WO2025171237A1 - Composés lipidoïdes et compositions et utilisations associées - Google Patents

Composés lipidoïdes et compositions et utilisations associées

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Publication number
WO2025171237A1
WO2025171237A1 PCT/US2025/014972 US2025014972W WO2025171237A1 WO 2025171237 A1 WO2025171237 A1 WO 2025171237A1 US 2025014972 W US2025014972 W US 2025014972W WO 2025171237 A1 WO2025171237 A1 WO 2025171237A1
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WIPO (PCT)
Prior art keywords
compound
composition
nucleic acid
aspects
cell
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PCT/US2025/014972
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English (en)
Inventor
Lijun Huang
Minghao XU
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Poseida Therapeutics Inc
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Poseida Therapeutics Inc
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Publication of WO2025171237A1 publication Critical patent/WO2025171237A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/08—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/10—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/20—Spiro-condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the present invention relates generally to lipidoid compounds, compositions containing such compounds, methods of preparing these compounds, and the use of these compositions in gene delivery’.
  • compositions and methods for delivering nucleic acids to cells and for genetically modifying cells in vivo, ex vivo and in vitro have been a long-felt but unmet need in the art for compositions and methods for delivering nucleic acids to cells and for genetically modifying cells in vivo, ex vivo and in vitro.
  • Widely accepted gene delivery and genetic modification techniques such as the use of viral vectors, including AAVs, can cause acute toxicity and harmful side-effects in patients.
  • the present disclosure provides improved compositions, methods and kits for the delivery of nucleic acids to various types of cells in vivo, ex vivo and in vitro. More specifically, the present disclosure provides improved lipid nanoparticle compositions and methods of using the same. These lipid nanoparticle compositions and methods allow for the delivery of nucleic acids to cells with high efficiency and low toxicity.
  • compositions and methods of the present disclosure have wide applicability’ to a diverse number of fields, including gene therapy. Further, these lipid nanoparticles and methods allow for the targeted delivery’ of nucleic acids to the lungs and lung cells, instead of to the liver which is the target of most developed lipid nanoparticle compositions. Thus, the compositions and methods of the present disclosure also have wide applicability to the development of treatments for a broad spectrum of pulmonary diseases.
  • novel compounds are provided.
  • the novel compound is a compound of Formula (I):
  • novel lipid nanoparticles comprising a novel compound.
  • the novel compound is a compound of Formula (I).
  • compositions comprising a composition of the present disclosure and at least one pharmaceutically-acceptable excipient or diluent.
  • provided are methods of delivering at least one nucleic acid to at least one cell comprising contacting the at least one cell with at least one composition of the present disclosure.
  • kits for genetically modifying at least one cell comprising contacting the at least one cell with at least one composition of the present disclosure.
  • provided are methods of treating at least one disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of at least one composition of the present disclosure.
  • provided are methods of delivering at least one nucleic acid to at least one cell comprising contacting the at least one cell with at least one composition of the present disclosure.
  • the present disclosure provides novel lipidoid compounds, novel lipid nanoparticle compositions (LNPs) comprising the novel lipidoid compounds, methods for preparing the LNPs, and methods for using the same.
  • the compositions and methods of the present limiting disclosure can be used for gene delivery.
  • the compositions and methods of the present disclosure can be broadly used to deliver a nucleic acid to lung cells, in vivo, ex vivo or in vitro, for the treatment of certain diseases and disorders, including, but not limited to lung disorders.
  • the compositions and methods of the present disclosure can be broadly used to deliver a nucleic acid to induce the expression of a secreted therapeutic protein.
  • compositions of the Present Disclosure Lipid Nanoparticles
  • the present disclosure provides a composition comprising at least one lipid nanoparticle comprising a compound of the present disclosure and at least one nucleic acid molecule.
  • a lipid nanoparticle can further comprise at least one structural lipid.
  • a lipid nanoparticle can further comprise at least one phospholipid.
  • a lipid nanoparticle can further comprise at least one PEGylated lipid.
  • R3 is H, methyl, C 1 -C 10 alkyl optionally substituted with one or more hydroxyl.
  • each of R 4a and Rib is independently C 1 -C 18 alkyd.
  • A is:
  • A is:
  • A is:
  • A is: [0026] In some aspects, A is:
  • each B is: O in which * indicates attachment to A and ** indicates attachment to C.
  • each B is: which * indicates attachment to A and ** indicates attachment to C.
  • each e is 1. In some embodiments, each e is 2.
  • A is: each Z is a covalent bond.
  • each R2 is H.
  • each R2 is methyl.
  • each Ri is C 2 -C 18 alkenyl. In some embodiments, each Ri is
  • each Ri is C 1 -C 18 alkyl.
  • a is 2 and b is 2.
  • a is 3 and b is 3.
  • c is 3 and d is 3.
  • c is 4 and d is 4.
  • R 3 is C 1 -C 10 alkyd optionally substituted with one or more hydroxyl.
  • n 4.
  • the compound of Formula (I) is a compound selected from:
  • the compounds of any one of the Formulas disclosed herein and any pharmaceutically acceptable salts thereof comprise stereoisomers, mixtures of stereoisomers, polymorphs of all isomeric forms of said compounds.
