WO2021030452A1 - Activateurs de perméation, compositions les contenant, et leurs procédés d'utilisation - Google Patents

Activateurs de perméation, compositions les contenant, et leurs procédés d'utilisation Download PDF

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Publication number
WO2021030452A1
WO2021030452A1 PCT/US2020/045954 US2020045954W WO2021030452A1 WO 2021030452 A1 WO2021030452 A1 WO 2021030452A1 US 2020045954 W US2020045954 W US 2020045954W WO 2021030452 A1 WO2021030452 A1 WO 2021030452A1
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Prior art keywords
auricular
dosage form
modulator
agent
amino acid
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PCT/US2020/045954
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English (en)
Inventor
Qi-Ying Hu
John Lee
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Decibel Therapeutics, Inc.
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Publication of WO2021030452A1 publication Critical patent/WO2021030452A1/fr

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    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0046—Ear
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals

Definitions

  • the invention relates to the field of therapeutic treatment, such as of otic diseases and conditions in human patients.
  • the inner ear represents an environment in which a variety of important cells and tissue systems reside.
  • sensory hair cells which are specialized mechanosensory receptors found in vertebrate auditory, vestibular and lateral line organs that transduce vibratory and acoustic stimuli into the sensations of hearing and balance.
  • Sensorineural hearing loss typically occurs when hair cells are damaged from infection, noise exposure, ototoxins, and age-related decline.
  • 1 .3 billion humans suffer some form of hearing loss, while 360 million suffer debilitating hearing loss as a direct result of the absence of these sensory hair cells.
  • the present disclosure relates to auricular dosage forms and methods for the otic delivery of therapeutic agents to subjects in need thereof, such as human subjects.
  • the auricular dosage forms and methods described herein can be used to effectuate the passage of therapeutic agents across the round window membrane of a subject into the inner ear, where the therapeutic agents may exert a beneficial effect.
  • the auricular dosage forms and methods described herein solve a challenging biological problem, as the administration of therapeutic agents - particularly large substances, such as proteins, viral vectors, nucleic acids, and nanoparticles, among others - across the round window membrane has been a difficult barrier to overcome.
  • the auricular dosage forms and methods described herein provide important clinical benefits, as these can be used not only to deliver therapeutic agents across the round window membrane and into the inner ear, but also sustain high, therapeutically effective concentrations of these agents in vivo for long periods of time.
  • the invention features an auricular dosage form comprising a therapeutic agent, a gelling agent, and a permeation enhancing amount of an alkyl glycoside or sucrose fatty ester.
  • the auricular dosage form is hypertonic.
  • the calculated osmolarity of the hypertonic pharmaceutical composition is 500-5,000 mOsm/L (e.g., 600- 5,000 mOsm/L, 700-5,000 mOsm/L, 800-5,000 mOsm/L, 900-5,000 mOsm/L, 1 ,000-5,000 mOsm/L,
  • the auricular dosage form comprises an alkyl glycoside (e.g., an alkyl maltoside).
  • the alkyl maltoside is tridecyl maltoside.
  • the alkyl maltoside is n-dodecyl b-D-maltoside.
  • the auricular dosage form comprises a sucrose fatty ester.
  • the permeation enhancing amount is at least 0.01% (w/v) (e.g., at least 0.025% (w/v), at least 0.05% (w/v), at least 0.1% (w/v), at least 0.25% (w/v), at least 0.5% (w/v), or at least 1% (w/v); e.g., 5% (w/v) or less, 3% (w/v) or less, 1% (w/v) or less, 0.5% (w/v) or less, 0.25% (w/v) or less, or 0.1% (w/v) or less; e.g., 0.01% (w/v) to 5% (w/v), 0.025% (w/v) to 5% (w/v), 0.05% (w/v) to 5% (w/v), 0.1% (w/v) to 5% (w/v), 0.25% (w/v) to 5% (w/v), 0.5% (w/v) to 5% (w/v), 0.5% (w
  • the gelling agent is hyaluronan, a polyoxyethylene-polyoxypropylene block copolymer, poly(lactic-co-glycolic) acid, polylactic acid, polycaprolactone, alginic acid or a salt thereof, polyethylene glycol, a cellulose, a cellulose ether, a carbomer, agar-agar, gelatin, glucomannan, galactomannan, xanthan gum, chitosan, pectin, starch, tragacanth, carrageenan, polyvinylpyrrolidone, polyvinyl alcohol, paraffin, petrolatum, silicates, fibroin, or a combination thereof.
  • the auricular dosage form further contains a gelling agent.
  • the gelling agent is hyaluronan, hyaluronic acid, a polyoxyethylene-polyoxypropylene block copolymer, poly(lactic-co-glycolic) acid, polylactic acid, polycaprolactone, alginic acid or a salt thereof, polyethylene glycol, a cellulose, a cellulose ether, agar-agar, gelatin, glucomannan, galactomannan (e.g., locust bean gum or tara gum), xanthan gum, guar gum, chitosan, pectin, starch, tragacanth, carrageenan, polyvinylpyrrolidone, polyvinyl alcohol, paraffin, polyethoxylated sorbitan monolaurate, petrolatum, silicates, fibroin, gellan, CARBOPOL 940®, polyoxamines, lecithin
  • the gelling agent is a polyoxyethylene- polyoxypropylene block copolymer, alginic acid or a pharmaceutically acceptable salt thereof, collagen, hyaluronic acid or a pharmaceutically acceptable salt thereof, gelatin, or fibroin.
  • the polyoxyethylene-polyoxypropylene block copolymer is poloxamer 407. In some embodiments, the polyoxyethylene-polyoxypropylene block copolymer is poloxamer 188.
  • the polyoxyethylene-polyoxypropylene block copolymer is present within the auricular dosage form at a concentration of from about 0.001% w/v to about 50% w/v. In some embodiments, the polyoxyethylene-polyoxypropylene block copolymer is present within the auricular dosage form at a concentration of from about 0.01% w/v to about 40% w/v. In some embodiments, the polyoxyethylene-polyoxypropylene block copolymer is present within the auricular dosage form at a concentration of from about 1% w/v to about 30% w/v. In some embodiments, the polyoxyethylene- polyoxypropylene block copolymer is present within the auricular dosage form at a concentration of about 20% w/v.
  • the gelling agent is hyaluronan.
  • the gelling agent is a polyoxyethylene-polyoxypropylene block copolymer.
  • the polyoxyethylene-polyoxypropylene block copolymer is poloxamer 407, poloxamer 188, or a combination thereof.
  • the gelling agent is a cellulose ether.
  • the cellulose ether is methylcellulose, carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, methyl hydroxyethylcellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, or a combination thereof.
  • the gelling agent is fibroin.
  • the gelling agent is alginic acid or a salt thereof.
  • the gelling agent is cross-linked.
  • the gelling agent is ionically cross-linked.
