
  • the LNP comprises a sterol, wherein the sterol is present at a molar percentage of about 20% to about 50%. According to some embodiments, the LNP comprises a sterol, wherein the sterol is present at a molar percentage of about 30% to about 50%. According to some embodiments, the LNP comprises a sterol, wherein the sterol is present at a molar percentage of about 40% to about 50%. According to some embodiments, the LNP comprises a sterol, wherein the sterol is present at a molar percentage of about 20% to about 40%. According to some embodiments, the LNP comprises a sterol, wherein the sterol is present at a molar percentage of about 30% to about 40%. In some embodiments, the LNP comprises more than one structural lipid, e.g., two or more sterols.
  • the non-cationic lipid is typically a phospholipid and serves to increase fusogenicity and/or increase stability of the LNP, including during formation.
  • Non-cationic lipids include amphipathic lipids, neutral lipids and anionic lipids. Accordingly, the non-cationic lipid can be a neutral uncharged, zwitterionic, or anionic lipid.
  • non-cationic lipids include, but are not limited to, distearoyl-sn- glycerophosphoethanolamine, distearoyl-phosphatidylcholine (DSPC), dioleoyl-phosphatidylcholine (DOPC), dipalmitoyl-phosphatidylcholine (DPPC), dioleoyl-phosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), dioleoyl-phosphatidylethanolamine (DOPE), palmitoyl-oleoyl- phosphatidylcholine (POPC), palmitoyl-oleoyl-phosphatidylethanolamine (POPE), dioleoylphosphatidylethanolamine 4-(N-maleimidomethyl)-cyclohexane-l-carboxylate (DOPE-mal), dipalmitoyl phosphatidyl ethanolamine (DPPE), dim
  • acyl groups in these lipids are preferably acyl groups derived from fatty acids having Ci 0 -C 24 carbon chains, e.g., lauroyl, myristoyl, palmitoyl, stearoyl, or oleoyl.
  • Preferred helper lipid DSPC, DPPC, DMPC, DOPC, POPC, DOPE, and SM.
  • the non-cationic lipid can comprise 0-20% (mol) of the total lipid present in the lipid nanoparticle. In some embodiments, the non-cationic lipid comprises 0.5-15% (mol) of the total lipid present in the lipid particle (e.g., lipid nanoparticle). In some embodiments, the non-cationic lipid comprises 5-12% (mol) or 5-10% (mol) of the total lipid present in the lipid particle (e.g., lipid nanoparticle).
  • the non-cationic lipid comprises about 6% (mol), about 7.0% (mol), about 7.5% (mol), about 8.0% (mol), about 9.0% (mol), about 10% (mol), or about 11 % (mol) of the total lipid present in the lipid particle (e.g., lipid nanoparticle).
  • non-cationic lipids are described in International Patent Application Publication WO2017/099823 and US Patent Application Publication US2018/0028664, the contents of both of which are incorporated herein by reference in their entirety.
  • the LNP comprises a non-cationic lipid, wherein the non-cationic lipid is present at a molar percentage of about 2 % to about 20%. According to some embodiments, the LNP comprises a non-cationic lipid, wherein the non-cationic lipid is present at a molar percentage of about 5% to about 20%, about 10% to about 20%, about 15% to about 20%, about 10% to about 20%, or about 10% to about 15%.
  • the lipid particle (e.g., lipid nanoparticle) can further comprise a polymer conjugated lipid molecule, e.g., polyethylene glycol (PEG)-conjugated ("PEGylated") lipid.
  • PEG polyethylene glycol
  • PEGylated polyethylene glycol
  • lipid particle e.g., lipid nanoparticle
  • PEG-lipid conjugates include, but are not limited to, PEG-lipid conjugates, polyoxazoline (POZ)-lipid conjugates, polyamide-lipid conjugates (such as ATTA-lipid conjugates, polysarcosine), cationic-polymer lipid (CPL) conjugates, and mixtures thereof.
  • the conjugated lipid molecule is a PEGylated lipid, for example, a (methoxy polyethylene glycol)- conjugated lipid.
  • the PEGylated lipid is PEG2000-DMG (dimyristoylglycerol).
  • PEGylated lipids include, but are not limited to, PEG-diacylglycerol (DAG) (such as l-(monomethoxy-polyethyleneglycol)-2,3-dimyristoylglycerol (PEG-DMG)), PEG- dialkyloxypropyl (DAA), PEG-phospholipid, PEG-ceramide (Cer), a pegylated phosphatidylethanolamine (PEG-PE), PEG succinate diacylglycerol (PEGS-DAG) 1,2-dimyristoyl-rac- glycero-3-methoxypolyethylene glycol-2000 (PEG2000-DMG), R-3-[(co-methoxy poly(ethylene glycol)2000)carbamoyl)]-l,2-dimyristyloxy-propyl-3-amine (PEG-c-DOMG), 1,2-Dimyristoyl-sn- Glycero-3-Phosphoethanolamine
  • PEG with mono-tail can be an amide, as in
  • This lipid may be used in LNP formulations, usually with a PEG2k segment, as defined below, as a sole surface stabilizer or in mixtures with other surface lipids.
  • the number of ethyleneoxy (-CH 2 CH 2 O-) repeating units in PEG polymers is usually referred to as n, often expressed as a range due to polydispersity of the preparation.
  • n ethyleneoxy (-CH 2 CH 2 O-) repeating units in PEG polymers
  • n ethyleneoxy (-CH 2 CH 2 O-) repeating units in PEG polymers
  • n often expressed as a range due to polydispersity of the preparation.
  • the values of n for a 2000 molecular weight (2k) PEG is between about 40-50 ethyleneoxy units.
  • the value of n is smaller for lower molecular weight PEG and larger when the PEG size is increased relative to PEG2000, also referred to as PEG2k.
  • PEG-lipid conjugates are described, for example, in US patents US5885613, US6287591, US8936942B2 and US patent applications US2003/0077829, US2003/0077829, US2005/0175682, US2008/0020058, US2011/0117125, US2010/0130588, US2016/0376224, and US2017/0119904, the contents of all of which are incorporated herein by reference in their entirety.
  • the PEG-DAA PEGylated lipid can be, for example, PEG-dilauryloxypropyl, PEG- dimyristyloxypropyl, PEG-dipalmityloxypropyl, or PEG-distearyloxypropyl.
  • the PEG-lipid can be one or more of PEG-DMG, PEG-dilaurylglycerol, PEG-dipalmitoylglycerol, PEG-distearylglycerol, PEG- dilaurylglycamide, PEG-dimyristylglycamide, PEG-dipalmitoylglycamide, PEG- distearylglycamide, PEG-cholesterol (l-[8'-(Cholest-5-en-3 [beta]- oxy)carboxamido-3',6'-dioxaoctanyl] carbamoyl- [omega]-methyl-poly(ethylene glycol), PEG-DMB (3,4-Ditetradecoxylbenzyl-[omega]-methyl- poly(ethylene glycol) ether), and 1,2-dimyristoyl-snglycero- 3-phosphoethanolamine-N- [methoxy(polyethylene glycol)
  • the PEG-lipid can be selected from the group consisting of PEG-DMG, and l,2-dimyristoyl-sn-glycero-3- phosphoethanolamine-N- [methoxy(polyethylene glycol)-2000].
  • the PEGylated lipid is selected from N-(Carbonyl-methoxypolyethyleneglycol n )- l,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (PEG n -DMPE, where PEG average molecular weight is 350, 500, 750, 1000 or 2000); N-(Carbonyl-methoxypolyethyleneglycol n )-l,2-distearoyl-sn- glycero-3-phosphoethanolamine (DSPE-PEG n , where PEG average molecular weight is 350, 500, 750, 1000, 2000, or 5000); DSPE-polyglycerol-cyclohexyl-carboxylic acid, DSPE-polyglycelin-2- methylglutaric acid; l,2-Distearoyl-sn-Glycero-3-Phosphoethanolamine (DSPE) conjugated Polyethylene Glycol (HO-PEG-DMPE, where
  • the PEG-lipid is N-(Carbonyl-methoxypolyethyleneglycol 2000)- l,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (PEG2000-DMPE).
  • PEG n - DSPE where PEG average molecular weight is 350, 500, 750, 1000 2000, or 5000 the PEG-lipid is N- (Carbonylmethoxypolyethyleneglycol 2000)-l,2-distearoyl-sn-glycero-3-phosphoethanolamine (PEG2000-DSPE).
  • the PEGylated lipid is HO-PEG-DSPE. In some embodiments, the PEGylated lipid is azide-PEG-DSPE. In some embodiments, the PEGylated lipid is PEG-DMG. In some embodiments, the PEGylated lipid is PEG-DSG. In some embodiments, the conjugated lipid, e.g., PEGylated lipid, includes a tissue-specific ligand, e.g., first or second ligand. For example, PEG-DSPE conjugated with a GalNAc ligand, PEG-DSG conjugated with a GalNAc ligand.