  • compounds disclosed herein may be presented without specified configuration (e.g.. without specified stereochemistry). Such presentation intends to encompass all available isomers, tautomers, regioisomers, and stereoisomers of the compound. In some embodiments, the presentation of a compound herein without specified configuration intends to refer to each of the available isomers, tautomers, regioisomers, and stereoisomers of the compound, or any mixture thereof.
  • any Formula described herein include the compounds themselves, as well as their salts, and their solvates, if applicable.
  • a salt for example, can be formed between an anion and a positively charged group (e.g.. amino) on a substituted compound disclosed herein.
  • Compounds of Formula (I) can be prepared using the reagents, intermediates, precursors, methods and schemes disclosed herein or using other commercially available reagents and methods known to those skilled in the art.
  • Disulfide diacid was dissolved in A C2 O and stirred for 24 hrs to get the desired anhydride after removing the AcOH under high vacuum. The anhydride was used directly in the next step without purification.
  • the at least one compound is at least one compound of Formula (I) as described herein. In some aspects, the at least one compound of the present disclosure is a mixture of two or more compounds of Formula (I).
  • a phospholipid can comprise DPPC (1,2-Dipalmitoyl-sn-glycero-3-phosphocholine).
  • a phospholipid can comprise DDPC (1,2-Didecanoyl-sn-glycero-3-phosphocholine), DEPA-NA (1,2-Dierucoyl-sn-glycero-3-phosphate (Sodium Salt)), DEPC (1,2-Dierucoyl-sn- glycero-3 -phosphocholine), DEPE (1.2-Dierucoyl-sn-glycero-3-phosphoethanolamine), DEPG-NA (1.2-Dierucoyl-sn-glycero-3[Phospho-rac-(l-glycerol) (Sodium Salt)).
  • DLOPC (1,2-Dilinoleoyl-sn-glycero-3-phosphocholine), DLPA-NA (1,2-Dilauroyl-sn-glycero-3- phosphate (Sodium Salt)), DLPC (1,2-Dilauroyl-sn-glycero-3-phosphocholine), DLPE (1,2- Dilauroyl-sn-glycero-3-phosphoethanolamine), DLPG-NA (1,2-Dilauroyl-sn-glycero- 3 [Phospho-rac-(l -glycerol) (Sodium Salt)), DLPG-NH4 (1,2-Dilauroyl-sn-glycero- 3[Phospho-rac-(l-glycerol) (Ammonium Salt)), DLPS-NA (1,2-Dilauroyl-sn-glycero-3- phosphoserine (Sodium Salt)), DMPA-NA (1,2-Dimyristoyl-sn-glycero
  • PSPC (l-Palmitoyl-2-stearoyl-sn-glycero-3-phosphocholine), SMPC (l-Stearoyl-2-myristoyl-sn-glycero-3-phosphocholine), SOPC (l-Stearoyl-2-oleoyl- sn-glycero-3-phosphocholine), SPPC (l-Stearoyl-2-palmitoyl-sn-glycero-3-phosphocholine), or any combination thereof.
  • PEGylated lipid is used to refer to any lipid that is modified (e.g. covalently linked to) at least one polyethylene glycol molecule.
  • a PEGylated lipid can comprise l,2-dimyristoyl-rac-glycero-3-methoxypoly ethylene gly col- 2000, hereafter referred to as DMG-PEG2000 or PEG-DMG.
  • the at least one PEGylated lipid is a mixture of two PEGylated lipids.
  • the phospholipid is DOPE.
  • the phospholipid is DSPC.
  • the phospholipid is DOPC.
  • the phospholipid is DPPC.
  • the phospholipid can be a mixture of DSPC and DOPC.
  • the mixture of DSPC and DOPC can comprise DSPC and DOPC at a 1 : 1 ratio (e.g. a LNP that comprises 10% phospholipid can comprise 5% DOPC and 5% DSPC).
  • the structural lipid can be cholesterol
  • the phospholipid can be DOPC
  • the PEGylated lipid can be DMG-PEG2000.
  • a lipid nanoparticle of the present disclosure can further comprise at least one nucleic acid.
  • a lipid nanoparticle can comprise a plurality' of nucleic acid molecules.
  • the at least one nucleic acid or the plurality of nucleic acid molecules can be formulated in a lipid nanoparticle.
  • a lipid nanoparticle can comprise at least one nucleic acid, at least one compound of the present disclosure, at least one structural lipid, at least one phospholipid, and at least one PEGylated lipid.
  • the at least one nucleic acid is a DNA molecule.
  • the at least one DNA molecule is a DoggyBone DNA molecule.
  • the at least one DNA molecule is a DNA nanoplasmid.
  • the at least one nucleic acid is an RNA molecule.
  • the RNA molecule is an mRNA molecule.
  • the mRNA molecule further comprises a 5’-CAP.
  • all of the cytidine residues in an mRNA molecule can be 5- methyl cytidine.
  • an at least one nucleic acid can comprise both mRNA molecules and guide RNA (gRNA) molecules. That is, the LNPs of the present disclosure can comprise both mRNA molecules and gRNA molecules. In some aspects wherein the LNPs comprise both mRNA molecules and gRNA molecules, the mRNA molecules comprise at least one nucleic acid sequence that encodes a fusion protein, wherein the fusion protein comprises: (i) an inactivated Cas9 (dCas9) protein or an inactivated nuclease domain thereof; and (ii) a Clo051 protein or a nuclease domain thereof, and wherein the gRNA molecules encode guide RNA sequence targeting one or more specific genomic loci. In some aspects, the fusion protein can be a Cas-CLOVER protein. In some aspects, the gRNA molecules can target the psk9 gene.
