WO2025106876A1 - Agents ciblant la fidgetine de type 2 et leurs utilisations - Google Patents

Agents ciblant la fidgetine de type 2 et leurs utilisations Download PDF

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WO2025106876A1
WO2025106876A1 PCT/US2024/056211 US2024056211W WO2025106876A1 WO 2025106876 A1 WO2025106876 A1 WO 2025106876A1 US 2024056211 W US2024056211 W US 2024056211W WO 2025106876 A1 WO2025106876 A1 WO 2025106876A1
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nucleic acid
seq
wound
acid molecule
sequence
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Adam H. KRAMER
David J. Sharp
Lisa Ann BAKER
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Microcures Inc
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Microcures Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/7115—Nucleic acids or oligonucleotides having modified bases, i.e. other than adenine, guanine, cytosine, uracil or thymine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/712—Nucleic acids or oligonucleotides having modified sugars, i.e. other than ribose or 2'-deoxyribose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/7125—Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering nucleic acids [NA]

Definitions

  • a nucleic acid molecule comprising the sequence GCCAUAUGCGCCGUGUACU[dT][dT] (SEQ ID NO:1).
  • a nucleic acid molecule comprising the sequence AGUACACGGCGCAUAUGGC[dT][dT] (SEQ ID NO:2). In some embodiments, the nucleic acid molecule comprises no more than 52 nucleotides. [006] In one aspect, a double stranded nucleic acid molecule is provided wherein one strand comprises the sequence GCCAUAUGCGCCGUGUACU[dT][dT] (SEQ ID NO:1). In some embodiments, the sequence comprising GCCAUAUGCGCCGUGUACU[dT][dT] (SEQ ID NO:1) comprises no more than 52 nucleotides.
  • a double stranded nucleic acid molecule wherein one strand comprises the sequence AGUACACGGCGCAUAUGGC[dT][dT] (SEQ ID NO:2).
  • the sequence comprising AGUACACGGCGCAUAUGGC[dT][dT] comprises no more than 52 nucleotides.
  • a double stranded nucleic acid molecule comprising a strand comprising the sequence GCCAUAUGCCGUGUACU[dT][dT] (SEQ ID NO:1) and a strand comprising the sequence AGUACACGGCGCAUAUGGC[dT][dT] (SEQ ID NO:2).
  • each sequence comprises no more than 52 nucleotides.
  • a nucleic acid molecule is provided consisting of the sequence GCCAUAUGCGCCGUGUACU[dT][dT] (SEQ ID NO:1).
  • a nucleic acid molecule consisting of the sequence AGUACACGGCGCAUAUGGC[dT][dT] (SEQ ID NO:2).
  • a double stranded nucleic acid molecule is provided wherein one strand consists of GCCAUAUGCGCCGUGUACU[dT][dT] (SEQ ID NO:1).
  • a double stranded nucleic acid molecule wherein one strand consists of AGUACACGGCGCAUAUGGC[dT][dT] (SEQ ID NO:2) [0013] In one aspect, a double stranded nucleic acid molecule is provided consisting of GCCAUAUGCGCCGUGUACU[dT][dT] (SEQ ID NO:1) and AGUACACGGCGCAUAUGGC[dT][dT] (SEQ ID NO:2).
  • SEQ ID NO:1 comprises ribonucleotides at positions 1- 19, and deoxyribonucleotides at positions 20 and 21; and SEQ ID NO:2 comprises ribonucleotides at positions 1-19, and deoxyribonucleotides at positions 20 and 21.
  • the nucleic acid has at least one modification selected from a 3’ overhang, a 5’ overhang, a 5’ phosphorylation, a 2’ sugar modification, a nucleic acid base modification, a phosphate backbone modification, a phosphodiester cap, or any combination of one or more of any of the foregoing.
  • the one or more modification is 2’-O-methyl-adenosine, 2’-O-methyl-uridine, 2’-O-methyl-cytosine, 2’-O- methyl-guanosine, 2’-O-methyl-thymidine, 2’-fluoro-adenosine, 2’-fluoro-cytidine, 2’-fluoro- guanosine, 2’-fluoro-uracil, 2’-fluoro-thymidine, deoxycytosine, deoxyguanosine, deoxyadenosine, deoxythymidine, deoxyuridine, a locked adenosine, a locked uridine, a locked guanosine, a locked cytidine, a phosphorothioate, a phosphodiester cap, or any combination thereof.
  • a composition comprising any of the foregoing nucleic acid molecules or double-stranded nucleic acids, and a pharmaceutically acceptable carrier, vehicle, excipient or diluent.
  • the carrier comprises at least one of the following: saline, a sugar, a polypeptide, a polymer, a lipid, a cream, a gel, a micelle material, a wafer, a liposome or a nanoparticle.
  • the carrier comprises at least one of the following: a glucose solution, a polycationic binding agent, a cationic lipid, a cationic micelle, a cationic polypeptide, a hydrophilic polymer grafted polymer, a non-natural cationic polymer, a cationic polyacetal, a hydrophilic polymer grafted polyacetal, a ligand functionalized cationic polymer, a nucleic acid delivery vehicle, a ligand functionalized-hydrophilic polymer grafted polymer, or a ligand functionalized liposome.
  • the carrier comprises a cationic polymer-nucleic acid complex.
  • the hydrophilic polymer is polyethylene glycol (PEG).
  • the nanoparticle is a liposomal nanoparticle.
  • the carries comprises collagen.
  • the composition is collagen microparticles.
  • the nucleic acid molecule is adsorbed to the collagen.
  • the collagen microparticles are provided in a surfactant polymer dressing.
  • the polymer comprises a poloxamer.
  • the nucleic acid is provided in a liposome, microparticle or nanoparticle.
  • a method for treating a pathological process in a subject comprising administering to the subject a therapeutically effective amount of any of the foregoing nucleic acids or compositions thereof.
  • pathological processes include healing for example from a wound, burn, neuropathy, vasculopathy, or cardiopathy, whether as a result of external injury or trauma, or as a result of a disease process.
  • the disease process may be induced by an external injury or wound, or an infection, metabolic disorder, and the like.
  • the method is directed to treating the disease process that occurs after an initial disease induction event.
  • the pathological process or disease is acute.
  • the pathological process or disease is chronic.
  • a method for treating a wound, injury or other pathological process, or inhibiting, reducing or preventing a scar or other pathological process in a subject comprising administering to the subject a therapeutically effective amount of any of the foregoing nucleic acids or compositions thereof.
  • the wound, injury or scar is of the skin, eye, central nervous system, peripheral nervous system, cardiac tissue, blood vessel, tendon, ligament, muscle, oral cavity, lips, palate, internal organs, surgical wounds, abdominal cavity, pelvic cavity or thoracic cavity.
  • the wound, injury or scar of the eye is of the cornea or lens capsule.
  • the wound or scar results from eye surgery, LASIK surgery, LASEK surgery, PRK surgery, glaucoma filtration surgery, cataract surgery, and corneal cicatrisation.
  • the wound, injury or scar of the central nervous system is a wound, injury or scar of the brain.
  • the wound, injury or scar of the central nervous system is a wound, injury or scar of the spinal cord.
  • the wound, injury or scar is traumatic brain injury.
  • the wound, injury or scar is spinal cord injury.
  • inhibition of scarring reduces the number of incidences of adhesion formation and/or the size of adhesions formed.
  • the cardiac tissue wound is from a myocardial infraction.
  • the wound is a neuronal wound.
  • the wound results in a capsular contraction.
  • the wound is a surgical wound.
  • the wound is from a cosmetic procedure or a scar revision.
  • skin graft healing is enhanced using a composition of the disclosure.
  • a nucleic acid disclosed herein of composition thereof is used to treat or ameliorate a pathological condition in addition to those described above.
  • Such other pathological processes include the sequelae from a wound or injury, such as but not limited to nerve damage or chronic neuropathy, chronic pain resulting from an initial wound, injury or disease process, and neurotrophic keratitis resulting from, for example, an initial injury to the cornea.
  • a method for accelerating or improving the healing of a skin graft or skin grafting site in a subject comprising administering to the subject an effective amount of any pharmaceutical composition as described herein to accelerate healing of the skin graft or skin grafting site.
  • a method for accelerating or improving the healing of a spinal cord injury in a subject comprising administering to the subject an effective amount of any pharmaceutical composition disclosed herein to accelerate healing of the spinal cord injury.
  • DETAILED DESCRIPTION [0028] The present subject matter may be understood more readily by reference to the following detailed description which forms a part of this disclosure. It is to be understood that this disclosure is not limited to the specific products, methods, conditions or parameters described and/or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed disclosure.
  • the terms “treat”, “treatment”, or “therapy” refer to therapeutic treatment, including prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change associated with a disease or condition.