  • lipids conjugated with a molecule other than a PEG can also be used in place of PEG-lipid.
  • polyoxazoline (POZ)-lipid conjugates, polyamide-lipid conjugates (such as ATTA-lipid conjugates), and cationic -polymer lipid (CPL) conjugates can be used in place of or in addition to the PEG-lipid.
  • Exemplary conjugated lipids, i.e., PEG-lipids, (POZ)-lipid conjugates, ATTA-lipid conjugates and cationic polymer-lipids are described in the International Patent Application Publication Nos. WO 1996/010392, WO1998/051278, W02002/087541, W02005/026372, WO2008/147438,
  • the PEGylated lipid is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethylated lipid
  • the invention provides for a PEG-lipid with a structural formula of a compound in Table 4.
  • the LNP comprises at least one PEGylated lipid, wherein the PEGylated lipid is present at a molar percentage of about 0.5% to about 20% of the total lipid present in the lipid nanoparticle. In some embodiments, the LNP comprises at least one PEGylated lipid, wherein the PEGylated lipid is present at a molar percentage of about 2.0% to about 10% of the total lipid present in the lipid nanoparticle.
  • the LNP comprises about 1-5% (mol), about 2-4% (mol), about 2-3% (mol), about 1-3% (mol), about 0.75-2.5% (mol), about 0.75-2.0% (mol), about 0.75-1.8% (mol), about 1-2% (mol), about 0.75-1.5% (mol), about 1- 1.8% (mol), about 1-1.5% (mol), about 1-1.3% (mol), about 1-1.2% (mol), about 0.75-1.5% (mol), about 0.75-1.25% (mol), about 1.5-1.8% (mol), about 1.2-1.5% (mol), about 2% (mol), about 2.5% (mol), about 3% (mol), about 3.5% (mol) or about 4% (mol) of PEGylated lipid, based on the total lipid present in the lipid nanoparticle.
  • the LNP comprises at least one PEGylated lipid, wherein the PEGylated lipid is present at a molar percentage of about 5% to about 10%, about 7% to about 10%, about 2.1 % to about 8%, about 2.1 % to about 5%, about 5% to about 8%, about 1 % to about 2%. about 1.2% to about 2%. about 1.5% to about 2%. about 1.75% to about 2%, about 1 % to about 1.5%, about 1.25% to about 1.5%, or about 1.5% to about 1.75%.
  • the lipid particles may be conjugated with other moieties to prevent aggregation.
  • lipid conjugates include, but are not limited to, PEG-lipid conjugates such as, e.g., PEG coupled to dialkyloxypropyls (e.g., PEG-DAA conjugates), PEG coupled to diacylglycerols (e.g., PEG-DAG conjugates), PEG coupled to cholesterol, PEG coupled to phosphatidylethanolamines, and PEG conjugated to ceramides (see, e.g., U.S. Patent No.
  • POZ-lipid conjugates e.g., POZ-DAA conjugates; see, e.g., U.S. Provisional Application No. 61/294,828, filed Jan. 13, 2010, and U.S. Provisional Application No. 61/295,140, filed Jan. 14, 2010
  • polyamide oligomers e.g., ATTA-lipid conjugates and polysarcosine
  • PCT Publication No. WO 2010/006282 Additional examples of POZ-lipid conjugates are described in PCT Publication No. WO 2010/006282.
  • PEG or POZ can be conjugated directly to the lipid or may be linked to the lipid via a linker moiety.
  • linker moiety suitable for coupling the PEG or the POZ to a lipid can be used including, e.g., non-ester containing linker moieties and ester-containing linker moieties.
  • non-ester containing linker moieties such as amides or carbamates, are used.
  • the lipid particles of the present invention may further comprise one or more additional lipid(s), including triglycerides and fatty acids. Note that some of these additional lipids may also fall into one of the categories above. Additional lipids may be present to improve stability, fusogenicity, endosomal escape, tolerability/safety, efficacy, tissue tropism/targeting, etc.
  • Therapeutic Nucleic Acids (TNA) may be present to improve stability, fusogenicity, endosomal escape, tolerability/safety, efficacy, tissue tropism/targeting, etc.
  • the lipid particles of the present invention comprise a payload/cargo.
  • the payload is therapeutic nucleic acid (TNA).
  • TNA therapeutic nucleic acid
  • the length of the TNA can vary and include nucleic acid of 5-50,000 nucleotides in length.
  • the nucleic acid can be in any form, including single-stranded DNA, singlestranded RNA, double-stranded DNA or double-stranded RNA, or hybrids thereof.
  • the nucleotides may be modified, unmodified or a combination thereof.
  • the TNA may be chemically synthesized. Synthesis of mRNA includes in vitro transcription.
  • the TNA is selected from the group consisting of minigenes, plasmids, minicircles, antisense oligonucleotides (ASO), enhancer RNA (eRNA), aptamers, closed-ended (ceDNA), ministring, doggybone, protelomere closed ended DNA, dumbbell linear DNA, asymmetrical interfering RNA (aiRNA), microRNA (miRNA), messenger RNA (mRNA), small interfering RNA (siRNA), small activating RNA (saRNA), self-amplifying RNA (SAM), ribozymes, dicer substrate dsRNA, small hairpin RNA (shRNA), tRNA, tRNA derived RNA fragments (tRFs), rRNA, piwi-interacting RNA (piRNA), guide RNA (gRNA), DNA viral vectors, viral RNA vector, non-viral vector, transposable elements, including retrotransposons, e.g., class I (e.g., Long Terminal Repeat (
  • the payload of an LNP may include more than one TNA.
  • a guide RNA gRNA
  • gRNA guide RNA
  • LNP preparations containing different TNAs may be combined into a single formulation.
  • the LNPs of the invention are useful in methods of gene therapy and may comprise, mRNA encoding a therapeutic protein of interest or a protein/enzyme enabling the method.
  • the mRNA may encode: 1. Genome editing enzymes, including: a) endonucleases (e.g., ZFN (Zinc Finger Nucleases), TALEN (Transcription Activator-Like Effector Nucleases), Cas9 (CRISPR-Cas9), Casl2a (Cpfl), and CasX, CasY, Casd) (theta)); b) Base Editors (e.g., cytidine deaminase (e.g., APOBEC1), adenosine deaminase (e.g., TadA), and Cas9 nickase fused with deaminase); c) Prime Editors (e.g., Cas9 nickase + reverse transcriptase (
  • Gene addition and vector integration enzymes including: a) Integrases (e.g., HIV-1 integrase, Cp(theta)C31 integrase, Bxbl integrase, TP901-1 integrase and A118 integrase; b) Transposases (e.g., PiggyBac Transposase, Sleeping Beauty Transposase (SB100X) and Tol2 Transposase); 3.
  • Integrases e.g., HIV-1 integrase, Cp(theta)C31 integrase, Bxbl integrase, TP901-1 integrase and A118 integrase
  • Transposases e.g., PiggyBac Transposase, Sleeping Beauty Transposase (SB100X) and Tol2 Transposase
  • RNA-based enzymes in gene therapy including: a) RNA-targeting CRISPR Enzymes Casl3a, Casl3b, Casl3d; b) Reverse transcriptase (RT) (e.g., Moloney Murine Leukemia Virus RT (M-MLV RT) and HIV-1 RT); and c) RNA deaminases (e.g., ADAR (Adenosine Deaminases Acting on RNA), REPAIR system and LEAPER); 4. DNA repair enzymes (e.g., DNA Ligase IV, Rad51, BRCA1, BRCA2 and POLQ); and 5.
  • Nickases e.g., Cas9n (Cas9 nickase).
  • Additional payload nucleic acids used in the methods include: sgRNA/ crRNA (CRISPR RNA)/ tracrRNA (trans-activating crRNA)(CRISPR (Cas9, Casl2)), pegRNA/RNA donor templates (Prime editing), gRNA for Casl3 (RNA guide)(CRISPR-Casl3), ssODN/dsDNA (CRISPR, ZFN, TALEN), ASO (antisense oligonucleotides)/miRNA mimics (SMA, cancer, rare diseases), AAV donor template/plasmid DNA (Viral vector systems), Transposon DNA (with ITRs) (Sleeping Beauty, PiggyBac), circRNA/saRNA (LNP-based delivery), scaffold RNA (SAM, scRNA)(CRISPRa/i), and attP/attB DNA sites (site-specific integration (e.g., (PC31 integrase).
  • the LNP has a
  • a preferred payload of an LNP of the present invention is an mRNA.
  • An mRNA of the invention may include a nucleic acid sequence encoding a polypeptide of interest (e.g., a coding region), a first flanking untranslated region (UTR) located at the 5'-terminus of the first region (e.g., a 5'-UTR), a second flanking region located at the 3'-terminus of the first region (e.g., a 3'-UTR), at least one 5'-cap region, and a 3 '-stabilizing region.
  • a messenger RNA further includes a poly-A region or a Kozak sequence (e.g., in the 5'-UTR).