  • the gelling agent is covalently cross-linked.
  • the concentration of the therapeutic agent is at least 0.05M, at least 0.1 M, at least 0.2M, at least 0.3M, at least 0.4M, at least 0.5M, or at least 1 .0M; e.g., 2.5M or less, 2.0M or less, 1 .5M or less, 1 .0M or less, 0.5M or less, 0.4M or less, 0.3M or less, or 0.2M or less; e.g., 0.5M- 2.5M 0.05M to 1 .5 M, 0.05M to 0.5M, 0.05M to 0.2M, 0.05M to 0.1 M, 0.1 M to 1 5M, 0.1 M to 0.5M, 0.1 M to 0.2M, 0.2M to 1 5M, 0.2M to 0.5M, 0.5M to 1 5M, 0.05M to 1 .0 M, 0.05M to 0.5M, 0.05M to 0.2M, 0.05M to 0.1 M, 0.1 M to 1 0M, 0.05M to 0.5M,
  • the auricular dosage form comprises a pharmaceutically acceptable liquid solvent (e.g., water).
  • a pharmaceutically acceptable liquid solvent e.g., water
  • the pH of the dosage form is 6.5 to 8.5.
  • the auricular dosage form is an auricular unit dosage form.
  • the auricular unit dosage form has a volume of at least 0.05 ml_ (e.g., at least 0.1 ml_, at least 0.2 mL, at least 0.3 mL, at least 0.4 mL, at least 0.5 mL, at least 0.6 mL, at least 0.7 mL, at least 0.8 mL, at least 0.9 mL, or at least 1 mL; e.g., 1 .1 mL or less, 1 mL or less, 0.9 mL or less, 0.8 mL or less, 0.7 mL or less, 0.6 mL or less, 0.5 mL or less, 0.4 mL or less, 0.3 mL or less, or 0.2 mL or less; e.g., 0.05 mL to 1 .1 mL, 0.1 mL to 1 .1 m
  • the therapeutic agent upon administration (for example, upon intratympanic or transtympanic administration, such as intratympanic or transtympanic injection) to a mammalian subject, the therapeutic agent is delivered across the round window membrane of the subject.
  • the therapeutic agent upon administration (for example, upon intratympanic or transtympanic administration, such as intratympanic or transtympanic injection) to a mammalian subject, the therapeutic agent remains present within perilymph of the subject for at least from about 1 hour to about 6 weeks following the administration to the subject (e.g., at least 1 hour, about 12 hours, about 24 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, or more).
  • the therapeutic agent upon administration (for example, upon intratympanic or transtympanic administration, such as intratympanic or transtympanic injection) to a mammalian subject, the therapeutic agent remains present within perilymph of the subject for at least from about 4 hours to about 6 weeks following the administration to the subject. In some embodiments, upon administration (for example, upon intratympanic or transtympanic administration, such as intratympanic or transtympanic injection) to a mammalian subject, the therapeutic agent remains present within perilymph of the subject for at least from about 8 hours to about 6 weeks following the administration to the subject.
  • the therapeutic agent upon administration (for example, upon intratympanic or transtympanic administration, such as intratympanic or transtympanic injection) to a mammalian subject, the therapeutic agent remains present within perilymph of the subject for at least from about 12 hours to about 6 weeks following the administration to the subject. In some embodiments, upon administration (for example, upon intratympanic or transtympanic administration, such as intratympanic or transtympanic injection) to a mammalian subject, the therapeutic agent remains present within perilymph of the subject for at least from about 24 hours to about 6 weeks following the administration to the subject.
  • the therapeutic agent upon administration (for example, upon intratympanic or transtympanic administration, such as intratympanic or transtympanic injection, such as intratympanic or transtympanic injection) to a mammalian subject, the therapeutic agent remains present within perilymph of the subject for at least from about 48 hours to about 6 weeks following the administration to the subject. In some embodiments, upon administration (for example, upon intratympanic or transtympanic administration, such as intratympanic or transtympanic injection) to a mammalian subject, the therapeutic agent remains present within perilymph of the subject for at least from about 72 hours to about 6 weeks following the administration to the subject.
  • the therapeutic agent upon administration (for example, upon intratympanic or transtympanic administration, such as intratympanic or transtympanic injection) to a mammalian subject, the therapeutic agent remains present within perilymph of the subject for at least from about 96 hours to about 6 weeks following the administration to the subject.
  • the therapeutic agent is an anti-platinum chemoprotectant agent (e.g., an alkaline or ammonium thiosulfate salt or a solvate thereof, an alkaline diethyldithiocarbamate salt, amifostine, methionine, N-acetylcysteine, cysteine, 2-aminoethanethiol, glutathione (GSH) or a C1-C6 alkyl ester thereof, lysine, histidine, arginine, ethylene diamine tetraacetic acid, dimercaprol, dimercaptosuccinic acid, dimercapto-propane sulfonate salt, penicillamine, a-lipoic acid, or fursultiamine, or a salt thereof).
  • an anti-platinum chemoprotectant agent e.g., an alkaline or ammonium thiosulfate salt or a solvate thereof, an alkaline
  • the anti-platinum chemoprotectant agent is an alkaline thiosulfate salt, ammonium thiosulfate salt, or a solvate thereof.
  • the alkaline thiosulfate salt is sodium thiosulfate or a solvate thereof.
  • the anti-platinum chemoprotectant agent is N-acetylcysteine or a salt thereof.
  • the therapeutic agent is a neurotrophin, an immunomodulating agent, an aural pressure modulating agent, a corticosteroid, an antimicrobial agent, an antagonist of truncated TrkC or truncated TrkB, a non-natural TrkB or TrkC agonist, a TrkB receptor agonist antibody, a TrkB receptor agonist compound, a TrkC receptor agonist antibody, a TrkC receptor agonist compound, an Atohl modulator, a WNT modulator, or an anti-platinum chemoprotectant agent.
  • the therapeutic agent is a TrkB receptor agonist antibody.
  • the therapeutic agent is a TrkC receptor agonist antibody.
  • the therapeutic agent is a Wnt modulator.
  • the therapeutic agent is an Atohl modulator (e.g., an Atohl polypeptide or a nucleic acid vector engineered to express Atohl , e.g., human Atohl (Hathl )).
  • the therapeutic agent is an anti-platinum chemoprotectant agent.
  • the therapeutic agent is a neurotrophin.
  • the neurotrophin is selected from neurotrophin-3 (NT-3), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), a pan-neurotrophin (e.g., PNT-1) a chimeric neurotrophin, glial cell-line derived neurotrophic factor (GDNF), neurotrophin-4 (NT-4), fibroblast growth factor (FGF), insulin-like growth factor (IGF), epidermal growth factor (EGF), platelet-derived growth factor (PGF), mesencephalic astrocyte-derived neurotrophic factor (MANF), cerebral dopamine neurotrophic factor (CDNF), and combinations thereof.