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of the extent of a disease or condition, stabilization of a disease or condition (i.e., where the disease or condition does not worsen), delay or slowing of the progression of a disease or condition, amelioration or palliation of the disease or condition, and remission (whether partial or total) of the disease or condition, whether detectable or undetectable.
  • Those in need of treatment include those already with the disease or condition as well as those prone to having the disease or condition or those in which the disease or condition is to be prevented.
  • the terms “component,” “composition,” “formulation”, “composition of compounds,” “compound,” “drug,” “pharmacologically active agent,” “active agent,” “therapeutic,” “therapy,” “treatment,” or “medicament,” are used interchangeably herein, as context dictates, to refer to a compound or compounds or composition of matter which, when administered to a subject (human or animal) induces a desired pharmacological and/or physiologic effect by local and/or systemic action.
  • a personalized composition or method refers to a product or use of the product in a regimen tailored or individualized to meet specific needs identified or contemplated in the subject.
  • subject refers to an animal, for example a human, to whom treatment with a composition or formulation in accordance with the present disclosure, is provided.
  • subject refers to human and non-human animals.
  • non-human animals and “non-human mammals” are used interchangeably herein and include all vertebrates, e.g., mammals, such as non-human primates, (particularly higher primates), sheep, dog, rodent, (e.g., mouse or rat), guinea pig, goat, pig, cat, rabbits, cows, horses and non-mammals such as reptiles, amphibians, chickens, and turkeys.
  • the compositions described herein can be used to treat any suitable mammal, including primates, such as monkeys and humans, horses, cows, cats, dogs, rabbits, and rodents such as rats and mice.
  • the mammal to be treated is human.
  • the human can be any human of any age.
  • the human is an adult. In another embodiment, the human is a child.
  • the human can be male, female, pregnant, middle-aged, adolescent, or elderly.
  • the subject is human.
  • the subject is a non-human primate.
  • the subject is murine, which in some embodiments is a mouse, and, in another embodiment is a rat.
  • the subject is canine, feline, bovine, equine, laprine or porcine.
  • the subject is mammalian.
  • a non-human animals e.g., non-human primate, non-human mammal
  • treatment of a non-human animals may require use of a siRNAs directed to the orthologue of fidgetin-like 2 in the particular species.
  • Conditions and disorders in a subject for which a particular drug, compound, composition, formulation (or combination thereof) is said herein to be "indicated” are not restricted to conditions and disorders for which that drug or compound or composition or formulation has been expressly approved by a regulatory authority, but also include other conditions and disorders known or reasonably believed by a physician or other health or nutritional practitioner to be amenable to treatment with that drug or compound or composition or formulation or combination thereof.
  • the present disclosure is directed to nucleic acid sequences that inhibit human fidgetin- like 2 activity, pharmaceutical compositions thereof, and methods of their use for preventing or treating various injuries, wounds and diseases.
  • the nucleic acid sequence is a small interfering RNA (siRNA) sequence.
  • the siRNA comprises ribonucleotides and deoxyribonucleotides.
  • nucleic acid molecule comprising the sequence GCCAUAUGCGCCGUGUACU[dT][dT] (SEQ ID NO:1), AGUACACGGCGCAUAUGGC[dT][dT] (SEQ ID NO:2), or comprising a duplex comprising SEQ ID NO:1 and SEQ ID NO:2.
  • SEQ ID NO:1 comprises ribonucleotides at positions 1-19, and deoxyribonucleotides at positions 20 and 21.
  • SEQ ID NO:2 comprises ribonucleotides at positions 1-19, and deoxyribonucleotides at positions 20 and 21.
  • a duplex nucleic acid molecule comprising the sequence GCCAUAUGCGCCGUGUACU[dT][dT] (SEQ ID NO:1).
  • SEQ ID NO:1 comprises ribonucleotides at positions 1-19, and deoxyribonucleotides at positions 20 and 21.
  • a duplex nucleic acid molecule is provided comprising the sequence AGUACACGGCGCAUAUGGC[dT][dT] (SEQ ID NO:2).
  • any nucleic acid molecule comprises no more than 52 nucleotides.
  • the nucleic acid molecule comprises a single stranded sequence of GCCAUAUGCGCCGUGUACU[dT][dT] (SEQ ID NO:1) or AGUACACGGCGCAUAUGGC[dT][dT] (SEQ ID NO:2).
  • a double stranded nucleic acid is provided comprising SEQ ID NO:1 and SEQ ID NO:2.
  • one or both nucleic acids of a double stranded nucleic acid comprise no more than 52 nucleotides.
  • a nucleic acid molecule consisting of the sequence GCCAUAUGCGCCGUGUACU[dT][dT] (SEQ ID NO:1), AGUACACGGCGCAUAUGGC[dT][dT] (SEQ ID NO:2), or consisting of a duplex consisting of SEQ ID NO:1 and SEQ ID NO:2.
  • a duplex nucleic acid molecule is provided wherein one sequence consists of the sequence GCCAUAUGCGCCGUGUACU[dT][dT] (SEQ ID NO:1).
  • a duplex nucleic acid molecule wherein one sequence consists of the sequence AGUACACGGCGCAUAUGGC[dT][dT] (SEQ ID NO:2). [0050] In some embodiments, the nucleic acid molecule consists of no more than 52 nucleotides. [0051] In some embodiments, the nucleic acid molecule consists of a single stranded sequence of GCCAUAUGCGCCGUGUACU[dT][dT] (SEQ ID NO:1) or AGUACACGGCGCAUAUGGC[dT][dT] (SEQ ID NO:2).
  • a double stranded nucleic acid is provided consisting of SEQ ID NO:1 and SEQ ID NO:2.
  • SEQ ID NO:1 is referred to as a sense strand
  • SEQ ID NO:2 is referred to as an antisense strand.
  • the nucleic acids disclosed herein, and in particular double-stranded nucleic acids are referred to as small interfering RNA or siRNA.
  • a siRNA comprises a sense strand and an antisense strand.
  • the siRNA comprises deoxyribonucleotides at the 3’ end.
  • SEQ ID NO:1 comprises ribonucleotides at positions 1-19, and deoxyribonucleotides dT at positions 20 and 21.
  • SEQ ID NO:2 comprises ribonucleotides at positions 1-19, and deoxyribonucleotides dT at positions 20 and 21.
  • a nucleic acid comprises no more than 52 nucleotides.
  • a single strand component of a siRNA of the disclosure is from 14 to 50 nucleotides in length.
  • a single strand component of a siRNA of the disclosure is 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 nucleotides in length.
  • a single strand component of a siRNA of the disclosure is 20 nucleotides in length. In yet another embodiment, a single strand component of a siRNA of the disclosure is 21 nucleotides in length. In yet another embodiment, a single strand component of a siRNA of the disclosure is 22 nucleotides in length. In yet another embodiment, a single strand component of a siRNA of the disclosure is 23 nucleotides in length. In some embodiments, a siRNA of the disclosure is from 28 to 56 nucleotides in length. In another embodiment, a siRNA of the disclosure is 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 nucleotides in length.
  • one single strand component of a double-stranded siRNA of the disclosure is from 20 to 50 nucleotides in length. In another embodiment, one single strand component of a double-stranded siRNA of the disclosure is independently 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 nucleotides in length. In yet another embodiment, one single strand component of a double-stranded siRNA of the disclosure is 20 nucleotides in length. In yet another embodiment, one single strand component of a double-stranded siRNA of the disclosure is 21 nucleotides in length. In yet another embodiment, one single strand component of a double-stranded siRNA of the disclosure is 22 nucleotides in length.
  • one single strand component of a double-stranded siRNA of the disclosure is 23 nucleotides in length. In some embodiments, one single strand components of a double-stranded siRNA of the disclosure is from 28 to 56 nucleotides in length. In another embodiment, one single strand component of a double-stranded siRNA of the disclosure is 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 nucleotides in length.
  • a nucleic acid embodied herein may have at least about 90%, or at least about 95%, sequence identity to SEQ ID NO:1 or SEQ ID NO:2, wherein a change or modification of any nucleotide as described herein may be provided.
  • a nucleic acid embodied herein comprises or consists of 20 contiguous nucleotides within SEQ ID NO:1 or SEQ ID NO:2, in any single stranded or double stranded nucleic acid disclosed herein.
  • nucleic acid sequences consisting of CCAUAUGCGCCGUGUACU[dT][dT] (SEQ ID NO:5), GUACACGGCGCAUAUGGC[dT][dT] (SEQ ID NO:6), GCCAUAUGCGCCGUGUACU[dT] (SEQ ID NO:7), or AGUACACGGCGCAUAUGGC[dT] (SEQ ID NO:8).
  • SEQ ID NO:5 and SEQ ID NO:6 comprise ribonucleotides at positions 1-18, and deoxyribonucleotides at positions 19 and 20; and SEQ ID NO:7 and SEQ ID NO:8 comprise ribonucleotides at positions 1-19, and a deoxyribonucleotide at positions 20.