  • messenger RNAs may contain one or more intronic sequences capable of being excised from the messenger RNA.
  • a messenger RNA may include a 5' cap structure, a chain terminating nucleotide, a stem loop, a poly A sequence, and/or a polyadenylation signal. Any one of the regions of a messenger RNA may include one or more alternative components (e.g., an alternative nucleoside).
  • the 3'- stabilizing region may contain an alternative nucleoside such as an L-nucleoside, an inverted thymidine, or a 2'- O-methyl nucleoside and/or the coding region, 5'-UTR, 3'- UTR, or cap region may include an alternative nucleoside such as a 5 -substituted uridine (e.g., 5-methoxy uridine), a 1-substituted pseudouridine (e.g., 1-methyl-pseudo uridine or 1-ethyl-pseudo uridine), and/or a 5-substituted cytidine (e.g., 5-methyl-cytidine).
  • an alternative nucleoside such as an L-nucleoside, an inverted thymidine, or a 2'- O-methyl nucleoside
  • the coding region, 5'-UTR, 3'- UTR, or cap region may include an alternative nucleo
  • An mRNA of the invention may include an internal ribosome entry site (IRES).
  • IRES may act as a sole ribosome binding site, or as one of multiple ribosome binding sites.
  • a messenger RNA containing more than one functional ribosome binding site may encode several peptides or polypeptides that are translated independently by the ribosomes. Suitable IRES sequences that may be useful include those from picomaviruses (e.g.
  • mRNA of the invention may comprise a first region of linked nucleosides encoding an antigenic polypeptide, a first flanking region located at the 5'-terminus of the first region (e.g., a 5'-UTR), a second flanking region located at the 3'-terminus of the first region (e.g., a 3'-UTR), at least one 5'-cap region, and a 3'- stabilizing region.
  • Messenger RNA nucleotides may be naturally or non-naturally occurring.
  • the 5'-UTR, (b) the open reading frame (ORF), (c) the 3'-UTR, (d) the poly A tail, and any combination of (a, b, c, or d above) comprise naturally occurring canonical nucleotides A (adenosine), G (guanosine), C (cytosine), U (uridine), or T (thymidine).
  • the nucleobase is an alternative uracil.
  • nucleobases and nucleosides having an alternative uracil include pseudouridine (psi), pyridin-4-one ribonucleoside, 5-aza-uracil, 6-aza-uracil, 2-thio-5-aza-uracil, 2-thio- uracil (s2U), 4-thio-uracil (s4U),
  • 5-iodo-uracil or 5-bromo-uracil 3-methyl-uracil (m3U), 5-methoxy-uracil (mo5U), uracil 5-oxyacetic acid (cmo5U), uracil 5-oxyacetic acid methyl ester (mcmo5U), 5-carboxymethyl- uracil (cm5U), 1 - carboxymethyl-pseudo uridine, 5-carboxyhydroxymethyl- uracil (chm5U), 5-carboxyhydroxymethyl- uracil methyl ester (mchm5U), 5-methoxycarbonylmethyl- uracil (mcm5U), 5- methoxycarbonylmethyl-2-thio-uracil (mcm5s2U), 5-aminomethyl- 2-thio-uracil (nm5s2U), 5-aminomethyl- 2-thio-uracil (nm5s2U), 5-methylaminomethyl-uracil (mnm5
  • the mRNA one or more alternative components which impart useful properties including increased stability and/or the lack of a substantial induction of the innate immune response of a cell into which the poly messenger RNA is introduced.
  • an alternative messenger RNA exhibits reduced degradation in a cell into which the messenger RNA is introduced, relative to a corresponding unaltered messenger RNA.
  • These alternative species may enhance the efficiency of protein production, intracellular retention of the messenger RNA, and/or viability of contacted cells, as well as possess reduced immunogenicity.
  • the nucleobase is an alternative cytosine.
  • Exemplary nucleobases and nucleosides having an alternative cytosine include 5-aza-cytosine, 6-aza-cytosine, pseudoisocytidine, 3-methyl-cytosine (m3C), N4-acetyl-cytosine (ac4C), 5-formyl-cytosine (f5C), N4-methyl-cytosine (m4C), 5-methyl-cytosine (m5C), 5-halo-cytosine (e.g., 5-iodo-cytosine), 5-hydroxymethyl-cytosine (hm5C), 1-methyl-pseudoisocytidine, pyrrolo-cytosine, pyrrolo-pseudoisocytidine, 2-thio-cytosine (s2C), 2-thio-5-methyl-cytosine, 4-thio-pseudoisocytidine, 4-thio-l-methyl-pseudoi
  • the modified cytosine is 5-methyl-cytosine.
  • the nucleobase is an alternative adenine.
  • Exemplary nucleobases and nucleosides having an alternative adenine include 2-amino-purine, 2,6- diaminopurine, 2-amino-6-halo-purine (e.g., 2- amino-6-chloro-purine), 6-halo-purine (e.g., 6-chloro-purine), 2-amino-6-methyl-purine, 8-azido- adenine, 7-deaza-adenine, 7-deaza-8-aza-adenine, 7-deaza-2-amino-purine, 7-deaza-8-aza-2-amino- purine, 7-deaza-2,6-diaminopurine, 7-deaza-8-aza-2,6-diaminopurine, 1-methyl-adenine (mlA), 2- methyl-adenine (m
  • the nucleobase is an alternative guanine.
  • Exemplary nucleobases and nucleosides having an alternative guanine include inosine (I), 1-methyl-inosine (mil), wyosine (imG), methylwyosine (mimG), 4-demethyl-wyosine (imG-14), iso wyo sine (imG2), wybutosine (yW), peroxywybutosine (o2yW), hydroxywybutosine (OHyW), undermodified hydroxywybutosine (OHyW*), 7-deaza-guanine, queuosine (Q), epoxyqueuosine (oQ), galacto syl-queuo sine (galQ), manno syl-queuo sine (manQ), 7-cyano-7-deaza-guanine (preQO), 7-aminomethyl-7-deaza-guanine (preQi), arch
  • the alternative nucleobase of a nucleotide can be independently a purine, a pyrimidine, a purine or pyrimidine analog.
  • the nucleobase can be an alternative to adenine, cytosine, guanine, uracil, or hypoxanthine.
  • the nucleobase can also include, for example, naturally-occurring and synthetic derivatives of a base, including pyrazolo[3,4-d]pyrimidines, 5- methylcytosine (5-me-C), 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6- methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine and thymine, 5-uracil (pseudo uracil), 4-thiouracil, 8-halo (e.g., 8-bromo), 8- amino, 8-thiol, 8-thioalkyl, 8-hydroxy and other 8-substituted adenines
  • Messenger RNA may be prepared according to any available technique known in the art.
  • Messenger RNA may be prepared by, for example, enzymatic synthesis which provides a process of template-directed synthesis of RNA molecules from an engineered DNA template comprised of an upstream bacteriophage promoter sequence linked to a downstream sequence encoding the gene of interest.
  • Template DNA can be prepared for in vitro transcription from several sources with appropriate techniques which are well known in the art including, but not limited to, plasmid DNA and polymerase chain reaction amplification.
  • RNA polymerase adenosine, guanosine, uridine and cytidine ribonucleoside triphosphates (rNTPs) under conditions that support polymerase activity while minimizing potential degradation of the resultant mRNA transcripts.
  • rNTPs ribonucleoside triphosphates
  • In vitro transcription can be performed using a variety of commercially available kits including but not limited to RiboMax Large Scale RNA Production System (Promega), MegaScript Transcription kits (Life Technologies) as well as with commercially available reagents including RNA polymerases and rNTPs.
  • the methodology for in vitro transcription of mRNA is well-known in the art.
  • the desired in vitro transcribed messenger RNA is then purified from the undesired components of the transcription or associated reactions.
  • Techniques for the isolation of the messenger RNA transcripts are well known in the art and include phenol/chloroform extraction or precipitation with either alcohol in the presence of monovalent cations or lithium chloride.
  • the messenger RNA associated with the LNP is a self-amplifying messenger RNA (SAM) molecule.
  • SAM messenger RNA
  • the SAM is derived from or based on an alphavirus.
  • Such SAM molecules are known in the art and can be produced using replication elements derived from, for example, alphaviruses substituting the structural viral proteins with a nucleotide sequence encoding a protein of interest.
  • the target cell to which the SAM is delivered generates an exponential increase of encoded gene products, such as proteins or antigens, which can accumulate in the cells or be secreted therefrom.
  • the SAM may contain one or more genes selected from the group consisting of viral replicases, viral proteases, viral helicases and other nonstructural viral proteins, and may also comprise 5'- and 3'-end cis-active replication sequences and, optionally, a heterologous sequence that encodes a desired amino acid sequence.
  • a subgenomic promoter that directs expression of the heterologous sequence may be present.