  • the ratio of lipid to nucleic acid in the nanoparticle can be about 90:1 to about 110: 1 (w/w), or about 95: 1 to about 105: 1 (w/w). In some aspects, the ratio of lipid to nucleic acid in the nanoparticle can be about 100: 1 (w/w).
  • the cell in the plurality express at least one protein that was encoded in at least one nucleic acid that was delivered to the plurality of cells via a nanoparticle of the present disclosure.
  • the present disclosure provides a method of treating at least one disease in a subject, the method comprising administering a therapeutically effective amount of at least one nanoparticle of the present disclosure comprising at least one nucleic acid encoding a therapeutic protein.
  • the at least one disease can be a malignant disease, including, but not limited to, cancer.
  • the at least one disease can be a lung disease or disorder.
  • the at least one disease can be cystic fibrosis.
  • the present disclosure provides a method of treating a lung disease or disorder in a subject in need thereof comprising administering to the subject at least one composition comprising at least one lipid nanoparticle of the present disclosure.
  • the present disclosure provides a method of treating cystic fibrosis in a subject in need thereof comprising administering to the subject at least one composition comprising at least one lipid nanoparticle of the present disclosure.
  • a nucleic acid molecule can be a synthetic nucleic acid molecule. In some aspects, a nucleic acid molecule can be a non-naturally occurring nucleic acid molecule. In some aspects, a non-naturally occurring nucleic acid molecule can comprise at least one non-naturally occurring nucleotide. The at least one non-naturally occurring nucleotide can be any non-naturally occurring nucleotide known in the art. In some aspects, a nucleic acid molecule can be a modified nucleic acid molecule. In some aspects, a modified nucleic acid molecule can comprise at least one modified nucleotide. The at least one modified nucleotide can be any modified nucleic acid known in the art.
  • the at least one modified nucleic acid can comprise 5-methoxyuridine (5moU).
  • 5moU 5-methoxyuridine
  • at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 25%, or at least about 30%. or at least about 35%, or at least about 40%. or at least about 45%. or at least about 50%, or at least about 55%. or at least about 60%, or at least about 65%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, at least about 90%, or at least about 95%, or at least about 99% of the uridine bases in an mRNA molecule are 5-methoxyuridine bases.
  • all of the uridine bases in an mRNA molecule are pseudouridine bases.
  • pseudouridine can improve protein expression and reduce immunogenicity (see Li et al., Bioconjugate Chem. 2016, 27, 3, 849-853 and Vaidyanathan et al. Molecular Therapy - Nucleic Acids, 2018, 12, 530-542).
  • the at least one modified nucleic acid can comprise 5-methylcytidine (5-MeC).
  • 5-MeC 5-methylcytidine
  • a DNA plasmid or DNA nanoplasmid can comprise can be at least about 0.25 kb, or at least about 0.5 kb, or at least about 0.75 kb, or at least about 1.0 kb, or at least about 1.25 kb, or at least about 1.5 kb, or at least about 1.75 kb, or at least about 2.0 kb, or at least about 2.25 kb, or at least about 2.5 kb, or at least about 2.75 kb, or at least about 3.0 kb, or at least about 3.25 kb, or at least about 3.5 kb, or at least about 3.75 kb, or at least about 4.0 kb, or at least about 4.25 kb, or at least about 4.5 kb, or at least about 4.75 kb, or at least about 5.0 kb, or at least about 5.25 kb, or at least about 5.5 kb, or at least about 5.75 kb, or at least about 6.0 kb
  • a nucleic acid molecule formulated in a lipid nanoparticle of the present disclosure can comprise at least one transgene sequence.
  • a transgene sequence can comprise a nucleotide sequence encoding at least one therapeutic protein.
  • a transgene sequence can comprise a nucleotide sequence encoding at least one transposase.
  • a transgene sequence can comprise a nucleotide sequence encoding at least one transposon.
  • a transposon can comprise a nucleotide sequence encoding at least one therapeutic protein.
  • a transposon can comprise a nucleotide sequence encoding at least one therapeutic protein and at least one protomer sequence, wherein the at least one therapeutic protein is operatively linked to the at least one promoter sequence.
  • the lipid nanoparticles of the present disclosure can be produced using a microfluidic-mixing platform.
  • the microfluidic-mixing platform can be a non-turbulent microfluidic mixing platform.
  • a piggyBac ITR sequence can comprise any piggy Bac ITR sequence known in the art.
  • a nucleic acid can comprise a transposon or a nanotransposon comprising: a first nucleic acid sequence comprising: (a) a first inverted terminal repeat (ITR) or a sequence encoding a first ITR. (b) a second ITR or a sequence encoding a second ITR, and (c) an intra-ITR sequence or a sequence encoding an intra-ITR, wherein the intra-ITR sequence comprises a transposon sequence or a sequence encoding a transposon.
  • ITR inverted terminal repeat
  • the transposon or nanotransposon of the present disclosure can be a piggyBacTM (PB) transposon.