  • a single stranded nucleic acid molecule comprising CCAUAUGCGCCGUGUACU[dT][dT] (SEQ ID NO:5), GUACACGGCGCAUAUGGC[dT][dT] (SEQ ID NO:6), GCCAUAUGCGCCGUGUACU[dT] (SEQ ID NO:7), or AGUACACGGCGCAUAUGGC[dT] (SEQ ID NO:8).
  • the nucleic acid molecule comprises no more than 52 nucleotides.
  • a single stranded nucleic acid molecule consisting of CCAUAUGCGCCGUGUACU[dT][dT] (SEQ ID NO:5), GUACACGGCGCAUAUGGC[dT][dT] (SEQ ID NO:6), GCCAUAUGCGCCGUGUACU[dT] (SEQ ID NO:7), or AGUACACGGCGCAUAUGGC[dT] (SEQ ID NO:8).
  • a double stranded nucleic acid molecule wherein one strand comprises any one of sequences CCAUAUGCGCCGUGUACU[dT][dT] (SEQ ID NO:5), GUACACGGCGCAUAUGGC[dT][dT] (SEQ ID NO:6), GCCAUAUGCGCCGUGUACU[dT] (SEQ ID NO:7), or AGUACACGGCGCAUAUGGC[dT] (SEQ ID NO:8).
  • the sequence comprises no more than 52 nucleotides.
  • a double stranded nucleic acid molecule wherein one strand consists of any one of CCAUAUGCGCCGUGUACU[dT][dT] (SEQ ID NO:5), GUACACGGCGCAUAUGGC[dT][dT] (SEQ ID NO:6), GCCAUAUGCGCCGUGUACU[dT] (SEQ ID NO:7), or AGUACACGGCGCAUAUGGC[dT] (SEQ ID NO:8).
  • a double stranded nucleic acid molecule comprising a strand comprising the sequence CCAUAUGCGCCGUGUACU[dT][dT] (SEQ ID NO:5) and a strand comprising the sequence GUACACGGCGCAUAUGGC[dT][dT] (SEQ ID NO:6).
  • a double stranded nucleic acid molecule is provided comprising the sequence GCCAUAUGCGCCGUGUACU[dT] (SEQ ID NO:7) and a strand comprising the sequence AGUACACGGCGCAUAUGGC[dT] (SEQ ID NO:8).
  • each sequence comprises no more than 52 nucleotides.
  • a double stranded nucleic acid molecule comprising a strand consisting of the sequence CCAUAUGCGCCGUGUACU[dT][dT] (SEQ ID NO:5) and a strand consisting of the sequence GUACACGGCGCAUAUGGC[dT][dT] (SEQ ID NO:6).
  • a double stranded nucleic acid molecule is provided comprising a strand consisting of the sequence GCCAUAUGCGCCGUGUACU[dT] (SEQ ID NO:7) and a strand consisting of the sequence AGUACACGGCGCAUAUGGC[dT] (SEQ ID NO:8).
  • a double stranded nucleic acid molecule comprising a strand consisting of the sequence CCAUAUGCGCCGUGUACU[dT][dT] (SEQ ID NO:5) and a strand consisting of the sequence AGUACACGGCGCAUAUGGC[dT][dT] (SEQ ID NO:2).
  • a double stranded nucleic acid molecule is provided comprising a strand consisting of the sequence GCCAUAUGCGCCGUGUACU[dT] (SEQ ID NO:7) and a strand consisting of the sequence AGUACACGGCGCAUAUGGC[dT][dT] (SEQ ID NO:2).
  • a double stranded nucleic acid molecule comprising a strand comprising the sequence CCAUAUGCGCCGUGUACU[dT][dT] (SEQ ID NO:5) and a strand comprising the sequence AGUACACGGCGCAUAUGGC[dT][dT] (SEQ ID NO:2).
  • a double stranded nucleic acid molecule is provided comprising the sequences GCCAUAUGCGCCGUGUACU[dT] (SEQ ID NO:7) and AGUACACGGCGCAUAUGGC[dT][dT] (SEQ ID NO:2).
  • each sequence comprises no more than 52 nucleotides.
  • a double stranded nucleic acid molecule comprising a strand consisting of the sequence GCCAUAUGCGCCGUGUACU[dT][dT] (SEQ ID NO:1) and a strand consisting of the sequence GUACACGGCGCAUAUGGC[dT][dT] (SEQ ID NO:6).
  • a double stranded nucleic acid molecule is provided comprising a strand consisting of the sequence GCCAUAUGCGCCGUGUACU[dT][dT] (SEQ ID NO:1) and a strand consisting of the sequence AGUACACGGCGCAUAUGGC[dT] (SEQ ID NO:8).
  • a double stranded nucleic acid molecule comprising a strand comprising the sequence GCCAUAUGCCGUGUACU[dT][dT] (SEQ ID NO:1) and a strand comprising the sequence GUACACGGCGCAUAUGGC[dT][dT] (SEQ ID NO:6).
  • a double stranded nucleic acid molecule is provided comprising the sequences GCCAUAUGCCGUGUACU[dT][dT] (SEQ ID NO:1) and AGUACACGGCGCAUAUGGC[dT] (SEQ ID NO:8).
  • each sequence comprises no more than 52 nucleotides.
  • any U is changed to dT.
  • any nucleic acid embodied herein have a length of 20 nucleotides, 21 nucleotides, 22 nucleotides, 23 nucleotides, 24 nucleotides, 25 nucleotides, 26 nucleotides, 27 nucleotides, 28 nucleotides, 29 nucleotides, 30 nucleotides, 31 nucleotides, 32 nucleotides, 33 nucleotides, 34 nucleotides, 35 nucleotides, 36 nucleotides, 37 nucleotides, 38 nucleotides, 39 nucleotides, 40 nucleotides, 41 nucleotides, 42 nucleotides, 43 nucleotides, 44 nucleotides, 45 nucleotides, 46 nucleotides, 47 nucleotides, 48 nucleotides, 49 nucleo
  • any nucleic acid sequence disclosed herein has at least one modification selected from a 3’ overhang, a 5’ overhang, a 5’ phosphorylation, a 2’ sugar modification, a nucleic acid base modification, a phosphate backbone modification, or any combination of one or more of any of the foregoing.
  • Any of the sequences may have a phosphodiester cap. Any of the sequences may have one or more than one of the same or different modifications.
  • Non-limiting examples of one or more modifications include 2’-O-methyl-adenosine, 2’- O-methyl-uridine, 2’-O-methyl-cytosine, 2’-O-methyl-guanosine, 2’-O-methyl-thymidine, 2’- fluoro-adenosine, 2’-fluoro-cytidine, 2’-fluoro-guanosine, 2’-fluoro-uracil, 2’-fluoro-thymidine, deoxycytosine, deoxyguanosine, deoxyadenosine, deoxythymidine, deoxyuridine, a locked adenosine, a locked uridine, a locked guanosine, a locked cytidine, a phosphorothioate, and a phosphodiester cap.
  • any additional nucleotide or modified nucleotide such as but not limited to those aforementioned is added to an end of the nucleic acid.
  • any of the nucleic acid sequences disclosed herein may be modified or further modified with one or more nucleotide modifications as described herein.
  • any unmodified nucleotide in a sequence described herein may be modified to one of the modified nucleotides such as but not limited to those described herein.
  • a modified nucleotide in a sequence described herein may be changed to a different modified nucleotide such as but not limited to one of the modified nucleotides described herein.
  • Modified nucleotide or modified nucleic acid encompasses modified nucleotides, bonds between nucleotides or any component of a nucleotide, and addition of one or more modified or unmodified nucleotides to one or both ends of a sequence, or addition of a cap, as described herein.
  • the 5' terminal residue of a strand of the siRNA is phosphorylated.
  • the 5' terminal residue of the antisense strand of the siRNA is phosphorylated.
  • the 5' terminal residue of a strand of the siRNA is not phosphorylated.
  • the 5' terminal residue of the antisense strand of the siRNA is not phosphorylated.
  • the abbreviation “d(nucleotide)” refers to the deoxy-nucleotide.
  • the abbreviation “m(nucleotide)” refers to the 2 ⁇ -O-methyl nucleotide.
  • the abbreviation “T” refers to thymidine.
  • the abbreviation f(nucleotide) refers to the 2 ⁇ -fluorodeoxy nucleotide.
  • (Phos)” refers to a phosphodiester cap.
  • a capital letter residue refers to an RNA residue.
  • the abbreviation “l(nucleotide)” refers to a locked nucleotide.
  • a locked nucleotide has an extra bridge connecting the 2' oxygen and 4' carbon.