  • NT-3 neurotrophin-3
  • NGF nerve growth factor
  • BDNF brain-derived neurotrophic factor
  • CNTF ciliary neurotrophic factor
  • PNT-1 pan-neurotrophin
  • GDNF glial cell-line derived neurotrophic factor
  • NT-4 neuro
  • the neurotrophin is NT-3.
  • the NT-3 has an amino acid sequence having at least 85% sequence identity (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 1 .
  • the NT-3 has an amino acid sequence having at least 85% sequence identity (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 7.
  • the NT-3 has an amino acid sequence having at least 85% sequence identity (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 8.
  • the NT-3 has an amino acid sequence having at least 90% sequence identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 1 .
  • the NT-3 has an amino acid sequence having at least 90% sequence identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 7.
  • the NT-3 has an amino acid sequence having at least 90% sequence identity (e.g., at least 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 8.
  • the NT-3 has an amino acid sequence having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 1 . In some embodiments, the NT-3 has an amino acid sequence having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 7.
  • the NT-3 has an amino acid sequence having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 8.
  • the NT-3 has an amino acid sequence that differs from the amino acid sequence of SEQ ID NO: 1 , SEQ ID NO: 7, or SEQ ID NO: 8 by only one or more conservative amino acid substitutions, such as by up to 25, up to 20, up to 15, up to 10, or up to 5 conservative amino acid substitutions.
  • the NT-3 is an NT-3 variant having an amino acid sequence with one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 1 , SEQ ID NO: 7, or SEQ ID NO: 8.
  • the NT-3 variant has the sequence of any one of SEQ ID NOs: 34-46.
  • the NT-3 variant has the sequence of SEQ ID NO: 35.
  • the NT-3 variant has the sequence of SEQ ID NO: 43.
  • the NT-3 variant has the sequence of SEQ ID NO: 44.
  • the NT-3 is an NT-3 variant having an amino acid sequence with one or more (e.g., 1 , 2,
  • the NT-3 is encoded by a nucleic acid having the sequence of SEQ ID NO: 2 or SEQ ID NO: 56.
  • the neurotrophin is NGF.
  • the NGF has an amino acid sequence having at least 85% sequence identity (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 5.
  • the NGF has an amino acid sequence having at least 85% sequence identity (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 6.
  • the NGF has an amino acid sequence having at least 90% sequence identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 5.
  • the NGF has an amino acid sequence having at least 90% sequence identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 6.
  • the NGF has an amino acid sequence having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 5.
  • the NGF has an amino acid sequence having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 6.
  • the NGF has an amino acid sequence that differs from the amino acid sequence of SEQ ID NO: 5 or SEQ ID NO:6 by only one or more conservative amino acid substitutions, such as by up to 25, up to 20, up to 15, up to 10, or up to 5 conservative amino acid substitutions.
  • the NGF is an NGF variant having an amino acid sequence with one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 5 or SEQ ID NO: 6.
  • the NGF variant has the sequence any one of SEQ ID NOs: 20-23.
  • the NGF is an NGF variant having an amino acid sequence with one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 5 or SEQ ID NO: 6 and/or one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) deleted amino acids relative to the amino acid sequence of SEQ ID NO: 5 or SEQ ID NO: 6.
  • the NGF variant has the sequence of SEQ ID NO: 24.
  • the NGF is encoded by a nucleic acid having the sequence of SEQ ID NO: 55 or SEQ ID NO: 62.
  • the neurotrophin is NT-4.
  • the NT-4 has an amino acid sequence having at least 85% sequence identity (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 9.
  • the NT-4 has an amino acid sequence having at least 85% sequence identity (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 10.
  • the NT-4 has an amino acid sequence having at least 90% sequence identity (e.g., at least 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 9.
  • the NT-4 has an amino acid sequence having at least 90% sequence identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 10.
  • the NT-4 has an amino acid sequence having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 9.
  • the NT-4 has an amino acid sequence having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 10.
  • the NT- 4 has an amino acid sequence that differs from the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO:10 by only one or more conservative amino acid substitutions, such as by up to 25, up to 20, up to 15, up to 10, or up to 5 conservative amino acid substitutions.
  • the NT-4 is an NT-4 variant having an amino acid sequence with one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 10.
  • the NT-4 is an NT-4 variant having an amino acid sequence with one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 10 and/or one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) deleted amino acids relative to the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 10.
  • the NT- 4 is encoded by a nucleic acid having the sequence of SEQ ID NO: 57.
  • the neurotrophin is BDNF.
  • the BDNF has an amino acid sequence having at least 85% sequence identity (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 11.
  • the BDNF has an amino acid sequence having at least 85% sequence identity (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of any one of SEQ ID NOs: 12-15.
  • the BDNF has an amino acid sequence having at least 85% sequence identity (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 16.
  • the BDNF has an amino acid sequence having at least 90% sequence identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 11.
  • the BDNF has an amino acid sequence having at least 90% sequence identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of any one of SEQ ID NOs: 12-15.
  • the BDNF has an amino acid sequence having at least 90% sequence identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 16.
  • the BDNF has an amino acid sequence having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 11. In some embodiments, the BDNF has an amino acid sequence having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of any one of SEQ ID NOs: 12-15.
  • the BDNF has an amino acid sequence having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 16.
  • the BDNF has an amino acid sequence that differs from the amino acid sequence of any one of SEQ ID NOs: 11 -16 by only one or more conservative amino acid substitutions, such as by up to 25, up to 20, up to 15, up to 10, or up to 5 conservative amino acid substitutions.
  • the BDNF is a BDNF variant having an amino acid sequence with one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8,
  • the BDNF is a BDNF variant having an amino acid sequence with one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs: 11 -16 and/or one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) deleted amino acids relative to the amino acid sequence of any one of SEQ ID NOs: 11 -16.
  • the BDNF is encoded by a nucleic acid having the sequence of any one of SEQ ID NOs: 58-61.
  • the neurotrophin is a pan-neurotrophin.
  • the pan- neurotrophin is PNT-1 .
  • the PNT-1 has an amino acid sequence having at least 85% sequence identity (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%,
  • the PNT-1 has an amino acid sequence having at least 90% sequence identity (e.g., at least 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 17.
  • the PNT-1 has an amino acid sequence having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%,
  • the PNT-1 has an amino acid sequence that differs from the amino acid sequence of SEQ ID NO: 17 by only one or more conservative amino acid substitutions, such as by up to 25, up to 20, up to 15, up to 10, or up to 5 conservative amino acid substitutions.
  • the PNT-1 is a PNT-1 variant having an amino acid sequence with one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 17.
  • the PNT-1 variant has the sequence any one of SEQ ID NOs: 25-28 or 31 -33.
  • the PNT-1 is a PNT-1 variant having an amino acid sequence with one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9,
  • amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 17 and/or one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) deleted amino acids relative to the amino acid sequence of SEQ ID NO: 17.