  • the heterologous sequence may be fused in frame to other coding regions in the SAM and/or be under the control of an internal ribosome entry site (IRES).
  • IRS internal ribosome entry site
  • the RNA associated with the LNP is a small activating RNA (saRNA), which is a TNA that causes enhancement of endogenous messenger RNA transcription.
  • saRNA small activating RNA
  • the saRNA molecules are small double-stranded nucleic acids (See e.g., Voutila et al. Mol Ther. 2017 Dec 6;25(12):2705-2714).
  • the RNA of the invention may encode one or more polypeptide antigens that contain a range of epitopes such as epitopes capable of eliciting either a helper T-cell response or a cytotoxic T-cell response, or both via antigen presentation by professional antigen presenting cells (APCs) or other presenting cells including somatic cells and followed by a humoral response mediated by B-cells.
  • the RNA may be engineered to express multiple nucleotide sequences, from two or more open reading frames, thereby allowing co- expression of proteins, such as two or more antigens together with cytokines or other immunomodulators, which can enhance the generation of an immune response.
  • RNA including mRNA and self-amplifying RNA
  • An RNA molecule that contains modified nucleotides can be prepared by transcribing a DNA that encodes the RNA molecule using a suitable DNA-dependent RNA polymerase, such as T7 phage RNA polymerase, SP6 phage RNA polymerase, T3 phage RNA polymerase, and the like, or mutants of the polymerases which allow efficient incorporation of modified nucleotides into RNA.
  • a suitable DNA-dependent RNA polymerase such as T7 phage RNA polymerase, SP6 phage RNA polymerase, T3 phage RNA polymerase, and the like, or mutants of the polymerases which allow efficient incorporation of modified nucleotides into RNA.
  • RNA may be employed to alter the stability of such RNA molecule, to increase resistance against RNases, to establish replication after introduction into appropriate host cells ("infectivity" of the RNA), and/or to induce or reduce innate and adaptive immune responses.
  • LNPs of the invention can be made using approaches which are well-known in the art of formulation.
  • suitable LNPs can be formed using mixing processes such as microfluidics, including herringbone micromixing, and T-junction mixing of two fluid streams, one of which contains an RNA, e.g., mRNA, typically in an aqueous solution, and the other of which has the various required lipid components, typically in ethanol.
  • Lipid particles can form spontaneously upon mixing of the nucleic acid, e.g., mRNA, and the lipid(s).
  • the resultant nanoparticle mixture can be extruded through a membrane (e.g., 100 nm cut-off) using, for example, a thermobarrel extruder, such as Lipex Extruder (Evonik).
  • a thermobarrel extruder such as Lipex Extruder (Evonik).
  • the extrusion step can be omitted. Ethanol removal and simultaneous buffer exchange can be accomplished by, for example, dialysis or tangential flow filtration.
  • the lipid nanoparticles are formed as described in Example 3 described in U.S. Provisional Application No. 63/194,620.
  • LNPs Methods for preparing LNPs are disclosed, e.g., in W02022/261101 WO2019051289, US2013/0037977, US2010/0015218, US2013/0156845, US2013/0164400, US2012/0225129, US2010/0130588, US2007/0042031, US2004/0142025, Kulkarni et al., 2018, ACS Nano, 12:4787 and Kulkarni et al., 2017, Nanoscale, 36: 133347, the content of each of which is incorporated herein by reference in its entirety.
  • lipid particles e.g., lipid nanoparticles
  • lipid particles can be prepared using a continuous mixing method, a direct dilution process, or an in-line dilution process.
  • the processes and apparatuses for apparatuses for preparing lipid nanoparticles using direct dilution and in-line dilution processes are described, e.g., in US2007/0042031.
  • the processes and apparatuses for preparing lipid nanoparticles using stepwise dilution processes are described in US2004/0142025.
  • a general small-scale formulation can be prepared as follows: An mRNA solution and an anhydrous ethanol lipid solution are prepared for mixing. mRNA/acidic buffer mRNA stream is prepared in acidic buffer at a concentration between 0.05 to 0.25 mg/mL in either sodium acetate, sodium citrate or other appropriate acid with buffer at a molar concentration ranging from about 10 to about 100 mM at a pH between 3 to 6. For certain formulations, sodium chloride (NaCI) can be added to the acidic buffer up to 150 mM.
  • NaCI sodium chloride
  • Lipids are a mixture of several components dissolved in anhydrous ethanol.
  • the lipid mixture typically comprises four components: ionizable lipid(s), phospholipid(s) (e.g. DSPC and DOPE), sterol(s) (e.g. cholesterol), and polymer conjugated lipid(s) (e.g. PEG-lipid such as DMG-PEG2k).
  • ionizable lipid(s) e.g. DSPC and DOPE
  • sterol(s) e.g. cholesterol
  • polymer conjugated lipid(s) e.g. PEG-lipid such as DMG-PEG2k
  • PEG-lipid 1 to 3%
  • the concentration of the lipid mixture is a function of the N:P ratio.
  • the N:P ratio is the molar ratio of ionizable amine of ionizable lipids (N) to phosphate group of mRNA (P).
  • the N:P ratio generally ranges from 3 to 6.
  • the lipid mixture concentration in ethanol generally ranges from 3 to 18 mg/mL.
  • the mixing volume ratio of lipid/ethanol to mRNA/acidic buffer is typically 1 to 3.
  • mRNA stream and lipid stream can be mixed through different types of mixers such as microTee mixer, microfluidics, vortex mixer.
  • pipette mixing can also be adapted for a very small-scale formulation.
  • lipids/ethanol can be added into mRNA/acidic buffers using a pipette or liquid handler.
  • the mixing volume of lipid/ethanol to mRNA/acidic buffer is typically 1:3.
  • buffer exchange will be performed to rapidly reduce the level of ethanol percentage and increase pH.
  • Buffer exchange can be done through performing dialysis, using a desalting column combined with centrifuge, or dilution with a storage buffer.
  • Concentration is needed if a higher concentration than the output is required.
  • concentration is typically carried out using a centrifugal filter combined with centrifuge.
  • sterile filtration is conducted through passing the LNP solution through a 0.22 um sterile filter.
  • the disclosure provides for an LNP comprising a TNA and an ionizable lipid.
  • a lipid nanoparticle formulation that is made and loaded with a TNA is disclosed in WO2019051289.
  • the lipid particles e.g., lipid nanoparticles
  • the TNA is encapsulated in the lipid(s) thereby protecting it from degradation by a nuclease, e.g., in an aqueous solution.
  • the TNA in the lipid nanoparticle is not substantially degraded after exposure of the lipid particle to a nuclease at 37°C. for at least about 20, 30, 45, or 60 minutes.
  • the efficiency of encapsulation of the TNA, e.g., mRNA, within the LNPs may be at least 50%, for example about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%.
  • the encapsulation efficiency may be at least 80%. In certain embodiments, the encapsulation efficiency may be at least 90%.
  • the lipid particle formulation is an aqueous, non-viscous and opaque nanosuspension.
  • the lipid particle (e.g., lipid nanoparticle) formulation is a lyophilized powder.
  • the disclosure provides for a lipid particle formulation further comprising one or more pharmaceutical excipients.
  • the lipid particle (e.g., lipid nanoparticle) formulation further comprises sucrose, tris buffer, trehalose and/or glycine.
  • Pharmaceutical compositions for therapeutic purposes can be formulated as a solution, microemulsion, dispersion, liposomes, or other ordered structure suitable for high TNA (e.g., mRNA) concentration.
  • Sterile injectable solutions can be prepared by incorporating the TNA (e.g., mRNA) in the required amount in an appropriate buffer (e.g., pharmaceutically acceptable excipient) with one or a combination of ingredients enumerated above, as required, followed by filtration sterilization.
  • lipid particles e.g., lipid nanoparticles
  • the lipid particles have a non- bilayer structure, i.e., a non-lamellar (i.e., non-bilayer) morphology.
  • the non- bilayer morphology can include, for example, three dimensional tubes, rods, cubic symmetries, etc.
  • the non-lamellar morphology (i.e., non-bilayer structure) of the lipid particles (e.g., lipid nanoparticles) can be determined using analytical techniques known to and used by those of skill in the art. Such techniques include, but are not limited to, Cryo-Transmission Electron Microscopy ("Cryo-TEM”), Differential Scanning calorimetry (“DSC”), X-Ray Diffraction, and the like.
  • the lipid particles (e.g., lipid nanoparticles) having a non-lamellar morphology are electron dense.
  • the disclosure provides for a lipid particle (e.g., lipid nanoparticle) that is either unilamellar or multilamellar in structure.
  • the disclosure provides for a lipid particle (e.g., lipid nanoparticle) formulation that comprises multi-vesicular particles and/or foam-based particles.
  • composition and concentration of the lipid components By controlling the composition and concentration of the lipid components, one can control the rate at which the lipid conjugate exchanges out of the lipid particle and, in turn, the rate at which the lipid particle (e.g., lipid nanoparticle) becomes fusogenic.