  • the abbreviation “(s)” refers to phosphorothioate, i.e., a phosphorothioate bond between the adjacent nucleotides or modified nucleotides. Otherwise, the abbreviations for nucleotides and ribonucleotides have the meaning known in the art. [0076] The abbreviations of the modifications of nucleotides described herein are as follows. mU refers to 2’-O-methyl-uridine. mA refers to 2’-O-methyl-adenosine. mC refers to 2’-O-methyl- cytidine.
  • mG refers to 2’-O-methyl-guanosine.
  • fA refers to 2’-fluoro-adenosine.
  • fC refers to 2’- fluoro-cytidine.
  • fG refers to 2’-fluoro-guanosine.
  • fU refers to 2’-fluoro-uridine.
  • dC refers to deoxycytidine.
  • dG refers to deoxyguanosine.
  • dA refers to deoxyadenosine.
  • dT refers to deoxythymidine.
  • A refers to adenine
  • U refers to uracil
  • G refers to guanine
  • C refers to cytosine
  • T refers to thymine.
  • lA lower case L followed by A
  • lU refers to a locked uridine
  • lG refers to a locked guanosine
  • lC refers to a locked cytidine.
  • any G may be replaced by mG.
  • any of G in positions 1, 8, 10, 13 and/or 15 may be replaced by mG.
  • any C may be replaced by fC or mC.
  • any of C in positions 2, 3, 9, 11, 12, and/or 18 may be replaced independently by fC or mC.
  • any A may be replaced by a mA.
  • any of A in positions 4, 6 and/or 17 may be replaced by mA.
  • any U may be replaced by fU or mU.
  • any of U in positions 5, 7, 14, 16 and/or 19 may be replaced independently by fU or mU.
  • the G in position 1 is be replaced by mG.
  • C in position 2 is replaced fC.
  • C in position 2 is replaced by mC.
  • C in position 3 is replaced fC. In some embodiments, C in position 3 is replaced by mC. In some embodiments, A in position 6 is replaced by mA. In some embodiments, A in position 6 is replaced by mA. In some embodiments, U in positions 5 is replaced fU. In some embodiments, U in position 7 is replaced by fU. In some embodiments, U in position 5 is replaced mU. In some embodiments, U in position 7 is replaced by mU. [0080] By way of non-limiting example, in SEQ ID NO:2, any G may be replaced by mG. In some embodiments, any of G in positions 2, 8, 9, 11, 17 and/or 18 may be replaced by mG.
  • any C may be replaced by fC or mC. In some embodiments, any of C in positions 5, 7, 10, 12 and/or 19 may be replaced independently by fC or mC. In some embodiments, any A may be replaced by a mA. In some embodiments, any of A in positions 1, 4, 6, 13 and/or 15 may be replaced by mA. In some embodiments, any U may be replaced by fU or mU. In some embodiments, any of U in positions 3, 14 and/or 16 may be replaced independently by fU or mU. [0081] In SEQ ID NO:2, in some embodiments, the G in position 2 is be replaced by mG. In some embodiments, C in position 5 is replaced fC.
  • C in position 5 is replaced mC.
  • a in position 1 is replaced by mA.
  • a in position 4 is replaced by mA.
  • a in position 6 is replaced by mA.
  • U in position 3 is replaced fU.
  • U in position 3 is replaced by mU.
  • a phosphorothioate bond (abbreviated as “(s)”) may be present between the first and second nucleotide, and/or the second and third nucleotide.
  • SEQ ID NO:1 comprises G(s)CC, GC(s)C, or G(s)C(s)C as the first three nucleotides.
  • SEQ ID NO:2 comprises A(s)GU, AG(s)U, or A(s)G(s)UC as the first three nucleotides.
  • Such phosphorothioate bonds are in addition to any nucleotide modifications as described above, for example, in SEQ ID NO:1, mG(s)CC, G(s)fCmC or G(s)fC(s)mC; in SEQ ID NO:2, mA(s)GU, A(s)mGU, or A9s)G(s)fU.
  • any of the foregoing modifications may be made to the corresponding position(s) in any of SEQ ID Nos. 5-8.
  • the abbreviations herein of the unmodified and modified nucleic acid abbreviations may refer to the nucleic acid base, the nucleoside (i.e., the base and the sugar), or the nucleotide (the nucleoside and the phosphate group).
  • the nucleic acid base i.e., the base and the sugar
  • nucleotide the nucleoside and the phosphate group
  • a ribonucleotide that is modified is replaced with a modified ribonucleotide.
  • ribonucleotide that is modified is replaced with a modified deoxyribonucleotide.
  • a locked nucleic acid often referred to as inaccessible RNA, is a modified RNA nucleotide in which the ribose moiety is modified with an extra bridge connecting the 2' oxygen and 4' carbon.
  • a nucleic acid comprises a locked adenosine.
  • a nucleic acid comprises a locked cytosine.
  • a nucleic acid comprises a locked guanosine.
  • a nucleic acid comprises a locked uridine.
  • a nucleic acid comprises a locked thymidine.
  • the 5' terminal residue of a strand of the siRNA is phosphorylated.
  • the 5' terminal residue of the antisense strand of the siRNA is phosphorylated.
  • both are phosphorylated.
  • the nucleic acid sequences disclosed herein target the mRNA of fidgetin-like 2 (FL2).
  • NCBI reference sequence NM 001013690.4 (SEQ ID NO:3), to the nucleic acid encoding human fidgetin-like 2, is: 1 agtgagctat ggggacacta ctgcactgta gcctgggcaa cagagcaaga ccttgtctca 61 aaaatgtata tatattttgg gcttttttc ctaaacggg aactacaaca gcatatttgc 121 gagctgatga gagtgaccca gcagagaggg aaatggatca gctctgttga agatgcactg 181 gacaccagaa cacgcccagc cctcaacca gtggccagag cagcacctgg acgtctctctc 241 caccacccg tcgcggccccccc
  • nucleic acid sequences disclosed herein that are useful for treatment of a non-human animals (e.g., non-human primate, non-human mammal).
  • modifications of the nucleic acids disclosed herein comprise siRNAs directed to the orthologue of fidgetin-like 2 in the particular species.
  • Pharmaceutical Compositions [0089]
  • a formulation, pharmaceutical composition, or delivery system of any of the nucleic acids described herein is provided.
  • the formulation, pharmaceutical composition, or delivery system comprises a nucleic acid consisting of or comprising any of those nucleic acids described herein, such as single stranded or double stranded (e.g., a duplex.
  • the formulation comprises one or more nucleic acids comprising those selected from among SEQ ID NO:1 or SEQ ID NO:2, or a duplex or double-stranded nucleic acid comprising a nucleic acid comprising two nucleic acid molecules selected from among SEQ ID NO:1 and SEQ ID NO:2. In some embodiments, the formulation comprises one or more nucleic acids consisting of those selected from among SEQ ID NO:1 and SEQ ID NO:2, or a duplex or double-stranded nucleic acid consisting of two nucleic acid molecules selected from among SEQ ID NO:1 and SEQ ID NO:2. In some embodiments, the formulation comprises a duplex comprising SEQ ID NO:1 and any other nucleic acid.
  • the formulation comprises a duplex comprising SEQ ID NO:2 and any other nucleic acid. In some embodiments, the formulation comprises a duplex comprising a sequence consisting of SEQ ID NO:1 and any other nucleic acid. In some embodiments, the formulation comprises a duplex comprising a sequence consisting of SEQ ID NO:2 and any other nucleic acid. In other embodiments, any of SEQ ID NOs:5-8 may be used, as or part of single stranded nucleic acids, or consisting of or comprising one or both strands of a double stranded nucleic acids, in any formulation, pharmaceutical composition, or delivery system such as but not limited to those disclosed herein.
  • the inhibitor of fidgetin-like 2 by a nucleic acid disclosed herein is provided by a subcutaneous implant or depot medicament system for the pulsatile delivery of the inhibitor to a pathological site such as a wound or damaged nerve or to a site where a pathology is expected to be formed, for example, after surgery, to promote wound healing.
  • the inhibitor can be provided, for example, in a therapeutically effective amount to each centimeter of a wound margin or each centimeter of a site at which a wound is expected to be formed.
  • a medicament in accordance with this aspect of the disclosure may be formulated in any appropriate carrier, vehicle, diluent, excipient or other delivery system.
  • Suitable carriers are pharmaceutically acceptable carriers, preferably those consistent with administration topically or administration by injection, for example, intravenous administration or depot injection at a site.
  • different incidences of treatment may provide the inhibitor of fidgetin-like 2 by different formulations and/or different routes of administration.
  • the initial incidence of treatment may provide the inhibitor of fidgetin-like 2 by means of an injection, such as an intradermal injection, while the second (and any subsequent) incidences of treatment may involve provision of the inhibitor of fidgetin-like 2 by alternative routes, such as topical formulations, or vice versa.