  • the transposase is a piggy BacTM (PB) transposase a piggyBac-like (PBL) transposase or a Super piggyBacTM (SPB) transposase.
  • PB piggy BacTM
  • PBL piggyBac-like
  • SPB Super piggyBacTM
  • the sequence encoding the SPB transposase is an mRNA sequence.
  • the PB, PBL and SPB transposases recognize transposon-specific inverted terminal repeat sequences (ITRs) on the ends of the transposon, and inserts the contents between the ITRs at the sequence 5’-TTAT-3‘ within a chromosomal site (a TTAT target sequence) or at the sequence 5’-TTAA-3’ within a chromosomal site (a TTAA target sequence).
  • ITRs inverted terminal repeat sequences
  • the target sequence of the PB or PBL transposon can comprise or consist of 5’-CTAA-3’, 5’-TTAG-3’, 5’-ATAA-3’, 5’-TCAA-3’, 5’AGTT-3’, 5 -ATTA-3’, 5 -GTTA-3’, 5 -TTGA-3’, 5 -TTTA-3’, 5’-TTAC-3’, 5’-ACTA-3’, 5’-AGGG-3’, 5’-CTAG-3’, 5 -TGAA-3’, 5 -AGGT-3’, 5’-ATCA- 3’, 5 -CTCC-3’. 5’-TAAA-3’, 5’-TCTC-3’, 5’TGAA-3’, 5’-AAAT-3’.
  • the PB or PBL transposase can comprise or consist of an amino acid sequence having an amino acid substitution at two or more, at three or more or at each of positions 30, 165, 282, and/or 538 of the sequence of SEQ ID NO: 1.
  • the transposase can be a SPB transposase that comprises or consists of the amino acid sequence of the sequence of SEQ ID NO: 1 wherein the amino acid substitution at position 30 can be a substitution of a valine (V) for an isoleucine (I), the amino acid substitution at position 165 can be a substitution of a serine (S) for a glycine (G), the amino acid substitution at position 282 can be a substitution of a valine (V) for a methionine (M), and the amino acid substitution at position 538 can be a substitution of a lysine (K) for an asparagine (N).
  • the amino acid substitution at position 30 can be a substitution of a valine (V) for an isoleucine (I)
  • the amino acid substitution at position 165 can be a substitution of a serine (S) for a glycine (G)
  • the amino acid substitution at position 282 can be a substitution of a valine (V) for
  • the SPB transposase comprises or consists of an amino acid sequence at least 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%. 99% or 100% (or any percentage in between) identical to SEQ ID NO: 2.
  • PBL and SPB transposases can further comprise an amino acid substitution at one or more of positions 3, 46, 82, 103, 1 19, 125, 177, 180, 185, 187, 200, 207, 209, 226, 235, 240, 241, 243, 258, 296, 298, 311, 315, 319, 327, 328, 340, 421, 436, 456, 470, 486, 503, 552, 570 and 591 of the sequence of SEQ ID NO: 1 or SEQ ID NO: 2 are described in more detail in PCT Publication No. WO 2019/173636 and PCT/US2019/049816.
  • the SPB transposase comprises or consists of an amino acid sequence at least 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% (or any percentage in between) identical to SEQ ID NO: 4.
  • a transposon or nanotransposon of the present disclosure can be a Helraiser transposon.
  • An exemplary Helraiser transposon includes Helibat 1.
  • the transposase is a Helitron transposase (for example, as disclosed in WO 2019/173636).
  • a mutant TcBuster transposase comprises one or more sequence variations when compared to a wild ty pe TcBuster transposase as described in more detail in PCT Publication No. WO 2019/173636 and PCT/US2019/049816.
  • Non-limiting examples of pharmaceutical excipients and additives suitable for use include proteins, peptides, amino acids, lipids, and carbohydrates (e.g., sugars, including monosaccharides, di-, tri-, tetra-, and oligosaccharides; derivatized sugars, such as alditols, aldonic acids, esterified sugars and the like; and polysaccharides or sugar polymers), which can be present singly or in combination, comprising alone or in combination 1-99.99% by weight or volume.
  • Non-limiting examples of protein excipients include serum albumin, such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, and the like.
  • Suitable dosages are well known in the art. See, e.g., Wells et al., eds., Pharmacotherapy Handbook’ 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000); Nursing 2001 Handbook of Drugs, 2 lst edition. Springhouse Corp., Springhouse, Pa., 2001; Health Professional's Drug Guide 2001, ed., Shannon, Wilson, Stang, Prentice-Hall, Inc, Upper Saddle River, N.J.
  • the disclosure provides the use of a disclosed composition or pharmaceutical composition for the treatment of a disease or disorder in a cell, tissue, organ, animal, or subject, as known in the art or as described herein, using the disclosed compositions and pharmaceutical compositions, e.g., administering or contacting the cell, tissue, organ, animal, or subject with a therapeutic effective amount of the composition or pharmaceutical composition.
  • the subject is a mammal.
  • the subject is human.
  • the terms ‘‘subject” and “patient” are used interchangeably herein.
  • the disclosure provides a method for modulating or treating at least one malignant disease or disorder in a cell, tissue, organ, animal or subject.