  • other variables including, for example, pH, temperature, or ionic strength, can be used to vary and/or control the rate at which the lipid particle (e.g., lipid nanoparticle) becomes fusogenic.
  • concentration of the lipid conjugate By controlling the composition and concentration of the lipid conjugate, one can control the lipid particle size.
  • the pKa' of formulated cationic lipids can be correlated with the effectiveness of the LNPs for delivery of nucleic acids (see Jayaraman et al., Angewandte Chemie, International Edition (2012), 51(34), 8529- 8533; Semple et al., Nature Biotechnology 28, 172-176 (2010), both of which are incorporated by reference in their entireties).
  • the preferred range of pKa' for the ionizable lipid particle is about 6-7.
  • the pKa' of the ionizable lipid can be determined in lipid particles (e.g., lipid nanoparticles) using an assay based on fluorescence of 2-(p-toluidino)-6- napthalene sulfonic acid (TNS).
  • lipid particles e.g., lipid nanoparticles
  • TMS 2-(p-toluidino)-6- napthalene sulfonic acid
  • compositions or formulations can optionally comprise one or more additional active substances, e.g., therapeutically and/or prophylactically active substances.
  • Pharmaceutical compositions or formulations of the present invention can be sterile and/or pyrogen-free. General considerations in the formulation and/or manufacture of pharmaceutical agents can be found, for example, in Remington: The Science and Practice of Pharmacy 21st ed., Lippincott Williams & Wilkins, 2005 (incorporated herein by reference in its entirety).
  • compositions are administered to humans, human patients or subjects.
  • the phrase "active ingredient" generally refers to a TNA, e.g., mRNA, to be delivered as described herein.
  • Formulations and pharmaceutical compositions described herein can be prepared by any method known or hereafter developed in the art of pharmacology.
  • a pharmaceutical composition or formulation in accordance with the present disclosure can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses.
  • a "unit dose" refers to a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
  • the amount of the active ingredient is generally equal to the dosage of the active ingredient that would be administered to a subject and/or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.
  • compositions and formulations described herein may contain at least one TNA, such as a mRNA.
  • the composition or formulation can contain 1, 2, 3, 4 or 5 TNAs.
  • the composition or formulation can comprise a TNA in linear and/or circular form, and in single-stranded, double-stranded, triplex and quadriplex form.
  • compositions and formulations are principally directed to pharmaceutical compositions and formulations that are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to any other animal, e.g., to non-human animals, e.g., non-human mammals.
  • Pharmaceutically acceptable excipient includes, but are not limited to, any and all solvents, dispersion media, or other liquid vehicles, dispersion or suspension aids, diluents, granulating and/or dispersing agents, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, binders, lubricants or oil, coloring, sweetening or flavoring agents, stabilizers, antioxidants, antimicrobial or antifungal agents, osmolality adjusting agents, pH adjusting agents, buffers, chelators, cyoprotectants, anticacking and humectants, deflocculating agents and/or bulking crosslinked polyvinyl pyrrolidone (crospovidone), cellulose, methylcellulose, carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), magnesium aluminum silicate (VEEGUM®), sodium lauryl sulfate, etc., and/or combinations thereof.
  • crospovidone
  • Exemplary surface active agents and/or emulsifiers include, but are not limited to, natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monooleate [TWEEN®80], sorbitan monopalmitate [SPAN®40], glyceryl monooleate, polyoxyethylene esters, polyethylene glycol fatty acid esters (e.g., CREMOPHOR®), polyoxyethylene ethers (e.g., polyoxyethylene lauryl ether [BRIJ®30]), PLURONIC® block copolymers, e.g.
  • natural emulsifiers e.g., acacia, agar, al
  • binding agents include, but are not limited to, starch, gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol), sugar cyclic analogs (cyclodextrins, alpha, beta, gamma, delta), amino acids (e.g., glycine), natural and synthetic gums (e.g., acacia, sodium alginate), ethylcellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose, etc., and combinations thereof.
  • sugars e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol
  • sugar cyclic analogs cyclodextrins, alpha, beta, gamma, delta
  • amino acids e.g., glycine
  • natural and synthetic gums e.g.,
  • Oxidation is a potential degradation pathway for TNAs, especially for liquid or freeze-dried DNA formulations.
  • antioxidants and chelators can be added to the formulations.
  • Exemplary antioxidants include, but are not limited to, alpha tocopherol, ascorbic acid, ascorbyl palmitate, benzyl alcohol, butylated hydroxyanisole, m-cresol, methionine, butylated hydroxytoluene, monothioglycerol, sodium or potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, etc., and combinations thereof.
  • Exemplary chelating agents include, but are not limited to, ethylenediaminetetraacetic acid (EDTA), disodium edetate, diethylenetriaminepentaacetic acid (DTPA, in ionized forms), citric acid monohydrate, maleic acid, fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaric acid, trisodium edetate, etc., and combinations thereof.
  • EDTA ethylenediaminetetraacetic acid
  • DTPA diethylenetriaminepentaacetic acid
  • citric acid monohydrate maleic acid, fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaric acid, trisodium edetate, etc., and combinations thereof.
  • antimicrobial or antifungal agents include, but are not limited to, benzalkonium chloride, benzethonium chloride, methyl paraben, ethyl paraben, propyl paraben, butyl paraben, benzoic acid, hydroxybenzoic acid, potassium or sodium benzoate, potassium or sodium sorbate, sodium propionate, sorbic acid, etc., and combinations thereof.
  • Exemplary preservatives include, but are not limited to, vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, ascorbic acid, butylated hydroxyanisole, ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), p- amino benzoic acid, methyl and/or propyl parabens, etc., and combinations thereof.
  • the pH of polynucleotide solutions is maintained between pH 5 and pH 8 to improve stability.
  • Exemplary buffers to control pH can include, but are not limited to sodium phosphate, sodium citrate, sodium succinate, histidine (or histidine acid salts), sodium malate, sodium carbonate, etc., and/or combinations thereof.
  • Exemplary lubricating agents include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium or magnesium lauryl sulfate, etc., and combinations thereof.
  • the pharmaceutical composition or formulation described here can contain a cryoprotectant to stabilize a polynucleotide described herein during freezing.
  • cryoprotectants include, but are not limited to mannitol, sucrose, trehalose, lactose, glycerol, dextrose, etc., and combinations thereof.
  • the pharmaceutical composition or formulation described here can contain a bulking agent in lyophilized polynucleotide formulations to yield a "pharmaceutically elegant" cake, stabilize the lyophilized polynucleotides during long term (e.g., 36-month) storage.
  • Exemplary bulking agents of the present invention can include, but are not limited to sucrose, trehalose, mannitol, glycine, lactose, raffinose, and combinations thereof.
  • the pharmaceutical composition or formulation further comprises a delivery agent.
  • the delivery agent of the present disclosure can include, without limitation, liposomes, lipid nanoparticles, lipidoids, polymers, saccharides, dextrans, cyclodextrins, lipoplexes, microvesicles, exosomes, peptides, proteins, cells transfected with polynucleotides, hyaluronidase, nanoparticle mimics, nanotubes, conjugates, and combinations thereof.
  • the pharmaceutical compositions can be presented in unit dosage form.
  • a unit dosage form will typically be adapted to one or more specific routes of administration of the pharmaceutical composition.
  • the unit dosage form is adapted for intravenous, intramuscular, or subcutaneous administration.
  • the unit dosage form is adapted for intrathecal or intracerebroventricular administration.
  • the unit dosage form is adapted for administration by inhalation.
  • the unit dosage form is adapted for administration by a vaporizer or spray device.
  • the unit dosage form is adapted for administration by a nebulizer.
  • the unit dosage form is adapted for administration by an aerosolizer.
  • the unit dosage form is adapted for oral administration, for buccal administration, or for sublingual administration.
  • the pharmaceutical composition is formulated for topical administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect.
  • the LNP/TNA is for administration at a dose of about 0.02 ⁇ g to about 50 mg, about 0.02 ⁇ g to about 0.2 ⁇ g, or about 0.2 ⁇ g to about 2.0 ⁇ g, about 1 ⁇ g to about 25 ⁇ g, about 25 ⁇ g to about 50 ⁇ g, about 50 ⁇ g to about 100 ⁇ g, about 100 ⁇ g to about 200 ⁇ g, about 200 ⁇ g to about 300 ⁇ g, about 300 ⁇ g to about 400 ⁇ g, about 400 ⁇ g to about 500 ⁇ g, about 500 ⁇ g to about 750 ⁇ g, about 750 ⁇ g to about 1.0 mg, about 1 mg to about 10 mg, about 10 mg to about 25 mg, about 25 mg to about 50 mg, about 50 mg to about 100 mg.
  • the pharmaceutical compositions comprising a lipid nanoparticle (LNP) and a therapeutic nucleic acid (TNA) can be used to introduce a nucleic acid sequence (e.g., a TNA) into a host cell.