  • the inhibitor of fidgetin-like 2 is provided in a pharmaceutical composition comprising saline. In some embodiments the pharmaceutical composition is normal saline or phosphate-buffered saline. [0094] In some embodiments the inhibitor of fidgetin-like 2 is provided in a pharmaceutical composition comprising a sugar. In some embodiments, the pharmaceutical composition is a glucose solution. [0095] In some embodiments the inhibitor of fidgetin-like 2 is provided in a pharmaceutical composition comprising a polypeptide. In some embodiments the polypeptide is a cationic polypeptide.
  • the cationic polypeptide is a histidine-lysine copolypeptide.
  • the inhibitor of fidgetin-like 2 is provided in a pharmaceutical composition comprising a polymer.
  • the hydrophilic polymer is polyethylene glycol (PEG).
  • the polymer is a hydrophilic polymer grafted polymer, a non-natural cationic polymer, a cationic polyacetal, a hydrophilic polymer grafted polyacetal, a ligand functionalized cationic polymer, or a ligand functionalized-hydrophilic polymer grafted polymer.
  • the hydrophilic polymer is polyethylene glycol (PEG).
  • the pharmaceutical composition comprises a polycationic binding agent.
  • the pharmaceutical composition comprises a nucleic acid delivery vehicle.
  • the pharmaceutical composition comprises a cationic polymer- nucleic acid complex.
  • the inhibitor of fidgetin-like 2 is provided in a pharmaceutical composition comprising a lipid.
  • the lipid is a cationic lipid.
  • the inhibitor of fidgetin-like 2 is provided in a pharmaceutical composition comprising a cream.
  • the inhibitor of fidgetin-like 2 is provided in a pharmaceutical composition comprising an eye drop.
  • the inhibitor of fidgetin-like 2 is provided in a pharmaceutical composition comprising a gel. [00104] In some embodiments the inhibitor of fidgetin-like 2 is provided in a pharmaceutical composition comprising a micelle material. [00105] In some embodiments the inhibitor of fidgetin-like 2 is provided in a pharmaceutical composition comprising a wafer. In some embodiments, a wafer comprises collagen, chondroitin sulfate, polyvinylpyrrolidone and polyethylene glycol 400. One non-limiting example of a wafer is described in an example herein. [00106] In some embodiments, the inhibitor of fidgetin-like 2 is provided in or associated with a collagen particle.
  • the collagen particle is a microparticle. In some embodiments the collagen particle is in a surfactant polymer dressing such as a poloxamer, such as but not limited to PluroGel®.
  • the inhibitor of fidgetin-like 2 is provided in a pharmaceutical composition comprising a microemulsion of nanoparticles. One non-limiting example of a microemulsion is described in an example herein.
  • the inhibitor of fidgetin-like 2 is provided in a pharmaceutical composition comprising a liposome. In some embodiments, the liposome is a ligand functionalized liposome. In some embodiments, the liposome is further functionalized with at least one 2’ sugar modification.
  • the inhibitor of fidgetin-like 2 is provided in a pharmaceutical composition comprising a nanoparticle.
  • the inhibitor of fidgetin-like 2 is encapsulated in a nanoparticle.
  • the nanoparticle is a liposomal nanoparticle.
  • Such microparticles, nanoparticles or liposomes comprising a nucleic acid disclosed herein may be provided in any of the aforementioned compositions, such as but not limited to a cream, eye drop, gel, wafer, parenterally administered formulation, wound dressing, collagen particle, poloxamer, depot-administrable gel, and the like.
  • the nanoparticle comprises poly(lactic-co-glycolic acid) (PLGA, PLG), a copolymer, produced using methods known in the art.
  • the nanoparticle is sized between 1-100 nm.
  • the nanoparticle is biocompatible and/or biodegradable. This addition may in certain embodiments enhance purification of microparticles or nanoparticles using methods well known in the art.
  • nanoparticles are prepared as follows. Five hundred ⁇ l of tetramethyl orthosilicate (TMOS) was hydrolyzed in the presence of 100 ⁇ l of 1 mM HCl by sonication on ice for about 15 min, until a single phase formed. The hydrolyzed TMOS (100 ⁇ l) was added to 900 ⁇ l of 20 ⁇ M of siRNA solution containing 10 mM phosphate, pH 7.4. A gel was formed within 10 minutes. The gel was frozen at ⁇ 80°C for 15 minutes and lyophilized.
  • TMOS tetramethyl orthosilicate
  • Such copolymer comprising a nucleic acid disclosed herein may be provided in any of the aforementioned compositions, such as but not limited to a cream, eye drop, gel, wafer, parenterally administered formulation, wound dressing, collagen particle, poloxamer, depot-administrable gel, and the like.
  • the inhibitor of fidgetin-like 2 is provided in a bulk- eroding system such as polylactic acid and glycolic acid (PLGA) copolymer-based microspheres or microcapsules systems containing the inhibitor of fidgetin-like 2.
  • PLGA polylactic acid and glycolic acid
  • blends of PLGA:ethylcellulose systems may be used as an appropriate carrier.
  • a further medicament in accordance with this aspect of the disclosure may be formulated in a surface-eroding system wherein the inhibitor of fidgetin-like 2 is embedded in an erodible matrix such as the poly(ortho) ester and polyanhydride matrices wherein the hydrolysis of the polymer is rapid.
  • a surface-eroding system comprising a nucleic acid disclosed herein may be provided in any of the aforementioned compositions, such as but not limited to a cream, eye drop, gel, wafer, parenterally administered formulation, wound dressing, collagen particle, poloxamer, depot- administrable gel, and the like.
  • the inhibitor of fidgetin-like 2 may also be formulated by combining a pulsatile delivery system as described above and an immediate release system such as a lyophilized injectable composition described above.
  • the inhibitor of fidgetin-like 2 may be used in a composition with additives.
  • suitable additives are sodium alginate, as a gelatinizing agent for preparing a suitable base, or cellulose derivatives, such as guar or xanthan gum, inorganic gelatinizing agents, such as aluminum hydroxide or bentonites (termed thixotropic gel-formers), polyacrylic acid derivatives, such as Carbopol®, polyvinylpyrrolidone, microcrystalline cellulose and carboxymethylcellulose.
  • Amphiphilic low molecular weight and higher molecular weight compounds, and also phospholipids are also suitable.
  • the gels can be present either as water- based hydrogels or as hydrophobic organogels, for example based on mixtures of low and high molecular weight paraffin hydrocarbons and vaseline.
  • the hydrophilic organogels can be prepared, for example, on the basis of high molecular weight polyethylene glycols. These gelatinous forms are washable.
  • Hydrophobic organogels are also suitable. Hydrophobic additives, such as petroleum jelly, wax, oleyl alcohol, propylene glycol monostearate and/or propylene glycol monopalmitostearate, in particular isopropyl myristate can be included.
  • the inhibitor is in a composition comprising one or more dyes, for example yellow and/or red iron oxide and/or titanium dioxide for the purpose of matching as regards color.
  • Compositions may be in any suitable form including gels, lotions, balms, pastes, sprays, powders, wafers, bandages, wound dressing, emulsions, creams and ointments of the mixed- phase or amphiphilic emulsion systems (oil/water-water/oil mixed phase), liposomes and transfersomes or plasters/band aid-type coverings.
  • Emulsifiers which can be employed in compositions comprising the inhibitor of fidgetin-like 2 include anionic, cationic or neutral surfactants, for example alkali metal soaps, metal soaps, amine soaps, sulphurated and sulphonated compounds, invert soaps, higher fatty alcohols, partial fatty acid esters of sorbitan and polyoxyethylene sorbitan, e.g. lanette types, wool wax, lanolin or other synthetic products for preparing the oil/water and/or water/oil emulsions.
  • anionic, cationic or neutral surfactants for example alkali metal soaps, metal soaps, amine soaps, sulphurated and sulphonated compounds, invert soaps, higher fatty alcohols, partial fatty acid esters of sorbitan and polyoxyethylene sorbitan, e.g. lanette types, wool wax, lanolin or other synthetic products for preparing the oil/water and/or water/oil emulsions.
  • compositions comprising the inhibitor of fidgetin-like 2 can also comprise vaseline, natural or synthetic waxes, fatty acids, fatty alcohols, fatty acid esters, for example as monoglycerides, diglycerides or triglycerides, paraffin oil or vegetable oils, hydrogenated castor oil or coconut oil, hog fat, synthetic fats (for example based on caprylic acid, capric acid, lauric acid or stearic acid, such as Softisan®), or triglyceride mixtures, such as Miglyol®, can be used as lipids, in the form of fatty and/or oleaginous and/or waxy components for preparing the ointments, creams or emulsions of the compositions comprising the inhibitor of fidgetin-like 2 used in the methods described herein.