  • the neurotrophin is a chimeric neurotrophin.
  • the chimeric neurotrophin is an NGF/BDNF chimera.
  • the chimeric neurotrophin has an amino acid sequence having at least 85% sequence identity (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 18.
  • the chimeric neurotrophin has an amino acid sequence having at least 85% sequence identity (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 19.
  • the chimeric neurotrophin has an amino acid sequence having at least 85% sequence identity (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 29.
  • the chimeric neurotrophin has an amino acid sequence having at least 85% sequence identity (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 30.
  • the chimeric neurotrophin has an amino acid sequence having at least 90% sequence identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 18.
  • the chimeric neurotrophin has an amino acid sequence having at least 90% sequence identity (e.g., at least 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 19.
  • the chimeric neurotrophin has an amino acid sequence having at least 90% sequence identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 29.
  • the chimeric neurotrophin has an amino acid sequence having at least 90% sequence identity (e.g., at least 90%,
  • the chimeric neurotrophin has an amino acid sequence having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 18.
  • the chimeric neurotrophin has an amino acid sequence having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 19. In some embodiments, the chimeric neurotrophin has an amino acid sequence having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 29.
  • the chimeric neurotrophin has an amino acid sequence having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 30.
  • the chimeric neurotrophin has an amino acid sequence that differs from the amino acid sequence of any one of SEQ ID NOs: 18, 19, 29, or 30 by only one or more conservative amino acid substitutions, such as by up to 25, up to 20, up to 15, up to 10, or up to 5 conservative amino acid substitutions.
  • the chimeric neurotrophin is a chimeric neurotrophin variant having an amino acid sequence with one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs: 18, 19, 29, or 30.
  • the chimeric neurotrophin is a chimeric neurotrophin variant having an amino acid sequence with one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs: 18, 19, 29, or 30 and/or one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) deleted amino acids relative to the amino acid sequence of any one of SEQ ID NOs: 18, 19, 29, or 30.
  • one or more e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more
  • the neurotrophin is CNTF.
  • the CNTF has an amino acid sequence having at least 85% sequence identity (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 47.
  • the CNTF has an amino acid sequence having at least 90% sequence identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 47.
  • the CNTF has an amino acid sequence having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 47.
  • the CNTF has an amino acid sequence that differs from the amino acid sequence of SEQ ID NO: 47 by only one or more conservative amino acid substitutions, such as by up to 25, up to 20, up to 15, up to 10, or up to 5 conservative amino acid substitutions.
  • the CNTF is a CNTF variant having an amino acid sequence with one or more (e.g., 1 , 2,
  • the CNTF is a CNTF variant having an amino acid sequence with one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 47 and/or one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) deleted amino acids relative to the amino acid sequence of SEQ ID NO: 47.
  • the CNTF is encoded by a nucleic acid having the sequence of SEQ ID NO: 63.
  • the neurotrophin is IGF (e.g., IGF1 or IGF2).
  • the IGF is IGF1 and has an amino acid sequence having at least 85% sequence identity (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 48.
  • the IGF is IGF1 and has an amino acid sequence having at least 85% sequence identity (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 49.
  • the IGF is IGF1 and has an amino acid sequence having at least 85% sequence identity (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 50 or SEQ ID NO: 51 .
  • the IGF is IGF2 and has an amino acid sequence having at least 85% sequence identity (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 52.
  • the IGF is IGF2 and has an amino acid sequence having at least 85% sequence identity (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 53.
  • the IGF is IGF2 and has an amino acid sequence having at least 85% sequence identity (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 54.
  • the IGF is IGF1 and has an amino acid sequence having at least 90% sequence identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 48.
  • the IGF is IGF1 and has an amino acid sequence having at least 90% sequence identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 49.
  • the IGF is IGF1 and has an amino acid sequence having at least 90% sequence identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 50 or SEQ ID NO: 65.
  • the IGF is IGF2 and has an amino acid sequence having at least 90% sequence identity (e.g., at least 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 52.
  • the IGF is IGF2 and has an amino acid sequence having at least 90% sequence identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 53.
  • the IGF is IGF2 and has an amino acid sequence having at least 90% sequence identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 54.
  • the IGF is IGF1 and has an amino acid sequence having at least 95% sequence identity (e.g., at least 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 48.
  • the IGF is IGF1 and has an amino acid sequence having at least 95% sequence identity (e.g., at least 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 49. In some embodiments, the IGF is IGF1 and has an amino acid sequence having at least 95% sequence identity (e.g., at least 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 50 or SEQ ID NO: 51 .
  • the IGF is IGF2 and has an amino acid sequence having at least 95% sequence identity (e.g., at least 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 52.
  • the IGF is IGF2 and has an amino acid sequence having at least 95% sequence identity (e.g., at least 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 53.
  • the IGF is IGF2 and has an amino acid sequence having at least 95% sequence identity (e.g., at least 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 54.
  • the IGF is IGF1 and has an amino acid sequence that differs from the amino acid sequence of any one of SEQ ID NOs: 48-51 by only one or more conservative amino acid substitutions, such as by up to 25, up to 20, up to 15, up to 10, or up to 5 conservative amino acid substitutions.
  • the IGF is IGF2 and has an amino acid sequence that differs from the amino acid sequence of any one of SEQ ID NOs: 52-54 by only one or more conservative amino acid substitutions, such as by up to 25, up to 20, up to 15, up to 10, or up to 5 conservative amino acid substitutions.
  • the IGF is an IGF1 variant having an amino acid sequence with one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs: 48-51 .
  • the IGF is an IGF2 variant having an amino acid sequence with one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs: 52-54.
  • the IGF is an IGF1 variant having an amino acid sequence with one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs: 48-51 and/or one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) deleted amino acids relative to the amino acid sequence of any one of SEQ ID NOs: 48-51 .
  • the IGF is an IGF2 variant having an amino acid sequence with one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs: 52-54 and/or one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) deleted amino acids relative to the amino acid sequence of any one of SEQ ID NOs: 52-54.
  • the IGF is IGF1 and is encoded by a nucleic acid having the sequence of any one of SEQ ID NOs: 64-66.
  • the IGF is IGF1 and is encoded by a nucleic acid having the sequence of SEQ ID NO: 67 or SEQ ID NO: 68.
  • the therapeutic agent is an anti-platinum chemoprotectant agent.
  • the anti-platinum chemoprotectant agent is an alkaline or ammonium thiosulfate salt or a solvate thereof, an alkaline diethyldithiocarbamate salt, amifostine, methionine, N-acetylcysteine, cysteine, 2-aminoethanethiol, glutathione (GSH) or a C1-C6 alkyl ester thereof, lysine, histidine, arginine, ethylene diamine tetraacetic acid, dimercaprol, dimercaptosuccinic acid, dimercapto-propane sulfonate salt, penicillamine, a-lipoic acid, or fursultiamine, or a salt thereof.