  • Non-limiting examples of a malignant disease or disorder include cancer, lung diseases or disorders, and cystic fibrosis.
  • Any method can comprise administering an effective amount of any composition or pharmaceutical composition disclosed herein to a cell, tissue, organ, animal or subject in need of such modulation, treatment or therapy.
  • Such a method can optionally further comprise co- administration or combination therapy for treating such diseases or disorders, wherein the administering of any composition or pharmaceutical composition disclosed herein, further comprises administering, before concurrently, and/or after, at least one chemotherapeutic agent (e.g., an alkylating agent, a mitotic inhibitor, a radiopharmaceutical).
  • chemotherapeutic agent e.g., an alkylating agent, a mitotic inhibitor, a radiopharmaceutical
  • the therapeutically effective dose is a single dose.
  • the single dose is one of at least 2, 5, 10, 15, 20, 25, 30, 35, 40, 45. 50. 55. 60. 65. 70, 75, 80, 85, 90, 95, 100 or any number of doses in between that are manufactured simultaneously.
  • the dose is an amount sufficient for the cells to engraft and/or persist for a sufficient time to treat the disease or disorder.
  • the treatment can be modified or terminated.
  • the composition used for treatment comprises an inducible proapoptotic polypeptide
  • apoptosis may be selectively induced in the cell by contacting the cell with an induction agent.
  • a treatment may be modified or terminated in response to, for example, a sign of recovery or a sign of decreasing disease severity/progression, a sign of disease remission/cessation, and/or the occurrence of an adverse event.
  • the method comprises the step of administering an inhibitor of the induction agent to inhibit modification of the cell therapy, thereby restoring the function and/or efficacy of the cell therapy (for example, when a sign or symptom of the disease reappear or increase in severity’ and/or an adverse event is resolved).
  • the isolated nucleic acids of the disclosure can be made using (a) recombinant methods, (b) synthetic techniques, (c) purification techniques, and/or (d) combinations thereof, as well- known in the art.
  • the nucleic acids can conveniently comprise sequences in addition to a polynucleotide of the present disclosure.
  • a multi-cloning site comprising one or more endonuclease restriction sites can be inserted into the nucleic acid to aid in isolation of the polynucleotide.
  • translatable sequences can be inserted to aid in the isolation of the translated polynucleotide of the disclosure.
  • a hexa-histidine marker sequence provides a convenient means to purify the proteins of the disclosure.
  • the nucleic acid of the disclosure, excluding the coding sequence is optionally a vector, adapter, or linker for cloning and/or expression of a polynucleotide of the disclosure.
  • Additional sequences can be added to such cloning and/or expression sequences to optimize their function in cloning and/or expression, to aid in isolation of the polynucleotide, or to improve the introduction of the polynucleotide into a cell.
  • Use of cloning vectors, expression vectors, adapters, and linkers is well known in the art. (See, e.g. Ausubel. supra; or Sambrook, supra).
  • a cDNA or genomic library can be screened using a probe based upon the sequence of a polynucleotide of the disclosure. Probes can be used to hybridize with genomic DNA or cDNA sequences to isolate homologous genes in the same or different organisms.
  • Those of skill in the art will appreciate that various degrees of stringency of hybridization can be employed in the assay; and either the hybridization or the wash medium can be stringent. As the conditions for hybridization become more stringent, there must be a greater degree of complementarity 7 between the probe and the target for duplex formation to occur.
  • the degree of stringency can be controlled by one or more of temperature, ionic strength, pH and the presence of a partially denaturing solvent, such as formamide.
  • PCR polymerase chain reaction
  • in vitro amplification methods can also be useful, for example, to clone nucleic acid sequences that code for proteins to be expressed, to make nucleic acids to use as probes for detecting the presence of the desired mRNA in samples, for nucleic acid sequencing, or for other purposes.
  • examples of techniques sufficient to direct persons of skill through in vitro amplification methods are found in Berger, supra, Sambrook, supra, and Ausubel, supra, as well as Mullis, et al., U.S. Pat. No.
  • isolated nucleic acids that serve as promoter, enhancer, or other elements can be introduced in the appropriate position (upstream, downstream or in the intron) of a non-heterologous form of a polynucleotide of the disclosure so as to up or down regulate expression of a polynucleotide of the disclosure.
  • endogenous promoters can be altered in vivo or in vitro by mutation, deletion and/or substitution.
  • Suitable vectors will be readily apparent to the skilled artisan.
  • Introduction of a vector construct into a host cell can be effected by calcium phosphate transfection, DEAE-dextran mediated transfection, cationic lipid-mediated transfection, electroporation, transduction, infection or other known methods. Such methods are described in the art, such as Sambrook, supra. Chapters 1-4 and 16-18; Ausubel, supra, Chapters 1, 9, 13, 15, 16.
  • a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary', where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically -active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
  • protecting group it is meant that a particular functional moiety, e.g., O, S, or N, is temporarily blocked so that a reaction can be carried out selectively at another reactive site in a multifunctional compound.
  • a protecting group reacts selectively in good yield to give a protected substrate that is stable to the projected reactions: the protecting group should be selectively removable in good yield by readily available, preferably non-toxic reagents that do not attack the other functional groups; the protecting group forms an easily separable derivative (more preferably without the generation of new stereogenic centers); and the protecting group has a minimum of additional functionality to avoid further sites of reaction.