  • natural or synthetic waxes for example as monoglycerides, diglycerides or triglycerides, paraffin oil or vegetable oils, hydrogenated castor oil or coconut oil,
  • the pharmaceutical composition comprises an osmotically active acid or alkaline solution, for example hydrochloric acid, citric acid, sodium hydroxide solution, potassium hydroxide solution, sodium hydrogen carbonate, may also be ingredients of the compositions and, in addition, buffer systems, such as citrate, phosphate, tris buffer or triethanolamine, for adjusting the pH. It is possible to add preservatives as well, such as methyl benzoate or propyl benzoate (parabens) or sorbic acid, for increasing the stability.
  • Pastes, powders and solutions are additional forms of compositions comprising the inhibitor of fidgetin-like 2 which can be applied topically.
  • the pastes frequently contain hydrophobic and hydrophilic auxiliary substances, preferably, however, hydrophobic auxiliary substances containing a very high proportion of solids.
  • the powders or topically applicable powders can, for example, contain starch species, such as wheat or rice starch, flame-dispersed silicon dioxide or siliceous earth, which also serve as diluent.
  • the compositions comprise further active ingredients suitable for protecting or aiding in healing of the wound, for example one or more antibiotics, antiseptics, vitamins, anesthetics, antihistamines, anti-inflammatory agents, moisturizers, penetration- enhancing agents and/or anti-irritants.
  • the carrier further comprises a targeting ligand.
  • the targeting ligand is a protein.
  • the targeting ligand binds an epithelial cell, a vascular endothelial cell, a vascular smooth muscle cell, a myocardial (heart) cell or a passenger leukocyte cell resident in cutaneous tissue at a time of wound healing.
  • the carrier comprises: (a) a histidine-lysine co-polymer; (b) a hydrophilic polymer comprising PEG; and, optionally, (c) a targeting ligand.
  • the composition may further comprise one or more additional nucleic acid molecules that induce RNA interference and decrease the expression of a gene of interest.
  • the one or more additional nucleic acid molecules decrease the expression of a gene selected from the group consisting of fidgetin and fidgetin-like 2.
  • methods of use are provided using a nucleic acid comprising any of SEQ ID NO:1 or SEQ ID NO:2, or a duplex or double-stranded nucleic acid comprising either SEQ ID NO:1 or SEQ ID NO:2 or both.
  • methods of use are provided using a nucleic acid consisting of any one of SEQ ID NO:1 or SEQ ID NO:2, or a duplex or double-stranded nucleic acid consisting of SEQ ID NO: 1 or SEQ ID NO:2 or both.
  • any of SEQ ID NOs:5-8 may be used, consisting of or comprising single stranded nucleic acids, or in double stranded nucleic acids (consisting of or comprising one or both strands), for any methods disclosed herein.
  • modifications or additional modifications to the nucleic acid such as but not limited to those described herein is embraced herein.
  • any of the foregoing nucleic acids or those described elsewhere herein including modifications therein are embodied.
  • the term “an inhibitor of fidgetin-like 2” is meant to encompass any of the nucleic acid sequences described herein or any modifications thereof.
  • each individual strand within the double-stranded nucleic acid is no longer than 52 nucleotides.
  • the disclosure embraces method of use for treatment of a human as well as non-human animals (e.g., non-human primate, non-human mammal) comprising modifications of the nucleic acid sequences disclosed herein.
  • modifications of the nucleic acids disclosed herein comprise siRNAs directed to the orthologue of fidgetin-like 2 in the particular species.
  • the nucleic acids and siRNA disclosed herein are cross-reactive and therefore useful in at least one other species.
  • a method of treating a skin wound or injury in a subject comprising administering to the subject an amount of an inhibitor of fidgetin-like 2 effective to treat the skin wound or injury.
  • the amount of inhibitor of fidgetin-like 2 is effective to accelerate wound healing.
  • the wound is an epidermal wound.
  • the wound is a skin wound.
  • Non-limiting examples of specific wounds in which healing may be promoted using the medicaments and methods of the disclosure include, but are not limited to, the results of sun damage such as wrinkles, non-responsive skin after a facelift, lasabrasion, aged or sun- damaged skin, skin liver spots, birthmark, wart, enlarged oil glands, port wine stains, hemangiomas, telangiectasias, or to change the appearance of skin complexion.
  • the birthmark is a linear epidermal nevus.
  • the method is directed to enhancing skin health recovery from a skin procedure comprising laser application to the skin. In some embodiments, the method is directed to rejuvenating skin from a skin procedure comprising laser application to the skin.
  • compounds of the disclosure are useful for improving or accelerating healing of skin grafting sites, such as on burns, scar revision, plastic surgery, or other procedures involving placement of a skin graft. As described elsewhere, the healing of the skin site from which a graft is taken is also a benefit of the compounds described herein.
  • compounds of the disclosure are useful in enhancing healing of a skin graft or a skin grafting site. In some embodiments, the skin grafting is provided to treat a burn.
  • the burn is a partial-thickness burn. In some embodiments the burn is a full-thickness burn.
  • the skin grafting is provided to treat an injury, such as from a large open wound. In some embodiments, the skin grafting is provided to treat an ulcer such as but not limited to a bedsore. In some embodiments, the skin grafting is provided to treat a skin infection. In some embodiments, the skin grafting is provided to treat a skin cancer surgery site. In some embodiments, the skin grafting is provided to cover a larger surface area than available from the supply of donor skin.
  • a method of enhancing hair follicle growth in skin comprises directly administering to the skin an amount of an inhibitor of fidgetin-like 2 effective to enhance hair follicle growth in skin. In some embodiments, the method increases hair growth in skin.
  • the wound is a cardiac tissue wound. In an embodiment, the wound is a cardiovascular wound, for example resulting from a myocardial infarction. In some embodiments, a compound of the disclosure promotes cardiac angiogenesis. In some embodiments, a compound of the disclosure improves cardiac function post myocardial infarction. . Treatment of the Nervous System [00131] In an embodiment, the wound is a neuronal wound.
  • the wound is a wound of the central nervous system. In some embodiments, the wound in a spinal cord injury. In some embodiments, the prevention, reduction or inhibition of scarring may enhance neuronal reconnection and/or neuronal function. In some embodiments, a compound of the disclosure promotes nerve growth. In some embodiments, a compound of the disclosure reduces neuronal inflammation. In some embodiments, a compound of the disclosure promotes recovery from nerve transection. In some embodiments, a compound of the disclosure promotes nerve regeneration after injury. [00133] In some embodiments, the spinal cord injury is acute spinal cord injury or chronic spinal cord injury.
  • the chronic spinal cord injury is of a duration of about 1 month or longer, two months or longer, two months or longer, three months or longer, four months or longer, five months or longer, or six months or longer. In some embodiments, such durations are following an acute spinal cord injury or other traumatic or acute event.
  • the spinal cord injury is traumatic, surgically induced, congenital, inflammatory, infection related, degenerative, or cancer related.
  • the wound is a wound of the peripheral nervous system. In some embodiments the wound is a cavernous nerve injury. In some embodiments, the prevention, reduction or inhibition of scarring may enhance neuronal reconnection and/or neuronal function.
  • a compound of the disclosure promotes peripheral nerve growth. In some embodiments, a compound of the disclosure reduces neuronal inflammation. In some embodiments, a compound of the disclosure promotes recovery from nerve transection. In some embodiments, a compound of the disclosure promotes nerve regeneration after injury. In some embodiments, a compound of the disclosure has anti-inflammatory activity in neuronal and other tissues. [00135] In some embodiments, a compound of the disclosure treats or prevents neuropraxia. [00136] In some embodiments, a compound of the disclosure treats or prevents adverse sequelae of nerve sparing surgery. [00137] In some embodiments, a compound of the disclosure promotes recovery of erectile response after unilateral or bilateral cavernous nerve transection.
  • a compound of the disclosure recovery of erectile response within two weeks of cavernous nerve injury.
  • cavernous nerve injury is a result of a surgical procedure such as prostatectomy.
  • prostatectomy is radical prostatectomy.
  • a wafer comprising a siRNA of the disclosure is implanted at the site of surgery.
  • siRNA concentrations of about 6.6, about 13.3 or about 26.6 micrograms per 100 mg wafer is implanted.
  • the wafer comprises about 2.5% collagen, about 7.5% chondroitin sulfate, about 82.5% polyvinylpyrrolidone, and about 7.5% polyethylene glycol 400.
  • the wound is a wound of the eye (including the inhibition of scarring resulting from eye surgery such as LASIK surgery, LASEK surgery, PRK surgery, glaucoma filtration surgery, cataract surgery, or surgery in which the lens capsule may be subject to scarring) such as those giving rise to corneal cicatrisation; wounds subject to capsular contraction (which is common surrounding breast implants).
  • a compound of the disclosure is useful for treating eye disease that are not a direct injury to the eye, such as a degenerative disease.