  • the anti platinum chemoprotectant agent is an alkaline thiosulfate salt, ammonium thiosulfate salt, or a solvate thereof. In some embodiments, wherein the alkaline thiosulfate salt is sodium thiosulfate or a solvate thereof. In some embodiments, the anti-platinum chemoprotectant agent is N-acetylcysteine or a salt thereof.
  • the therapeutic agent is a glial cell line-derived neurotrophic factor family ligand, a neuropoietic cytokine, an anti-inflammatory cytokine, a neuroprotection agent, growth differentiation factor 11 , erythropoietin (EPO), granulocyte-colony stimulating factor, granulocyte- macrophage colony stimulating factor, growth differentiation factor-9, thrombopoietin, transforming growth factor alpha (TGF-a), stromal cell-derived factor 1 , myostatin (growth differentiation factor 8), parathyroid hormone, parathyroid hormone related peptide, interleukin 1 receptor antagonist, fibroblast growth factor 18, high-mobility group protein 2, glucocorticoid receptor, fibroblast growth factor 9, hepatocyte growth factor, or a TGFp-superfamily protein.
  • the therapeutic agent is a glial cell line-derived neurotrophic factor family ligand selected from glial cell line-derived neurotrophic factor (GDNF), neurturin, artemin, and persephin.
  • GDNF glial cell line-derived neurotrophic factor
  • neurturin glial cell line-derived neurotrophic factor
  • artemin artemin
  • persephin persephin
  • the therapeutic agent is a neuropoietic cytokine selected from interleukin- 6, interleukin-11 , inteleukin-27, leukemia inhibitory factor, cardiotrophin 1 , neuropoietin, cardiotrophin-like cytokine, and fibroblast growth factor 2.
  • the therapeutic agent is an anti-inflammatory cytokine selected from interleukin-4 and interleukin-10. In some embodiments, the therapeutic agent is a neuroprotection agent selected from neuregulin-1 and vascular endothelial growth factor (VEGF).
  • cytokine selected from interleukin-4 and interleukin-10.
  • therapeutic agent is a neuroprotection agent selected from neuregulin-1 and vascular endothelial growth factor (VEGF).
  • VEGF vascular endothelial growth factor
  • the therapeutic agent is a TGFp-superfamily protein selected from TGFp, TGFp3, BMP2, and BMP7.
  • the therapeutic agent is a nucleic acid vector.
  • the nucleic acid vector is a plasmid, cosmid, artificial chromosome, or viral vector.
  • the viral vector is an adeno-associated virus (AAV), adenovirus, lentivirus, retrovirus, poxvirus, baculovirus, herpes simplex virus, or a vaccinia virus.
  • the viral vector is an AAV vector.
  • the serotype of the AAV vector is selected from the group consisting of AAV1 , AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, rh10, rh39, rh43, rh74, Anc80, Anc80L65, DJ/8, DJ/9, 7m8, PHP.B, PHP.eb, and PHP.S.
  • the serotype of the AAV vector is AAV1 .
  • the serotype of the AAV vector isAAV2.
  • the serotype of the AAV vector is 7m8.
  • the AAV vector has a mutation at one or more surface- exposed tyrosine residues on capsid proteins, such as Tyr252 to Phe272 (Y252F), Tyr272 to Phe272 (Y272F), Tyr444 to Phe444 (Y444F), Tyr500 to Phe500 (Y500F), Tyr700 to Phe700 (Y700F), Tyr704 to Phe704 (Y704F), Tyr730 to Phe730 (Y730F), and Tyr 733 to Phe733 (Y733F).
  • the nucleic acid vector (e.g., AAV vector) is engineered to express a protein described herein (e.g., a neurotrophin, such as NT-3, NGF, NT-4, BDNF, CNTF, IGF, PNT-1 , or a chimeric neurotrophin, or Atohl ).
  • a protein described herein e.g., a neurotrophin, such as NT-3, NGF, NT-4, BDNF, CNTF, IGF, PNT-1 , or a chimeric neurotrophin, or Atohl.
  • the nucleic acid vector includes the sequence of any one of SEQ ID NOs: 2 or 55-68.
  • the therapeutic agent is an antibody or antigen-binding fragment thereof.
  • the antibody or antigen-binding fragment thereof may be, for example, a monoclonal antibody or antigen binding fragment thereof, a polyclonal antibody or antigen-binding fragment thereof, a humanized antibody or antigen-binding fragment thereof, a bispecific antibody or antigen-binding fragment thereof, a dual-variable immunoglobulin domain, a single-chain Fv molecule (scFv), a diabody, a triabody, a nanobody, an antibody-like protein scaffold, a Fv fragment, a Fab fragment, a F(ab’)2 molecule, or a tandem di-scFv.
  • scFv single-chain Fv molecule
  • the therapeutic agent is a liposome, vesicle, synthetic vesicle, exosome, synthetic exosome, dendrimer, or nanoparticle.
  • the therapeutic agent is a small molecule, such as a small molecule that is not naturally round window membrane-penetrant.
  • the therapeutic agent is an interfering RNA, such as a short interfering RNA (siRNA), a short hairpin RNA (shRNA), or a micro RNA (miRNA).
  • interfering RNA such as a short interfering RNA (siRNA), a short hairpin RNA (shRNA), or a micro RNA (miRNA).
  • the auricular dosage form is a gel at normal human body temperature.
  • the gel has a dynamic viscosity of at about 100 cP to about 1 ,000,000 cP, such as a dynamic viscosity of about 100 cP, 200 cP, 300 cP, 400 cP, 500 cP, 600 cP, 700 cP, 800 cP, 900 cP, 1 ,000 cP, 2,000 cP, 3,000 cP, 4,000 cP, 5,000 cP, 6,000 cP, 7,000 cP, 8,000 cP, 9,000 cP, 10,000 cP, 20,000 cP, 30,000 cP, 40,000 cP, 50,000 cP, 60,000 cP, 70,000 cP, 80,000 cP, 90,000 cP, 100,000 cP, 200,000 cP, 300,000 cP, 400,000 cP, 500,000 cP, 600,000 cP, 700,000 cP, 800,000 cP, 900,000 cP, 100,000
  • the auricular dosage form further contains a pharmaceutically acceptable liquid solvent, such as water.