  • oxygen, sulfur, nitrogen, and carbon protecting groups may be utilized.
  • the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-6 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-4 carbon atoms. Illustrative aliphatic groups thus include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, —CH 2 -cyclopropyl.
  • Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1- methyl-2-buten-l-yl, and the like.
  • Representative alkynyl groups include, but are not limited to, ethynyl. 2-propynyl (propargyl), 1 -propynyl. and the like.
  • alkynyl refers to an unsaturated straight or, when applicable, branched chain aliphatic group with one or more carbon-carbon triple bonds, having from 2 to 18 carbon atoms.
  • alkynyl encompasses C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 groups.
  • Representative alkynyl groups include ethynyl. 2-propynyl (propargyl), 1 -propynyl, and the like.
  • aryl group is a Ce - C14 aromatic moiety comprising one to three aromatic rings, which is optionally substituted.
  • aryl includes C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , and C 14 cyclic hydrocarbon groups.
  • An exemplary aryl group is a Ce-Cio aryl group.
  • Particular aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, and fluorenyl.
  • substituted refers to the ability, as appreciated by one skilled in this art, to change one functional group for another functional group provided that the valency of all atoms is maintained.
  • substituents may also be further substituted (e.g., an aryl group substituent may have another substituent off it, such as another aryl group, which is further substituted with fluorine at one or more positions).
  • an "isolated" polynucleotide is free of sequences (optimally protein encoding sequences) that naturally flank the polynucleotide (i.e., sequences located at the 5' and 3' ends of the polynucleotide) in the genomic DNA of the organism from which the polynucleotide is derived.
  • the isolated polynucleotide can contain less than about 5 kb, 4 kb, 3 kb, 2 kb, 1 kb, 0.5 kb, or 0.1 kb of nucleotide sequence that naturally flank the polynucleotide in genomic DNA of the cell from which the polynucleotide is derived.
  • a protein that is substantially free of cellular material includes preparations of protein having less than about 30%, 20%, 10%, 5%, or 1% (by dry weight) of contaminating protein.
  • optimally culture medium represents less than about 30%, 20%, 10%, 5%, or 1% (by dry weight) of chemical precursors or non-protein-of-interest chemicals.
  • Nucleic acids or proteins of the disclosure can be constructed by a modular approach including preassembling monomer units and/or repeat units in target vectors that can subsequently be assembled into a final destination vector.
  • Polypeptides of the disclosure may comprise repeat monomers of the disclosure and can be constructed by a modular approach by preassembling repeat units in target vectors that can subsequently be assembled into a final destination vector.
  • the disclosure provides polypeptides produced by this method as well as nucleic acid sequences encoding these polypeptides.
  • the disclosure provides host organisms and cells comprising nucleic acid sequences encoding polypeptides produced by this modular approach.
  • Gene expression refers to the conversion of the information, contained in a gene, into a gene product.
  • a gene product can be the direct transcriptional product of a gene (e.g., mRNA, tRNA, rRNA, antisense RNA, ribozyme, shRNA, micro RNA, structural RNA or any other type of RNA) or a protein produced by translation of an mRNA.
  • Gene products also include RNAs which are modified, by processes such as capping, polyadenylation, methylation, and editing, and proteins modified by, for example, methylation, acetylation, phosphorylation, ubiquitination, ADP-ribosylation, myristilation, and glycosylation.
  • Nucleic acids of the disclosure may contain combinations of bases including uracil, adenine, thymine, cytosine, guanine, inosine, xanthine hypoxanthine, isocytosine and isoguanine. Nucleic acids of the disclosure may be synthesized to comprise non-natural amino acid modifications. Nucleic acids of the disclosure may be obtained by chemical synthesis methods or by recombinant methods.
  • nucleic acid refers to (i) a portion or fragment of a referenced nucleotide sequence; (ii) the complement of a referenced nucleotide sequence or portion thereof; (iii) a nucleic acid that is substantially identical to a referenced nucleic acid or the complement thereof; or (iv) a nucleic acid that hybridizes under stringent conditions to the referenced nucleic acid, complement thereof, or a sequences substantially identical thereto.
  • vector refers to a nucleic acid sequence containing an origin of replication.
  • a vector can be a viral vector, bacteriophage, bacterial artificial chromosome or yeast artificial chromosome.
  • a vector can be a DNA or RNA vector.
  • a vector can be a self-replicating extrachromosomal vector, and preferably, is a DNA plasmid.
  • a vector may comprise a combination of an amino acid with a DNA sequence, an RNA sequence, or both a DNA and an RNA sequence.
  • a conservative substitution of an amino acid i.e., replacing an amino acid with a different amino acid of similar properties (e.g., hydrophilicity, degree and distribution of charged regions) is recognized in the art as typically involving a minor change. These minor changes can be identified, in part, by considering the hydropathic index of amino acids, as understood in the art. Kyte et al., J. Mol. Biol. 157: 105-132 (1982). The hydropathic index of an amino acid is based on a consideration of its hydrophobicity and charge. Amino acids of similar hydropathic indexes can be substituted and still retain protein function. In an aspect, amino acids having hydropathic indexes of ⁇ 2 are substituted.