  • the methods and agents for uses disclosed herein are for use in patients with neurotrophic keratitis (NK) are directed to treating the degenerative disease of the cornea caused by damage to the trigeminal nerve, which may be triggered by any number of induction events that do not typically develop into NK.
  • NK neurotrophic keratitis
  • such methods and agents for are distinct from treatment of the causes of NK, and such treatment of NK typically would be initiated at diagnosis of NK as described herein, and not necessarily contiguous with any treatment of the causes or induction events.
  • the wound is a wound of the circulatory system, such as but not limited to a blood vessel, venous or arterial valves, heart valves, or enhancing the integration of a replacement heart valve, bypass graft, vasculature of a transplanted organ, by way of non- limiting examples.
  • Treatment of the Musculoskeletal System [00141]
  • the wound is a wound of tendons, ligaments or muscle.
  • Treatment of the Oral Cavity [00142]
  • the wound is a wound of the oral cavity, including the gums, lips and palate. In some embodiments, the method inhibits scarring resulting from treatment of cleft lip or palate.
  • the wound is a wound of an internal organ such as but not limited to the liver, heart, brain, digestive tissues and reproductive tissues.
  • the wound is a wound a body cavity such as but not limited to the abdominal cavity, pelvic cavity and thoracic cavity.
  • inhibition of scarring may reduce the number of incidences of adhesion formation and/or the size of adhesions formed.
  • Treatment of Surgical Wounds is a surgical wound, such as but not limited to particular wounds associated with cosmetic procedures, such as scar revision. It is particularly preferred that the medicaments and methods of the disclosure be used to promote healing of wounds of the skin.
  • the subject is a mammal. In an embodiment the subject is human. As noted herein, a modification of the nucleic acid sequences disclosed herein to target a corresponding non-human FL2 is fully embraced herein.
  • promotion of wound healing means an acceleration in any one or more of visual appearance of wound recovery, reduction in wound size, reduction in distance between wound margins, scab formation, fibroplasia and re-epithelialization as compared to the corresponding parameter in an untreated wound.
  • wound is a break or discontinuity in the structure of an organ or tissue (including skin), which includes epithelium, connective tissue, and muscle tissue, caused by an external agent.
  • wounds include, but are not limited to, skin wounds, ulcerations, bedsores, grazes, tears, cuts, punctures, tympanic membrane perforations, bums, and those that are a consequence of plastic surgery procedures.
  • Methods of Administration The benefits that may be derived from the present disclosure may be applicable to pathological or biological processes occurring at any site, cells, tissue, organs, organ systems, or any component thereof, anywhere throughout the body. Non-limiting examples of such pathologies are described elsewhere herein. Non-limiting examples include treating a wound, for example the wound for which healing is promoted is a skin wound.
  • the embodiments of the disclosure will generally be described with reference to skin wounds, although they remain applicable to other tissues and organs.
  • the wound may be a wound of the circulatory system, particularly of a blood vessel.
  • Other wounds in which wound healing may be promoted in accordance with the present disclosure include as a result of surgery or as a result of a burn.
  • Other wounds in which wound healing may be promoted in accordance with the present disclosure include skin ulcers caused by pressure, venous stasis, or diabetes mellitus.
  • the result of a wound is a scar, which may be treated as described herein to prevent or reduce scarring of a wound at any site in or on the body.
  • Other wounds include acute or chronic spinal cord injury.
  • the inhibitor of fidgetin-like 2 is administered locally to the wound.
  • the inhibitor of fidgetin-like 2 is administered via a vein or artery. In an embodiment, the inhibitor of fidgetin-like 2 is administered by injection, catheterization or cannulation. In an embodiment, the inhibitor of fidgetin-like 2 is administered from an implant that elutes the inhibitor, for example an eluting wafer, gel, implant, stent or an eluting skin patch.
  • the dosage of the nucleic acid administered in treatment will vary depending upon factors such as the pharmacodynamic characteristics of a specific nucleic acid and its mode and route of administration; the age, sex, metabolic rate, absorptive efficiency, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment being administered; the frequency of treatment with the inhibitor and the desired therapeutic effect.
  • a dosage unit of the inhibitor may comprise a single compound, or a mixture of the compound with one or more anti-infection compound(s) or other wound healing-promoting compound(s).
  • the inhibitor of fidgetin-like 2 is applied to the wound once.
  • the inhibitor of fidgetin-like 2 is applied to the wound more than once. In some embodiments, the inhibitor of fidgetin-like 2 is applied to the wound in the form of an controlled delivery device such as but not limited to a stent, wafer, implant, bandage, or any other slow or controlled release device. In some embodiments, the inhibitor of fidgetin-like 2 is applied to the wound each time the dressing is changed. [00154] In some embodiments, the inhibitor of fidgetin-like 2 is applied to the wound until healing occurs. In some embodiments, the inhibitor of fidgetin-like 2 is applied to or maintained at the site for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days.
  • the inhibitor of fidgetin-like 2 is implanted or placed in a surgical site at the time of surgery. In some embodiments such placement is in the form of a controlled release composition such that the inhibitor of fidgetin-like 2 can act at the site for a period of time.
  • administration schedule may be determined by the concentration and volume administered, as well as the potency, half-life and other factors.
  • an eyedrop formulation of liposomes comprising a nucleic acid disclosed herein may be one drop in each eye every two days.
  • the 2 ⁇ TBDMS protecting group is then cleaved to yield the crude sense or antisense strand.
  • the sense and antisense strands are then individually purified.
  • the purified single strands are analyzed to confirm the correct molecular weight and impurity profile prior to annealing into the siRNA duplex.
  • the annealed duplex is freeze-dried to yield the active pharmaceutical ingredient (API).
  • API is stored at –20°C.
  • Example 2 siRNA transfection of U2OS cells [00157] The following methods are used to transfect U2OS cells in preparation for testing the efficacy of nucleic acids described herein. [00158] siRNA transfection protocol (6 well plate).
  • Lipofectamine 3000 dilute 3.5 ⁇ L of siRNA (20 ⁇ M stock)/transfection (70 pmol) into 250 ⁇ L OptiMEM. Then dilute 3.5 ⁇ L of Lipofectamine 3000 into 250 ⁇ L of OptimMEM. Mix siRNA/OptiMEM into Lipofectamine/ OptiMEM solution. Incubate for 15 minutes at room temperature. Add mixture dropwise to wells. [00159] siRNA transfection protocol (24 well plate). Seed 20,000 U2OS cells per well (6 well dish) and culture for 2 days ( ⁇ 80% confluency). Follow Lipofectamine 3000 protocol.
  • a scratch wound was introduced in the cell monolayer using a sterile 200 ⁇ L pipette tip, and the detached cells were removed by washing with PBS. Fresh media was added, and the migration of cells was monitored using the EVOS live-cell imaging system (Invitrogen). Time-lapse phase-contrast images were acquired every hour for up to 24 hours post-scratch. [00162] Images were analyzed to measure cell migration distance. Directionality was quantified by calculating the ratio of the net displacement (D) to the total path length (L) of each cell trajectory. Data from three independent scratch assays were averaged, and representative images were included. Control cells were transfected with non-targeting siRNA, while experimental cells received FL2-targeting siRNA.
  • Example 4 Activity Testing – Knockdown Assay [00163] U2OS cells were transfected as described in Example 3. Cells were harvested at 24, 48, and 72 hours post-transfection for protein analysis. Cells were washed twice with ice-cold PBS, lysed with RIPA buffer containing protease and phosphatase inhibitors, and centrifuged at 14,000 rpm for 10 minutes at 4°C. The supernatant was collected, and protein concentration was determined using a BCA protein assay kit.
  • Equal amounts of protein (20 ⁇ g) from each sample were resolved on a 10% SDS-PAGE gel and transferred to a PVDF membrane.
  • the membrane was blocked with 5% non-fat dry milk in TBS-T for 1 hour at room temperature and incubated overnight at 4°C with primary antibodies against FL2 (1:1000 dilution) and GAPDH (1:5000 dilution) as a loading control. Following washes, membranes were incubated with HRP- conjugated secondary antibodies (1:3000 dilution) for 1 hour at room temperature. Protein bands were visualized using ECL chemiluminescent substrate and imaged on a gel documentation system (iBright Imaging Systems, Invitrogen).
  • Nanoparticles (np) comprising a siRNA of the disclosure are formulated using five hundred ⁇ l of tetramethyl orthosilicate (TMOS) hydrolyzed in the presence of 100 ⁇ l of 1 mM HCl by sonication on ice for about 15 min, until a single phase forms.
  • TMOS tetramethyl orthosilicate
  • TMOS The hydrolyzed TMOS (100 ⁇ l) is added to 900 ⁇ l of 20 ⁇ M of siRNA (or the negative control) solution containing 10 mM phosphate, pH 7.4. A gel is formed within 10 minutes. The gel is frozen at ⁇ 80°C for 15 minutes and lyophilized. Such siRNA nanoparticles are formulated into an eye drop useful for the various eye conditions described herein.