  • a nucleic acid sequence e.g., a TNA
  • the host cell is in vitro.
  • the host cell is in vivo.
  • the subject is a human.
  • introduction of a nucleic acid sequence in a host cell using the pharmaceutical compositions comprising a lipid nanoparticle (LNP) and a therapeutic nucleic acid (TNA), as described herein can be monitored with appropriate biomarkers from treated patients to assess gene expression.
  • a disease, disorder or condition in a subject comprising introducing into a cell in need thereof (for example, a muscle cell or tissue, or other affected cell type) of the subject a therapeutically effective amount of pharmaceutical composition comprising a lipid nanoparticle (LNP) and a therapeutic nucleic acid (TNA), wherein the LNP comprises an ApoE polypeptide, or a fragment thereof and/or an ApoB polypeptide, or a fragment thereof, linked to the LNP.
  • TNA lipid nanoparticles can be introduced in the presence of a carrier, such a carrier is not required.
  • methods for providing a subject in need thereof with a diagnostically- or therapeutically- effective amount of the pharmaceutical composition comprising an LNP and a TNA or combination of TNAs are provided herein.
  • the pharmaceutical composition comprising an LNP and a TNA can be used to deliver any TNA in accordance with the description above to treat, prevent, or ameliorate the symptoms associated with any disease, disorder or condition related to gene expression.
  • disease states include, but are not-limited to: cystic fibrosis (and other diseases of the lung), hemophilia A, hemophilia B, thalassemia, anemia and other blood disorders, AIDS, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, epilepsy, and other neurological disorders, cancer, diabetes mellitus, muscular dystrophies (e.g., Duchenne, Becker), Hurler's disease, adenosine deaminase deficiency, metabolic defects, retinal degenerative diseases (and other diseases of the eye), mitochondriopathies (e.g., Leber's hereditary optic neuropathy (LHON), Leigh syndrome, and subacute sclerosing ence
  • the ceDNA vectors as disclosed herein can be advantageously used in the treatment of individuals with metabolic disorders (e.g., ornithine transcarbamoylase deficiency).
  • the pharmaceutical composition comprising an LNP and a TNA can be used to treat, ameliorate, and/or prevent a disease or disorder caused by mutation in a gene or gene product (i.e., a genetic disorder) include, but are not limited to, metabolic diseases or disorders (e.g., Fabry disease, Gaucher disease, phenylketonuria (PKU), glycogen storage disease); urea cycle diseases or disorders (e.g., ornithine transcarbamoylase (OTC) deficiency); lysosomal storage diseases or disorders (e.g., metachromatic leukodystrophy (MLD), mucopolysaccharidosis Type II (MPSII; Hunter syndrome)); liver diseases or disorders (e.g., progressive familial intrahepatic cholesta
  • metabolic diseases or disorders
  • the genetic disorder is hemophilia A, hemophilia B, phenylketonuria (PKU, Gaucher disease Types I, II and III, Stargardt macular dystrophy, Leber congenital amaurosis (LCA), Usher syndrome, wet AMD.
  • the pharmaceutical composition comprising an LNP and a TNA may be employed to deliver a heterologous nucleotide sequence, e.g., to correct an abnormal level and/or function of a gene product, such as an absence of, or a defect in, a protein, that results in the disease or disorder.
  • the TNA in lipid nanoparticles as described herein can produce a functional protein and/or modify levels of the protein to alleviate or reduce symptoms resulting from, or confer benefit to, a particular disease or disorder caused by the absence or a defect in the protein.
  • the TNA may be used for production of a functional protein or increased expression of a protein, such as OTC enzyme, CPS1 enzyme, GSDla enzyme, Factor VIII, Factor IX, and Factor X, phenylalanine hydroxylase enzyme, alpha galactosidase or beta glucocerebrosidase, arylsulfatase A, iduronate-2-sulfatase, cystic fibrosis transmembrane conductance regulator, G6Pase enzyme, ATP8B 1, ABCB 11, ABCB4, or TJP2.
  • exemplary TNA encode a protein selected from: lysosomal enzymes (e.g., hexosaminidase A, iduronate sulfatase, associated, erythropoietin, angiostatin, endostatin, superoxide dismutase, globin, leptin, catalase, tyrosine hydroxylase, as well as cytokines (e.g., a interferon, b-interferon, interferon-gamma, interleukin-2, interleukin-4, interleukin 12, granulocytemacrophage colony stimulating factor, lymphotoxin, and the like), peptide growth factors and hormones (e.g., somatotropin, insulin, insulin-like growth factors 1 and 2, platelet derived growth factor (PDGF), epidermal growth factor (EGF), fibroblast growth factor (FGF), nerve growth factor (NGF), neurotrophic factor-3 and 4, brain-
  • the transgene encodes a monoclonal antibody specific for one or more desired targets.
  • the antibody may be a full- length antibody, bispecific, or antibody fragment, e.g., antigen binding fragment, thereof.
  • the pharmaceutical compositions comprising a lipid nanoparticle (LNP) and a therapeutic nucleic acid (TNA), as described herein, can be administered to an organism for transduction of cells in vivo.
  • the TNA can be administered to an organism for transduction of cells ex vivo.
  • administration is by any of the routes normally used for introducing a molecule into ultimate contact with blood or tissue cells. Suitable methods of administering such nucleic acids are available and well known to those of skill in the art, and, although more than one route can be used to administer a particular composition, a particular route can often provide a more immediate and more effective reaction than another route.
  • Exemplary modes of administration of the pharmaceutical composition of the invention include oral, rectal, transmucosal, intranasal, inhalation (e.g., via an aerosol, soft-mist or dry powder), buccal (e.g., sublingual), vaginal, intrathecal, intraocular, transdermal, intraendothelial, in utero (or in ovo), parenteral (e.g., intravenous, subcutaneous, intradermal, intracranial, intramuscular [including administration to skeletal, diaphragm and/or cardiac muscle], intrapleural, intracerebral, and intraarticular), topical (e.g., to both skin and mucosal surfaces, including airway surfaces, and transdermal administration), intralymphatic, intranodal and the like, as well as direct tissue or organ injection (e.g., to liver, eye, skeletal muscle, cardiac muscle, diaphragm muscle or brain).
  • buccal e.g., sublingual
  • vaginal intrat
  • Administration of the pharmaceutical composition can be to any site in a subject, including, without limitation, a site selected from the group consisting of the brain, a skeletal muscle, a smooth muscle, the heart, the diaphragm, the airway epithelium, the liver, the kidney, the spleen, the pancreas, the skin, and the eye.
  • the pharmaceutical composition can be administered to skeletal muscle includes but is not limited to administration to skeletal muscle in the limbs (e.g., upper arm, lower arm, upper leg, and/or lower leg), back, neck, head (e.g., tongue), thorax, abdomen, pelvis/perineum, and/or digits, by intravenous administration, intraarterial administration, intraperitoneal administration, limb perfusion, (optionally, isolated limb perfusion of a leg and/or arm; see, e.g., Arruda et al. 2005, Blood 105: 3458-3464), and/or direct intramuscular injection.
  • limbs e.g., upper arm, lower arm, upper leg, and/or lower leg
  • head e.g., tongue
  • thorax e.g., abdomen, pelvis/perineum, and/or digits
  • intravenous administration e.g., intraarterial administration, intraperitoneal administration, limb perfusion, (optionally,
  • pharmaceutical composition is administered to cardiac muscle, including left atrium, right atrium, left ventricle, right ventricle and/or septum, e.g., by intravenous administration, intra-arterial administration such as intra-aortic administration, direct cardiac injection (e.g., into left atrium, right atrium, left ventricle, right ventricle), and/or coronary artery perfusion.
  • intravenous administration intra-arterial administration such as intra-aortic administration
  • direct cardiac injection e.g., into left atrium, right atrium, left ventricle, right ventricle
  • coronary artery perfusion e.g., coronary artery perfusion.
  • Administration to diaphragm muscle can be by any suitable method including intravenous administration, intra-arterial administration, and/or intra-peritoneal administration.
  • Administration to smooth muscle can be by any suitable method including intravenous administration, intra-arterial administration, and/or intra-peritoneal administration.
  • administration can be to endothelial cells present in, near, and/or on smooth muscle.
  • pharmaceutical composition comprising is administered to the CNS (e.g., to the brain or to the eye).
  • the pharmaceutical composition may be introduced into the spinal cord, brainstem (medulla oblongata, pons), midbrain (hypothalamus, thalamus, epithalamus, pituitary gland, substantia nigra, pineal gland), cerebellum, telencephalon (corpus striatum, cerebrum including the occipital, temporal, parietal and frontal lobes, cortex, basal ganglia, hippocampus and porta amygdala), limbic system, neocortex, corpus striatum, cerebrum, and inferior colliculus.