  • fusion polypeptides and/or nucleic acids encoding such fusion polypeptides include conservative substitutions that have been introduced by modification of polynucleotides encoding polypeptides of the disclosure. Amino acids can be classified according to physical properties and contribution to secondary and tertiary protein structure. A conservative substitution is a substitution of one amino acid for another amino acid that has similar properties. Exemplary conservative substitutions are set out in Table 1.
  • the term ‘'more than one” of the aforementioned amino acid substitutions refers to 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 or more of the recited amino acid substitutions.
  • the term “more than one” may refer to 2, 3, 4, or 5 of the recited amino acid substitutions.
  • Polypeptides and proteins of the disclosure may be non-naturally occurring.
  • Polypeptides and proteins of the disclosure may contain one or more mutations, substitutions, deletions, or insertions that do not naturally occur, rendering the entire amino acid sequence non-naturally occurring.
  • Polypeptides and proteins of the disclosure may contain one or more duplicated, inverted or repeated sequences, the resultant sequence of which does not naturally occur, rendering the entire amino acid sequence non-naturally occurring.
  • Polypeptides and proteins of the disclosure may contain modified, artificial, or synthetic amino acids that do not naturally occur, rendering the entire amino acid sequence non-naturally occurring.
  • sequence identity may be determined by using the stand-alone executable BLAST engine program for blasting two sequences (bl2seq), which can be retrieved from the National Center for Biotechnology Information (NCBI) ftp site, using the default parameters (Tatusova and Madden, FEMS Microbiol Lett., 1999, 174, 247-250; which is incorporated herein by reference in its entirety).
  • NCBI National Center for Biotechnology Information
  • identity when used in the context of two or more nucleic acids or polypeptide sequences, refer to a specified percentage of residues that are the same over a specified region of each of the sequences.
  • the percentage can be calculated by optimally aligning the two sequences, comparing the two sequences over the specified region, determining the number of positions at which the identical residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the specified region, and multiplying the result by 100 to yield the percentage of sequence identity.
  • the two sequences are of different lengths or the alignment produces one or more staggered ends and the specified region of comparison includes only a single sequence, the residues of a single sequence are included in the denominator but not the numerator of the calculation.
  • thymine (T) and uracil (U) can be considered equivalent.
  • Identity can be performed manually or by using a computer sequence algorithm such as BLAST or BLAST 2.0.
  • endogenous refers to nucleic acid or protein sequences naturally associated with a target gene or a host cell into which it is introduced.
  • exogenous refers to nucleic acid or protein sequences not naturally associated with a target gene or a host cell into which it is introduced, including non-naturally occurring multiple copies of a naturally occurring nucleic acid, e.g., DNA sequence, or naturally occurring nucleic acid sequence located in a non- naturally occurring genome location.
  • the disclosure provides methods of introducing a polynucleotide construct comprising a DNA sequence into a host cell.
  • introducing is intended to present to the cell the polynucleotide construct in such a manner that the construct gains access to the interior of the host cell.
  • the methods of the disclosure do not depend on a particular method for introducing a polynucleotide construct into a host cell, only that the polynucleotide construct gains access to the interior of one cell of the host.
  • Methods for introducing polynucleotide constructs into bacteria, plants, fungi and animals are known in the art including, but not limited to, stable transformation methods, transient transformation methods, and virus-mediated methods.
  • Embodiment 1 A compound of Formula (I):
  • R3 is H, methyl, C 1 -C 10 alkyl optionally substituted with one or more hydroxyl, each of R 4a and R4b is independently C 1 -C 18 alkyl.
  • Embodiment 3 The compound of claim 1, wherein A is:
  • Embodiment 4 The compound of claim 1, wherein A is:
  • Embodiment 7 The compound of claim 1 or claim 2, wherein each B is: hich * indicates attachment to A and ** indicates attachment to C. he compound of any one of claims 1-6, wherein each B is: m which * indicates attachment to A and ** indicates attachment to C.
  • Embodiment 9 The compound of claim 8, wherein each e is 1.
  • Embodiment 11 The compound of any one of claims 1-10, wherein each C is , in which denotes a single or double bond.
  • Embodiment 12 The compound of any one of claims 1-11, wherein each C is [0339] Embodiment 13. The compound of any one of claims 1-11, wherein each C is
  • Embodiment 14 The compound of any one of claims 1 or 4, wherein A is
  • Embodiment 15 The compound of any one of claims 1 or 4, wherein A is each Z is a covalent bond.
  • Embodiment 16 The compound of any one of claims 1-15. wherein each R2 is H.
  • Embodiment 17 The compound of any one of claims 1-15, wherein each R2 is methyl.
  • Embodiment 19 The compound of claim 18, wherein each Ri
  • Embodiment 22 The compound of any of claims 1-20, wherein a is 3 and b is 3.
  • Embodiment 24 The compound of any of claims 1-22, wherein c is 4 and d is 4.
  • Embodiment 25 The compound of claim 1 or 2, wherein
  • Embodiment 26 The compound of any of claims 1-24, wherein R3 is C 1 -C 10 alkyl optionally substituted with one or more hydroxyl.
  • Embodiment 27 The compound of claim 26, wherein R3 is
  • Embodiment 28 The compound of any of claims 1-27, wherein n is 4.