  • the auricular dosage form contains one or more agents selected from an antimicrobial agent, an arylcycloalkylamine, an elipticine derivative, an anti-apoptotic agent, a c-JNK inhibitor, an antioxidant, an NSAID, an analgesic, a neuroprotection agent, a glutamate modulator, an interleukin 1 modulator, an interleukin-1 antagonist, a corticosteroid, an anti-TNF agent, a calcineurin inhibitor, an IKK inhibitor, an interleukin inhibitor, a platelet activating factor antagonist, a TNF-a converting enzyme (TACE) inhibitor, a Toll-like receptor inhibitor, an autoimmune agent, an IL-1 modulator, an RNA interference agent, an aquaporin modulator, an estrogen-related receptor beta modulator, a GAP junction protein, a vasopressin receptor modul
  • the auricular dosage form further comprises one or more agents selected from the group consisting of an antimicrobial agent, an anti-apoptotic agent, a c-JNK inhibitor, an antioxidant, an NSAID, an analgesic, a neuroprotection agent, a glutamate modulator, an interleukin 1 modulator, an interleukin-1 antagonist, a corticosteroid, an anti-TNF agent, a calcineurin inhibitor, an IKK inhibitor, an interleukin inhibitor, a platelet activating factor antagonist, a TNF-a converting enzyme (TACE) inhibitor, a Toll-like receptor inhibitor, an IL-1 modulator, an RNA interference agent, an aquaporin modulator, an estrogen-related receptor beta modulator, a GAP junction protein, a vasopressin receptor modulator, an NMDA receptor modulator, an ENaC receptor modulator, an osmotic diuretic, a progesterone receptor, a prostaglandin,
  • the invention features a method of delivering a therapeutic agent across the round window membrane of a subject (e.g., a mammalian subject, such as a human subject) by providing to the subject (e.g., by way of direct administration to the subject) a therapeutically effective amount of the auricular dosage form of any of the above aspects or embodiments of the invention.
  • auricular dosage form is administered to or near the round window membrane.
  • the auricular dosage form is administered intratympanically or transtympanically.
  • the method is used to treat an otic disease, such as ceruminosis or ceruminosis associated with an otic disease or condition, ear pruritus, otitis externa, otalgia, tinnitus, vestibular dysfunction (e.g., vertigo, dizziness, or loss of balance), ear fullness, hearing loss, Meniere's disease, sensorineural hearing loss (e.g., noise-induced hearing loss, age-related hearing loss (presbycusis), ototoxic drug-induced hearing loss, hearing loss related to head trauma, hearing loss related to infection), autoimmune ear disease, ototoxicity, excitotoxicity, hidden hearing loss, cochlear synaptopathy, endolymphatic hydrops, labyrinthitis, Ramsay Hunt's Syndrome, vestibular neuronitis, or microvascular compression syndrome, hyperacusis, presbystasis, central auditory processing disorder, auditory neuropathy, improvement of cochlea implant performance, or
  • the invention features a method of treating a subject (e.g., a mammalian subject, such as a human subject) having or at risk of developing hearing loss (e.g., sensorineural hearing loss, deafness, or auditory neuropathy) by administering to the subject a therapeutically effective amount of the auricular dosage form of any of the above aspects or embodiments of the invention, such as embodiments in which the therapeutic agent is a neurotrophin, an immunomodulating agent, an aural pressure modulating agent, a corticosteroid, an antimicrobial agent, an antagonist of truncated TrkC or truncated TrkB, a non-natural TrkB or TrkC agonist, a TrkB receptor agonist antibody, a TrkB receptor agonist compound, a TrkC receptor agonist antibody, a TrkC receptor agonist compound, an Atohl modulator, a neuroprotection agent, WNT modulator, or an anti-platinum chemoprotectant agent
  • the hearing loss is genetic hearing loss.
  • the genetic hearing loss is autosomal dominant hearing loss, autosomal recessive hearing loss, or X-linked hearing loss.
  • the hearing loss is acquired hearing loss.
  • the acquired hearing loss is noise-induced hearing loss, age-related hearing loss, disease or infection-related hearing loss, head trauma-related hearing loss, or ototoxic drug-induced hearing loss.
  • the invention features a method of treating a subject (e.g., a mammalian subject, such as a human subject) having or at risk of developing vestibular dysfunction by administering to the subject a therapeutically effective amount of the auricular dosage form of any of the above aspects or embodiments of the invention, such as embodiments in which the therapeutic agent is a neurotrophin, an immunomodulating agent, an aural pressure modulating agent, a corticosteroid, an antimicrobial agent, an antagonist of truncated TrkC or truncated TrkB, a non-natural TrkB or TrkC agonist, a TrkB receptor agonist antibody, a TrkB receptor agonist compound, a TrkC receptor agonist antibody, a TrkC receptor agonist compound, an Atohl modulator, a neuroprotection agent, WNT modulator, or an anti platinum chemoprotectant agent (e.g., embodiments in which the therapeutic agent is a neurotrophin selected from NT-3
  • the vestibular dysfunction is vertigo, dizziness, or loss of balance.
  • the invention features a method of promoting hair cell regeneration in a subject (e.g., a mammalian subject, such as a human subject) in need thereof by administering to the subject a therapeutically effective amount of the auricular dosage form of any of the above aspects or embodiments of the invention, such as embodiments in which the therapeutic agent is a neurotrophin, an immunomodulating agent, an aural pressure modulating agent, a corticosteroid, an antimicrobial agent, an antagonist of truncated TrkC or truncated TrkB, a non-natural TrkB or TrkC agonist, a TrkB receptor agonist antibody, a TrkB receptor agonist compound, a TrkC receptor agonist antibody, a TrkC receptor agonist compound, an Atohl modulator, a neuroprotection agent, WNT modulator, or an anti-platinum chemoprotectant agent (e.g., embodiments in which the therapeutic agent is a neurotrophin selected from NT
  • the invention features a method of promoting SGN regeneration in a subject (e.g., a mammalian subject, such as a human subject) in need thereof by administering to the subject a therapeutically effective amount of the auricular dosage form of any of the above aspects or embodiments of the invention, such as embodiments in which the therapeutic agent is a neurotrophin, an immunomodulating agent, an aural pressure modulating agent, a corticosteroid, an antimicrobial agent, an antagonist of truncated TrkC or truncated TrkB, a non-natural TrkB or TrkC agonist, a TrkB receptor agonist antibody, a TrkB receptor agonist compound, a TrkC receptor agonist antibody, a TrkC receptor agonist compound, an Atohl modulator, a neuroprotection agent, WNT modulator, or an anti-platinum chemoprotectant agent (e.g., embodiments in which the therapeutic agent is a neurotrophin selected from NT
  • the invention features a method of preventing or reducing ototoxic drug- induced hair cell damage or death in a subject (e.g., a mammalian subject, such as a human subject) in need thereof by administering to the subject a therapeutically effective amount of the auricular dosage form of any of the above aspects or embodiments of the invention, such as embodiments in which the therapeutic agent is a neurotrophin, an immunomodulating agent, an aural pressure modulating agent, a corticosteroid, an antimicrobial agent, an antagonist of truncated TrkC or truncated TrkB, a non-natural TrkB or TrkC agonist, a TrkB receptor agonist antibody, a TrkB receptor agonist compound, a TrkC receptor agonist antibody, a TrkC receptor agonist compound, an Atohl modulator, a neuroprotection agent, WNT modulator, or an anti-platinum chemoprotectant agent (e.g., embodiments in which the therapeutic agent
  • the invention features a method of preventing or reducing ototoxic drug- induced SGN damage or death in a subject (e.g., a mammalian subject, such as a human subject) in need thereof by administering to the subject a therapeutically effective amount of the auricular dosage form of any of the above aspects or embodiments of the invention, such as embodiments in which the therapeutic agent is a neurotrophin, an immunomodulating agent, an aural pressure modulating agent, a corticosteroid, an antimicrobial agent, an antagonist of truncated TrkC or truncated TrkB, a non-natural TrkB or TrkC agonist, a TrkB receptor agonist antibody, a TrkB receptor agonist compound, a TrkC receptor agonist antibody, a TrkC receptor agonist compound, an Atohl modulator, a neuroprotection agent, WNT modulator, or an anti-platinum chemoprotectant agent (e.g., embodiments in which the therapeutic agent
  • the ototoxic drug is selected from the group including aminoglycosides (e.g., gentamycin, neomycin, streptomycin, tobramycin, kanamycin, vancomycin, and amikacin), antineoplastic drugs (e.g., platinum-containing chemotherapeutic agents, such as cisplatin, carboplatin, and oxaliplatin), ethacrynic acid, furosemide, salicylates (e.g., aspirin, particularly at high doses), and quinine.