  • the pharmaceutical compositions may also be administered to different regions of the eye such as the retina, cornea and/or optic nerve., e.g., via subretinal injection, suprachoroidal injection, or intravitreal injection
  • the pharmaceutical composition may be delivered into the cerebrospinal fluid (e.g., by lumbar puncture).
  • the pharmaceutical composition may be administered to the desired region(s) of the CNS by any route known in the art, including but not limited to, intrathecal, intraocular, intracerebral, intraventricular, intravenous (e.g., in the presence of a sugar such as mannitol), intranasal, intra-aural, intra-ocular (e.g., intra-vitreous, sub-retinal, anterior chamber) and peri-ocular (e.g., sub-Tenon's region) delivery as well as intramuscular delivery with retrograde delivery to motor neurons.
  • repeat administrations of the therapeutic product can be made until the appropriate level of expression has been achieved.
  • a therapeutic nucleic acid can be administered and re-dosed, once or multiple times.
  • Step 2 Synthesis of (benzylazanediyl)bis(hexane-6,l-diyl) diacetate (A-4)
  • reaction mixture was diluted with water (500 mL) and extracted with EtOAc (2 x 500 mL) The combined organic layer dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum to afford (benzylazanediyl)bis(hexane-6,l-diyl) diacetate (A-4) (17.6 g, 44.94 mmol, 96 % yield) as colorless liquid.
  • the resulting crude compound was purified by Combi-flash column chromatography (40 g silica column) gradient elution of 10-100 % EtOAc in hexane. The resulting fractions containing desired product were combined and concentrated to afford 6,6'-(benzylazanediyl)bis(hexan-l-ol) (A-5) (12 g, 39.02 mmol, 87 % yield) as colorless liquid.
  • Step 6 Synthesis of 6-((6-((2-hexylnonanoyl)oxy)hexyl)amino)hexyl 2-hexyldecanoate (Lipid A)
  • Step 4 Synthesis of 3-((4,4-bis(octyloxy)butanoyl)oxy)-2-(hydroxymethyl)propyl (9Z,12Z)-octadeca- 9,12-dienoate (Lipid-B)
  • Step 5 Synthesis of 3-hydroxy-2-(hydroxymethyl)propyl (9Z,12Z)-octadeca-9,12-Dienoate (B-3) and 2-(hydroxymethyl)propane-l,3-diyl(9Z,9'Z,12Z,12'Z)-bis(octadeca-9,12-dienoate) (B-4)
  • reaction mixture was diluted with water (500.0 mL) and extracted with DCM (2X500 mL). the combined organic layers were washed with brine solution and dried over anhydrous sodium sulphate, and concentrated to obtain crude compound as light yellow color liquid.
  • Step 2 Synthesis of (benzylazanediyl)bis(hexane-6,l-diyl) bis(2-hexyldecanoate) (C-5)
  • Step 3 Synthesis of azanediylbis(hexane-6,l-diyl) bis(2-hexyldecanoate) (Lipid C)
  • Step 2 Synthesis of tert-butyl (2-(3-(((benzyloxy)carbonyl)amino)propoxy)ethyl)carbamate (E-5)
  • Step 3 Synthesis of tert-butyl (2-(3-aminopropoxy)ethyl)carbamate (E-6)
  • Step 4 Synthesis of 2,2-dimethyl-4-oxo-3,8-dioxa-5,12-diazaheptadecan-17-yl 2-hexyldecanoate (E- 8)
  • reaction mixture was diluted with DCM (50 mL) washed with water (70 mL), aqueous NaHCO 3 solution (70 mL) followed by brine solution (70 mL).
  • the organic layer was dried over Na 2 SO 4 , filtered and the filtrate was concentrated under reduced pressure.
  • the resulting crude compound was purified by Combi-flash (40 g silica column) with gradient elution of 20-100% EtOAc in Hexane followed by 0-20% MeOH in DCM.
  • Step 5 Synthesis of 12-(5-((2-hexyldecanoyl)oxy)pentyl)-2,2-dimethyl-4-oxo-3,8-dioxa-5,12- diazaheptadecan-17-yl 4-hexyldecanoate (E-10)
  • reaction mixture was cooled to RT, directly filtered using DCM (50 mL) and the filtrate was concentrated under reduced pressure.
  • the resulting crude compound was purified by Combi-flash (40 g silica column) with gradient elution of 20-100% EtOAc in Hexane followed by 0-20% MeOH in DCM.
  • Step 6 Synthesis of 5-((3-(2-aminoethoxy)propyl)(5-((2-hexyldecanoyl)oxy)pentyl)amino)pentyl 4- hexyldecanoate (Lipid E)
  • reaction mixture was diluted with DCM (20 mL) at 0 °C, quenched with aqueous NaHCO3 solution (30 mL), adjusted pH ⁇ 10 and extracted with DCM (2 x 30 mL).
  • the combined organic layer was washed with water (40 mL), aqueous NaHCO3 solution (40 mL) followed by brine solution (50 mL).
  • Step 2 7-((3-((tert-butoxycarbonyl)amino)propyl)amino)heptyl 2-hexyldecanoate (F-5)
  • Step 3 7-((3-((tert-butoxycarbonyl)amino)propyl)(7-((2-hexyldecanoyl)oxy)heptyl)amino)-heptyl 4- hexyldecanoate (F-7)
  • Step 4 7-((3-aminopropyl)(7-((2-hexyldecanoyl)oxy)heptyl)amino)heptyl 4-hexyldecanoate (Lipid F)
  • Step 7 Synthesis of 7-(benzyl(7-((2-hexyldecanoyl)oxy)heptyl)amino)heptyl 4-hexyldecanoate (G- 12)
  • Step 8 Synthesis of 7 7-((7-((2-hexyldecanoyl)oxy)heptyl)amino)heptyl 4-hexyldecanoate (Lipid G)
  • Step 2 Synthesis of ((4-((tert-butyldimethylsilyl)oxy)butyl)azanediyl)bis(hexane-6,l-diyl) bis(2- hexyldecanoate) (1-4)
  • Step 3 Synthesis of ((4-hydroxybutyl)azanediyl)bis(hexane-6,l-diyl) bis(2-hexyldecanoate) (Lipid I)
  • reaction mixture was diluted with DCM (100 mL) washed with water (100 mL), aqueous NaHCOs solution (100 mL) followed by brine solution (100 mL), dried over NajSCU, filtered and filtrate was concentrated under reduced pressure.
  • the resulting crude compound was purified by Combi-flash column chromatography (220 g silica column) with gradient elution of 5-10% EtoAc in hexane. The desired product containing fractions were combined and concentrated under reduced pressure to afford 6-bromohexyl 2-hexyldecanoate (1-3) (12 g, 28.63 mmol, 52% yield) as colorless liquid.
  • Step 2 Synthesis of methyl 3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)benzoate (Cl-3)
  • Step 4 Synthesis of methyl 3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)benzoate (Cl-6)
  • Step 2 Synthesis of methyl 3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)benzoate (C2-3)
  • Step 4 Synthesis of 4-(diethylamino)butyl 3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)benzoate (C2- 6)
  • reaction mixture was diluted with water (100 mL) and extracted with DCM (2 x 100 mL). The combined organic layers was washed with brine solution (2 x 70 mL) dried over Na 2 SO 4 , filtered and the filtrate was concentrated under reduced pressure.
  • the resulting crude compound was purified by Combi-flash column chromatography (12g silica column) gradient elution of 30-40 % EtOAc in hexane.
  • Step 5 Synthesis of 3-(methyl(2-(trityloxy)ethyl)amino)propyl 3-(hydroxymethyl)benzoate (Core-3)
  • Step 6 Synthesis of ethyl 3-((2-hydroxyethyl)(methyl)amino)propanoate (C3-9)
  • Step 7 Synthesis of ethyl 3-(methyl(2-(trityloxy)ethyl)amino)propanoate (C3-10)
  • Step 8 Synthesis of 3-(methyl(2-(trityloxy)ethyl)amino)propan-l-ol (C3-5)
  • Step 2 Synthesis of 3-(diethylamino)propyl 4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl) benzoate (C4-4)
  • C4-2 4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)benzoic acid (C4-2) (4.99 g, 21.13 mmol) in DCM (50 mL) at 0°C, were added EDC.HCI (6.75 g, 35.22 mmol), DMAP (0.430 g, 3.52 mmol) followed by 3-(diethylamino)propan-l-ol (C4-3) (2.31g, 17.61 mmol).
  • reaction mixture was stirred at RT for 16 h (monitored by TLC).
  • the reaction mixture was quenched with saturated aqueous NaHCO 3 solution (100 mL) extracted with DCM (2 x 80 mL).
  • the combined organic layers were dried over sodium sulphate and concentrated under vacuum.
  • the resulting crude material was purified by Combi- flash (40 g silica column) with gradient elution of 70 % EtOAc in hexane.