  • Embodiment 29 A compound selected from:
  • Embodiment 30 A composition comprising at least one lipid nanoparticle comprising at least one compound of Formula (I):
  • R 3 is H, methyl, C 1 -C 10 alkyd optionally substituted with one or more hydroxyl, each of R 4a and R-ib is independently C 1 -C 18 alkyl, wherein the at least one lipid nanoparticle further comprises at least one nucleic acid molecule.
  • Embodiment 31 The composition of claim 30, wherein A is:
  • Embodiment 32 The composition of claim 30, wherein A is:
  • Embodiment 33 The composition of claim 30, wherein A is: [0359] Embodiment 34. The composition of claim 30, wherein A is:
  • Embodiment 36 The composition of claim 30 or claim 31, wherein each B is: hich * indicates attachment to A and ** indicates attachment to C. he composition of any one of claims 30-35, wherein each B is: in which * indicates attachment to A and ** indicates attachment to C.
  • Embodiment 38 The composition of claim 37, wherein each e is 1.
  • Embodiment 39 The composition of claim 37, wherein each e is 2.
  • Embodiment 40 The composition of any one of claims 30-39, wherein each C is , in which > denotes a single or double bond.
  • Embodiment 43 The composition of any one of claims 30 or 33, wherein A is [0369]
  • Embodiment 44 The composition of any one of claims 30 or 33, wherein A is each Z is a covalent bond.
  • Embodiment 45 The composition of any one of claims 30-44, wherein each R2 is H.
  • Embodiment 46 The composition of any one of claims 30-44, wherein each R2 is methyl.
  • Embodiment 49 The composition of any of claims 30-46, wherein each Ri is Ci Cis alky l.
  • Embodiment 50 The composition of any of claims 30-49. wherein a is 2 and b is 2.
  • Embodiment 51 The composition of any of claims 30-49, wherein a is 3 and b is 3.
  • Embodiment 52 The composition of any of claims 30-51, wherein c is 3 and d is 3.
  • Embodiment 55 The composition of any of claims 30-53, wherein R3 is C 1 -C 10 alkyl optionally substituted with one or more hydroxyl.
  • Embodiment 56 The composition of claim 55, wherein R 3 is
  • Embodiment 57 The composition of any of claims 30-56. wherein n is 4.
  • Embodiment 58 The composition of claim 30, wherein the compound of Formula (I) is: [0384] Embodiment 59.
  • the composition of claim 30, wherein the at least one nucleic acid molecule comprises at least one RNA molecule and/or at least one DNA molecule.
  • Embodiment 62 The composition of claim 59, wherein the DNA molecule is a circular DNA molecule, DoggyBone DNA molecule, a DNA plasmid, a DNA nanoplasmid, or a linearized DNA molecule, preferably wherein the DNA molecule is a Doggy Bone DNA molecule or a DNA nanoplasmid.
  • Embodiment 63 The composition of claim 59, wherein the at least one DNA molecule comprises a nucleic acid sequence encoding at least one transposon.
  • Embodiment 64 The composition of any of the preceding claims, wherein the at least one nucleic acid molecule comprises a nucleic acid sequence encoding at least one therapeutic protein.
  • Embodiment 65 The composition of any of the preceding claims, wherein the at least one nucleic acid molecule comprises a nucleic acid sequence encoding at least one transposon, wherein the transposon comprises a nucleic acid sequence encoding at least one therapeutic protein.
  • Embodiment 66 A pharmaceutical composition, comprising a composition of any of the preceding claims and at least one pharmaceutically-acceptable excipient or diluent.
  • Embodiment 67 A method of delivering at least one nucleic acid to at least one cell comprising contacting the at least one cell with at least one composition of any of the preceding claims.
  • Embodiment 68 A method of genetically modifying at least one cell comprising contacting the at least one cell with at least one composition of any of the preceding claims.
  • Embodiment 69 The method of claims 67 or 68, wherein the at least one cell is a lung cell.
  • Embodiment 70 At least one cell modified according to the method of any one of claims 67-69.
  • Embodiment 71 A method of treating at least one disease or disorder in a subject in need thereof comprising administering to the subject at least one therapeutically effective amount of the composition of any one of claims 64-66 or the at least one cell of claim 70.
  • Embodiment 72 The method of claim 71, wherein the at least one disease or disorder is a lung disease or disorder.
  • Embodiment 73 The method of claim 72, wherein the lung disease or disorder is cystic fibrosis.
  • Embodiment 74 A method of preferential delivery of a composition to a lung or a lung cell in a subject in need thereof, the method comprising administering the composition according to any of the preceding claims, thereby providing a greater amount, expression or activity’ of the composition in the lung or the lung cell of the subject as compared to that achieved in a non-lung organ or a non-lung cell in the subject.
  • COMPOUND NO. 7 was prepared in accordance with General Scheme A.7. MS (ESI): calcd. for C101H163N7O20S4 [M+H] + 1923.1, found 1923.

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Abstract

L'invention concerne des compositions comprenant des composés lipidoïdes, des procédés de préparation de telles compositions, et l'utilisation de ces compositions dans des applications d'administration de gènes.
PCT/US2025/014972 2024-02-08 2025-02-07 Composés lipidoïdes et compositions et utilisations associées Pending WO2025171237A1 (fr)

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