  • aminoglycosides e.g., gentamycin, neomycin, streptomycin, tobramycin, kanamycin, vancomycin, and amikacin
  • antineoplastic drugs e.g., platinum-containing chemotherapeutic agents, such as cisplatin, carboplatin, and oxaliplatin
  • ethacrynic acid e.g., furosemide
  • the invention features a method of preventing or mitigating platinum-induced ototoxicity in a subject by administering to the subject a therapeutically effective amount of the auricular dosage form of any of the above aspects or embodiments of the invention, such as embodiments in which the therapeutic agent is a neurotrophin, an immunomodulating agent, an aural pressure modulating agent, a corticosteroid, an antimicrobial agent, an antagonist of truncated TrkC or truncated TrkB, a non natural TrkB or TrkC agonist, a TrkB receptor agonist antibody, a TrkB receptor agonist compound, a TrkC receptor agonist antibody, a TrkC receptor agonist compound, an Atohl modulator, a neuroprotection agent, WNT modulator, or an anti-platinum chemoprotectant agent (e.g., embodiments in which the therapeutic agent is a neurotrophin selected from NT-3, NGF, BDNF, CNTF, GDNF,
  • FGF FGF, IGF, EGF, PGF, MANF, CDNF, a pan-neurotrophin (e.g., PNT-1 ), a chimeric neurotrophin (e.g., a NGF/BDNF chimera), and combinations thereof, or embodiments in which the therapeutic agent is an anti-platinum chemoprotectant agent such as sodium thiosulfate or N-acetylcysteine).
  • the invention features a method of treating a subject (e.g., a mammalian subject, such as a human subject) having or at risk of developing tinnitus by administering to the subject a therapeutically effective amount of the auricular dosage form of any of the above aspects or embodiments of the invention, such as embodiments in which the therapeutic agent is a neurotrophin, an immunomodulating agent, an aural pressure modulating agent, a corticosteroid, an antimicrobial agent, an antagonist of truncated TrkC or truncated TrkB, a non-natural TrkB or TrkC agonist, a TrkB receptor agonist antibody, a TrkB receptor agonist compound, a TrkC receptor agonist antibody, a TrkC receptor agonist compound, an Atohl modulator, a neuroprotection agent, WNT modulator, or an anti-platinum chemoprotectant agent (e.g., embodiments in which the therapeutic agent is a neurotrophin, an immuno
  • the invention features a method of preventing or reducing hair cell damage or death in a subject (e.g., a mammalian subject, such as a human subject) in need thereof by administering to the subject a therapeutically effective amount of the auricular dosage form of any of the above aspects or embodiments of the invention, such as embodiments in which the therapeutic agent is a neurotrophin, an immunomodulating agent, an aural pressure modulating agent, a corticosteroid, an antimicrobial agent, an antagonist of truncated TrkC or truncated TrkB, a non-natural TrkB or TrkC agonist, a TrkB receptor agonist antibody, a TrkB receptor agonist compound, a TrkC receptor agonist antibody, a TrkC receptor agonist compound, an Atohl modulator, a neuroprotection agent, WNT modulator, or an anti platinum chemoprotectant agent (e.g., embodiments in which the therapeutic agent is a neurotrophin selected from
  • the invention features a method of preventing or reducing SGN damage or death in a subject (e.g., a mammalian subject, such as a human subject) in need thereof by administering to the subject a therapeutically effective amount of the auricular dosage form of any of the above aspects or embodiments of the invention, such as embodiments in which the therapeutic agent is a neurotrophin, an immunomodulating agent, an aural pressure modulating agent, a corticosteroid, an antimicrobial agent, an antagonist of truncated TrkC or truncated TrkB, a non-natural TrkB or TrkC agonist, a TrkB receptor agonist antibody, a TrkB receptor agonist compound, a TrkC receptor agonist antibody, a TrkC receptor agonist compound, an Atohl modulator, a neuroprotection agent, WNT modulator, or an anti platinum chemoprotectant agent (e.g., embodiments in which the therapeutic agent is a neurotrophin selected from
  • the invention features a method of increasing hair cell survival in a subject (e.g., a mammalian subject, such as a human subject) in need thereof by administering to the subject a therapeutically effective amount of the auricular dosage form of any of the above aspects or embodiments of the invention, such as embodiments in which the therapeutic agent is a neurotrophin, an immunomodulating agent, an aural pressure modulating agent, a corticosteroid, an antimicrobial agent, an antagonist of truncated TrkC or truncated TrkB, a non-natural TrkB or TrkC agonist, a TrkB receptor agonist antibody, a TrkB receptor agonist compound, a TrkC receptor agonist antibody, a TrkC receptor agonist compound, an Atohl modulator, a neuroprotection agent, or a WNT modulator (e.g., embodiments in which the therapeutic agent is a neurotrophin selected from NT-3, NGF, BDNF, CNTF
  • the invention features a method of increasing SGN survival in a subject (e.g., a mammalian subject, such as a human subject) in need thereof by administering to the subject a therapeutically effective amount of the auricular dosage form of any of the above aspects or embodiments of the invention, such as embodiments in which the therapeutic agent is a neurotrophin, an immunomodulating agent, an aural pressure modulating agent, a corticosteroid, an antimicrobial agent, an antagonist of truncated TrkC or truncated TrkB, a non-natural TrkB or TrkC agonist, a TrkB receptor agonist antibody, a TrkB receptor agonist compound, a TrkC receptor agonist antibody, a TrkC receptor agonist compound, an Atohl modulator, a neuroprotection agent, WNT modulator, or an anti-platinum chemoprotectant agent (e.g., embodiments in which the therapeutic agent is a neurotrophin selected from NT-3
  • the hair cell is a cochlear hair cell. In some embodiments of any of the above aspects, the cochlear hair cell is an inner hair cell. In some embodiments of any of the above aspects, the cochlear hair cell is an outer hair cell. In some embodiments of any of the above aspects, the hair cell is a vestibular hair cell. In some embodiments of any of the above aspects, the hair cell is a mammalian hair cell. In some embodiments, the mammalian hair cell is a human hair cell. In some embodiments of any of the above aspects, the SGN is a mammalian SGN. In some embodiments of any of the above aspects, the mammalian SGN is a human SGN.