  • Step 3 Synthesis of 3-(diethylamino)propyl 4-(hydroxymethyl)benzoate (Core 4)
  • Step 2 Synthesis of 4-(diethylamino)butyl 4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)benzoate (C5- 4)
  • Step 1 Synthesis of ethyl 3-((2-hydroxyethyl)(methyl)amino)propanoate (C6-3)
  • Step 2 Synthesis of ethyl 3-(methyl(2-(trityloxy)ethyl)amino)propanoate (C6-4)
  • Step 3 Synthesis of 3-(methyl(2-(trityloxy)ethyl)amino)propan-l-ol (C6-5)
  • Step 4 Synthesis of 4-(((tert-butyldiphenylsilyl)oxy)methyl)benzoic acid (C6-7)
  • 4-(hydroxymethyl)benzoic acid (C6-6) 1.0 g, 6.57 mmol
  • THF 2,3,4-butane
  • imidazole 0.894 g, 13.14 mmol
  • TBDPS-CI 1.9 g, 7.22 mmol
  • the reaction mixture was stirred at RT for 3 h (monitored byTLC). Then the reaction mixture was quenched with water (50 ml), extract with EtOAc (2 x 50 mL). The combined organic layer was washed with saturated aq.
  • Step 5 Synthesis of 3-(methyl (4,4,4-triphenylbutyl)amino)propyl 4 (((tertbutyldiphenylsilyl) oxy)methyl) benzoate (C6-8)
  • reaction mixture was quenched with saturated NaHCOs solution (50 mL), was added water (20 mL) and extracted with DCM (2 x 50 mL). The combined organic layer was dried over Na 2 SO 4 , filtered and filtrate was concentrated under reduced pressure. The resulting residue was purified by Combi-flash column chromatography (40 g silica column) with gradient elution of 1-40 % EtOAc in hexane.
  • Step 6 Synthesis of 3-(methyl(2-(trityloxy)ethyl)amino)propyl 4-(hydroxymethyl)benzoate (Core-6)
  • Step 1 Synthesis of 3-(diethylamino)propyl 3-(6-((((9Z,12Z)-octadeca-9,12-dienoyl)oxy)-methyl)-12- (octyloxy)-3,9-dioxo-2,4,8,13-tetraoxahenicosyl)benzoate (Compound 2-10)
  • the reaction mixture was stirred at RT for 2 h, then were added DIPEA (0.123 ml, 0.719 mmol) and 3-(diethylamino)propyl 3-(hydroxymethyl)benzoate (Core 1) (Synthesis described separately for Core 1) (191 mg, 0.719 mmol) then stirring continued for further 14 h (monitored by TLC).
  • the Reaction mixture was diluted with water (100 mL) extracted with DCM (2 X 100 mL). The combined organic layer was washed with brine solution (50 mL). The organic layer was dried over anhydrous NajSCU, filtered and the filtrate was concentrated under vacuum.
  • Step 1 Synthesis of ((((3-((3-(diethylamino)propoxy)carbonyl)benzyl)oxy)carbonyl)azanediyl) bis(hexane-6,l-diyl) bis(2-hexyldecanoate) (Compound 2-11)
  • the reaction mixture was stirred at RT for 16 h, then were added DIPEA (0.394 ml, 2.261mmol, 2.0 eq.) and a solution of ((((3-((3- (diethylamino)propoxy)carbonyl)benzyl)-oxy)carbonyl)azanediyl)bis(hexane-6,l-diyl) bis(2- hexyldecanoate) (Lipid C) (550 mg, 0.791 mmol, 0.7 eq.) in DCM (5 mL) then stirring continued for further 16 h (monitored by TLC). The reaction mixture was diluted with DCM (200 mL) washed with water (3 x 75 mL).
  • Step 1 Synthesis of ((((3-((4-(diethylamino)butoxy)carbonyl)benzyl)oxy)carbonyl)azanediyl) bis(hexane-6,l-diyl)bis(2-hexyldecanoate) (Compound 2-12)
  • reaction mixture was added DIPEA (0.750 mL, 4.30 mmol) followed by azanediylbis(hexane-6,l-diyl) bis(2-hexyldecanoate) (Lipid C) (0.596 g, 0.859 mmol) and stirred at RT for another 24 hr (monitored by TLC).
  • Lipid C azanediylbis(hexane-6,l-diyl) bis(2-hexyldecanoate)
  • the reaction mixture was diluted with water (50 mL) and extracted with DCM (2 x 50 mL). The combined organic layer was washed with brine solution, dried over anhydrous NajSCU, filtered and the filtrate was concentrated under vacuum.
  • Step 1 Synthesis of ((((3-((3-(methyl(2-(trityloxy)ethyl)amino) propoxy) carbonyl)benzyl) oxy)carbonyl)azanediyl)bis(hexane-6,l-diyl) bis(2-hexyldecanoate) (23-2)
  • the resulting crude compound was purified by Combi-flash column chromatography (24 g silica column) gradient elution of 5-7 % MeOH in DCM. The resulting fractions containing desired product were combined and concentrated to afford (((3-((3-(methyl(2-(trityloxy)ethyl)amino) propoxy) carbonyl)benzyl) oxy)carbonyl)azanediyl)bis(hexane-6,l-diyl) bis(2-hexyldecanoate) (23-2) (0.210 g, 0.017 mmol, 29.0 % yield) as colorless syrup.
  • Step 2 Synthesis of ((((3-((3-((2-hydroxyethyl) (methyl)amino) propoxy)carbonyl)benzyl) oxy)carbonyl)azanediyl)bis(hexane-6,l-diyl) bis(2-hexyldecanoate) (Compound 2-13)
  • the reaction mixture was quenched with water (30 mL), extracted with DCM (2 x 50 mL). The combined organic layer was washed with saturated brine solution (2 x 40 mL), dried over Na?SO4, filtered and the filtrate was concentrated under reduced pressure. The resulting crude compound was purified by Combi-flash column chromatography (24 g silica column) gradient elution of 1-5 % MeOH in DCM.
  • Step 1 Synthesis of 3-(diethylamino)propyl 4-((((6-((2-hexyldecanoyl)oxy)hexyl)(6-((2- hexylnonanoyl)oxy)hexyl)carbamoyl)oxy)methyl)benzoate (Compound 2-14)
  • Step 1 Synthesis of 3-(diethylamino)propyl 4-(6-((((9Z,12Z)-octadeca-9,12-dienoyl)oxy)methyl)-12- (octyloxy)-3,9-dioxo-2,4,8,13-tetraoxahenicosyl)benzoate (Compound 2-15)
  • reaction mixture was cooled to 0 °C, were added DIPEA (0.60 mL, 3.455 mmol) and 3-(diethylamino)propan-l-ol (Core 4) (460 mg, 3.455 mmol) stirring continued at RT for further 24 h (monitored by TLC).
  • the Reaction mixture was diluted with water (100 mL) extracted with DCM (2 X 100 mL). The combined organic layers were washed with brine solution (50 mL). The organic layer was dried over anhydrous NajSC , filtered and the filtrate was concentrated under vacuum.
  • Step 1 Synthesis of 4-(diethylamino)butyl 4-(6-((((9Z,12Z)-octadeca-9,12-dienoyl)oxy)methyl)-12- (octyloxy)-3,9-dioxo-2,4,8,13-tetraoxahenicosyl)benzoate (Compound 2-16)
  • Step 1 Synthesis of ((((4-((4-(diethylamino)butoxy)carbonyl)benzyl)oxy)carbonyl)azanediyl) bis(hexane-6,l-diyl) bis(2-hexyldecanoate) (Compound 2-17)
  • reaction mixture cooled to 0 °C, were added DIPEA (0.24 mL, 1.42 mmol) and azanediylbis(hexane-6,l-diyl) bis(2-hexyldecanoate) (Lipid C) (0.397 g, 0.57 mmol) and stirring continued at RT for further 24 h (monitored by TLC).
  • the reaction mixture was diluted with water (50 mL) extracted with DCM (2 x 50 mL). The combined organic layers was washed with brine solution (50 mL). The organic layer was dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under vacuum.
  • Step 1 Synthesis of ((((4-((3-(methyl(2-(trityloxy)ethyl)amino)propoxy)carbonyl)benzyl)oxy) carbonyl)azanediyl)bis(hexane-6,l-diyl)bis(2-hexyldecanoate) (28-2)

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Abstract

L'invention concerne des lipides qui peuvent être formulés dans un véhicule d'administration pour permettre l'encapsulation d'une large gamme de charges utiles simples ou multiples comprenant des agents thérapeutiques, théragnostiques, préventifs, prophylactiques, préemptifs et diagnostiques, tels que, sans limitation, des acides nucléiques (par exemple, ARN ou ADN), des protéines, des peptides et des ingrédients pharmaceutiques actifs (API) à petites molécules. L'invention concerne également des procédés d'administration et/ou de production d'un polypeptide d'intérêt dans une cellule.
PCT/IB2025/000348 2024-06-27 2025-06-27 Lipides et nanoparticules lipidiques Pending WO2026003582A2 (fr)

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