  • a wafer comprising siRNA of the disclosure is made from 2.5% collagen, 7.5% chondroitin sulfate, 82.5% polyvinylpyrrolidone, and 7.5% polyethylene glycol 400. Such wafers are made to contain 6.6, 13.3 or 26.6 micrograms siRNA per 100 mg wafer.
  • a wafer is implantable at a surgical site, such as during nerve-sparing surgery or procedures with high risk of neuronal dysfunction such as a radical prostatectomy.
  • Example 6. Nanoparticle Microemulsion Formulation [00167] Constituents needed for the methodology: Zonyl FSO-100 (FSO), Poloxamer 188, perfluorodecalin (PFD), DNAse/RNAse free water, siRNA as described herein, or Control. [00168] The protocol is performed in a sterile environment at room temperature using DNAse/RNAse free water. The containers necessary to process the formulation is pre- cleaned with RNAse zap, autoclaved and rinsed with DNAse/RNAse free water in a sterile laminar hood.
  • the mixture of PFD should be of a specific particle size preferably below 5 microns.
  • an aliquot (10 ⁇ L) of the mixture is diluted and is subjected to dynamic light scattering (DLS) to monitor the particle size optimized to have maximum stability.
  • DLS dynamic light scattering
  • the stability of the formulation is less viable and to have the maximum efficiency, it is better to have the particle size around or less than 5 micrometers.
  • an additional step of sonication using a probe is performed with slow pulse with 20 sec interval. Care should be taken not to exceed the sonication procedure for more than 10 minutes.
  • the mixture should be stirred overnight under sterile conditions to have a mixture of uniform particle size.
  • Preparation of aqueous phase In a separate 50 mL Falcon tube, prepare 4% of Poloxamer solution in DNAse/RNAse free water. Weigh 400mg of Poloxamer in 9mL of DNAse/RNAse free water and mix in a nutator for 2 hours checking for consistency every 30 minutes. Poloxamer should dissolve completely in DNAse/RNAse free water. The Poloxamer solution should be chilled in an ice water bath till use or refrigerated.
  • the Poloxamer solution should be made in the clean laminar hood and could be mixed using a nutator after tight capping outside the hood. (Note: The Poloxamer solution is made in 9mL of water and later 1mL of siRNA mixed in DNAse/RNAse free water is added to make the aqueous phase of Poloxamer). [00173] Addition of the siRNA/control in the aqueous phase. The siRNA powder or liquid is mixed in pre-chilled DNAse/RNAse free water and made up to 1mL. The siRNA is quickly thawed and diluted with DNAse/RNAse free water in an ice bucket just before making the formulation. Do not thaw the siRNA until everything is ready for the formulation.
  • the total 10 mL of the aqueous phase is added over a period of 20 minutes or more at the rate of 0.5mL/minute or less to obtain a stable emulsion.
  • the stability of the emulsion should be tested by monitoring the phase separation while the solution stands for 1h at 4 °C. Example 7.
  • siRNA collagen – surfactant polymer dressing [00175] A dressing for treating wounds, burns and other injuries using a collagen microparticle and surface polymer dressing (SPD) is made as follows: 10 g of sodium bis(2-ethylhexyl) sulfosuccinate (AOT) (Sigma-Aldrich) is dissolved in 34 ml of n-hexane and 2 ml of 5% collagen-I dissolved in acetic acid is added. The resulting microemulsion is stirred for 45 min until it becomes clear. This solution is then evaporated to remove the hexane. The residue is washed and is then suspended in nuclease free water and lyophilized.
  • AOT sodium bis(2-ethylhexyl) sulfosuccinate
  • siRNA improves outcome of radical prostatectomy
  • a radical prostatectomy is performed on a prostate cancer patient. Such surgeries may have an up to 50% risk of erectile dysfunction.
  • a 100 mg wafer prepared as described herein comprising 10 micrograms of duplex siRNA of SEQ ID NOs:7/8 is implanted at the surgical site proximal to the cavernous nerves.
  • the patient recovers erectile function post-surgery.
  • siRNA improves excisional wound healing
  • STSG split thickness skin graft
  • Subjects will receive initial hemostasis management using standard techniques (pressure, thrombin spray, epinephrine).
  • a wound photograph will be taken to fill 80% of the camera frame with a calibration ruler within the field of the photo.
  • a Telfa® pad saturated with fixed dose of SEQ ID NOs: 1/2 will be applied to one side STSG donor site.
  • a Telfa® pad saturated with the vehicle will be administered to the opposite side.
  • a sterile, non-adhesive film will be placed over the TegadermTM, followed by a gauze bolster that will be taped in place. During repeat dosing, the dressing will be taken down to include the film but not the Telfa pad.
  • Photographic planimetry will be performed by a blinded observer and rates of wound healing at all time points and time to complete epithelialization will be measured and reported. [00178] Subjects will return for photographs at one, three, and six months to ascertain durability of healing and quality of scar using Category 1 of the Hamilton Scar Assessment Scale. [00179] Frequency of dosing (qd, bid, and tid) will be explored among three cohorts. [00180] Primary Objective: Demonstrate that STSG donor site treatment with SiFi2 supports more rapid wound healing than STSG donor site areas treated with vehicle alone.
  • Secondary Objectives Demonstrate that wound healing after treatment of STSG donor sites with SiFi2 endures and is not associated with hypertrophic scarring as determined by the Hamilton Scar Assessment Scale, as compared to STSG donor site areas treated with vehicle.
  • Primary Endpoint Rate and completion of STSG donor site wound healing, as determined by interpretation of standardized photography at Days 5-19.
  • Secondary Endpoints (1) Maintenance of healed wound at one, three, and six months; (2) Degree of hypertrophic scarring in each treatment arm as assessed by Category 1 of the Hamilton Scar Assessment Scale6 score on photographs of the STSG donor sites at one, three, and six months as interpreted by three independent expert wound care surgeon reviewers; (3) Degree of pain and pruritus on the treated and untreated sides.
  • Inclusion Criteria (1) Male and female healthy subjects of all races; (2) Age Range: 21-65 inclusive; (3) Basal Metabolic Index between 18 and 30; (4) Willing and able to provide Informed Consent and to participate in scar evaluation postoperatively; (5) Willingness to adhere to the follow up evaluation schedule.
  • Exclusion Criteria (1) Inability to provide Informed Consent; (2) Unwillingness to participate in scar evaluation postoperatively; (3) Cutaneous disease (scleroderma or other collagen vascular disease, prior keloid, severe skin thinning with prior skin tears); (4) The use of systemic steroids or dermatological steroids in the last six months; (5) Pregnancy or trying to become pregnant; (6) On anticoagulants; (7) Immune deficiency state; (8) Diabetes mellitus; (9) Malnourished; (10) Platelet or NSAID use in the prior two weeks; (11) Known hypersensitivity to suture or bandage materials; (12) Known hypersensitivity to epinephrine or thrombin; (13) Infection within the previous two weeks; (14) Any condition that in the opinion of the investigator will not allow the subject to successfully complete the clinical trial.

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Abstract

L'invention concerne des molécules d'acide nucléique et des compositions de celles-ci ciblées sur la fidgetine de type 2, et des méthodes d'utilisation de celles-ci dans le traitement d'un état pathologique chez un sujet humain.
PCT/US2024/056211 2023-11-16 2024-11-15 Agents ciblant la fidgetine de type 2 et leurs utilisations Pending WO2025106876A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080220983A1 (en) * 2007-03-08 2008-09-11 Switchgear Genomics A California Corporation Functional arrays for high throughput characterization of regulatory elements in untranslated regions of genes
US20110287974A1 (en) * 2010-05-24 2011-11-24 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Methods and kits for ascertaining biosafety of an agent
US8853181B2 (en) * 2011-07-21 2014-10-07 Albert Einstein College Of Medicine Of Yeshiva University Fidgetin-like 2 as a target to enhance wound healing
WO2022049295A1 (fr) * 2020-09-07 2022-03-10 Centre National De La Recherche Scientifique Origine de réplication d'adn eucaryote, et vecteur la contenant

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080220983A1 (en) * 2007-03-08 2008-09-11 Switchgear Genomics A California Corporation Functional arrays for high throughput characterization of regulatory elements in untranslated regions of genes
US20110287974A1 (en) * 2010-05-24 2011-11-24 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Methods and kits for ascertaining biosafety of an agent
US8853181B2 (en) * 2011-07-21 2014-10-07 Albert Einstein College Of Medicine Of Yeshiva University Fidgetin-like 2 as a target to enhance wound healing
WO2022049295A1 (fr) * 2020-09-07 2022-03-10 Centre National De La Recherche Scientifique Origine de réplication d'adn eucaryote, et vecteur la contenant

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