  • the method further includes evaluating the hearing of the subject prior to administering the auricular dosage form (e.g., evaluating hearing using standard tests, such as audiometry, auditory brainstem response (ABR), electrochocleography (ECOG), or otoacoustic emissions). In some embodiments of any of the above aspects, the method further includes evaluating the hearing of the subject after administering the auricular dosage form (e.g., evaluating hearing using standard tests, such as audiometry, ABR, ECOG, or otoacoustic emissions).
  • standard tests such as audiometry, auditory brainstem response (ABR), electrochocleography (ECOG), or otoacoustic emissions.
  • the method further includes evaluating the vestibular function of the subject prior to administering the auricular dosage form (e.g., evaluating vestibular function using standard tests, such as electronystagmogram (ENG) or videonystagmogram (VNG), posturography, rotary-chair testing, ECOG, vestibular evoked myogenic potentials (VEMP), or specialized clinical balance tests).
  • ENG electronystagmogram
  • VNG videonystagmogram
  • ECOG vestibular evoked myogenic potentials
  • VEMP vestibular evoked myogenic potentials
  • the method further includes evaluating the vestibular function of the subject after administering the auricular dosage form (e.g., evaluating vestibular function using standard tests, such as ENG or VNG, posturography, rotary-chair testing, ECOG, VEMP, or specialized clinical balance tests).
  • standard tests such as ENG or VNG, posturography, rotary-chair testing, ECOG, VEMP, or specialized clinical balance tests.
  • the auricular dosage form is locally administered.
  • the auricular dosage form is administered to the ear of the subject (e.g., administered to the round window).
  • the auricular dosage form is administered intratympanically or transtympanically (e.g., administered by transtympanic or intratympanic injection).
  • the auricular dosage form is administered in an amount sufficient to prevent or reduce hearing loss, prevent or reduce vestibular dysfunction, prevent or reduce tinnitus, delay the development of hearing loss, delay the development of vestibular dysfunction, slow the progression of hearing loss, slow the progression of vestibular dysfunction, improve hearing, improve vestibular function, improve hair cell function, prevent or reduce hair cell damage, prevent, slow, or reduce hair cell death, promote or increase hair cell survival, increase hair cell numbers, promote or induce hair cell regeneration, improve SGN function, prevent or reduce SGN damage, prevent, slow, or reduce SGN death, promote or increase SGN survival, increase SGN numbers, promote or induce SGN regeneration, preserve ribbon synapses, promote or increase ribbon synapse formation, maintain the connections between hair cells and SGNs, or increase or restore the connections between hair cells and SGNs.
  • the invention features a kit containing the auricular dosage form of any of the above aspects or embodiments of the invention.
  • the kit contains a package insert instructing a user of the kit to administer the auricular dosage form to a subject (e.g., a mammalian subject, such as a human subject) in need thereof.
  • the subject is suffering from an otic disease, such as ceruminosis or ceruminosis associated with an otic disease or condition, ear pruritus, otitis externa, otalgia, tinnitus, vestibular dysfunction (e.g., vertigo, dizziness, or loss of balance), ear fullness, hearing loss, Meniere's disease, sensorineural hearing loss (e.g., noise-induced hearing loss, age-related hearing loss (presbycusis), ototoxic drug-induced hearing loss, hearing loss related to head trauma, hearing loss related to infection), auto immune ear disease, ototoxicity, excitotoxicity, hidden hearing loss, cochlear synaptopathy, endolymphatic hydrops, labyrinthitis, Ramsay Hunt's Syndrome, vestibular neuronitis, or microvascular compression syndrome, hyperacusis, presbystasis, central auditory processing disorder, auditory neuropathy, improvement of cochlea implant performance, or
  • the term “about” refers to a value that is within 10% above or below the noted value. For instance, a value of “about 5 pl_” refers to a quantity that is from 4.5 mI_ to 5.5 mI_.
  • cochlear hair cell refers to group of specialized cells in the inner ear that are involved in sensing sound. There are two types of cochlear hair cells: inner hair cells and outer hair cells. Damage to cochlear hair cells and genetic mutations that disrupt cochlear hair cell function are implicated in hearing loss and deafness.
  • the terms “conservative mutation,” “conservative substitution,” or “conservative amino acid substitution” refer to a substitution of one or more amino acids for one or more different amino acids that exhibit similar physicochemical properties, such as polarity, electrostatic charge, and steric volume. These properties are summarized for each of the twenty naturally-occurring amino acids in Table 1 , below.
  • ⁇ based on volume in A 3 50-100 is small, 100-150 is intermediate, 150-200 is large, and >200 is bulky
  • conservative amino acid families include, e.g., (i) G, A, V, L, I, P, and M; (ii) D and E; (iii) C, S and T; (iv) H, K and R; (v) N and Q; and (vi) F, Y and W.
  • a conservative mutation or substitution is therefore one that substitutes one amino acid for a member of the same amino acid family (e.g., a substitution of Ser for Thr or Lys for Arg).
  • HA designates the protonated form of the side-chain substituent
  • A- designates the deprotonated form of the side-chain substituent.
  • the Henderson-Hasselbalch equation may be applied multiple times to the same amino acid for those that contain side-chains that undergo more than one ionization at the pH of interest (e.g., pH of 7.4), such as those that contain a phosphate substituent, among others.
  • the formal charge of an amino acid as described herein refers to the charge of the predominant form (i.e., the form present in the highest quantity at chemical equilibrium) of the amino acid side chain substituent (e.g., “HA” or “A-”) as determined by the Henderson-Hasselbalch equation.
  • the terms “neurotrophin-3” and its abbreviation, “NT-3,” are used interchangeably and refer to the protein growth factor that exerts growth or survival activating effects on various neurons of the central and/or peripheral nervous system, as well as to the nucleic acid encoding the protein.
  • neurotrophin-3 and its abbreviation, “NT-3,” refer not only to wild-type forms of NT-3, but also to variants of wild-type NT-3 proteins that retain (or improve upon) the neuronal growth or survival activating properties of wild-type NT-3, as well as to nucleic acids encoding such variants.
  • the amino acid sequence and corresponding cDNA sequence of a wild-type form of human NT-3 are provided herein as
  • SEQ ID NOs: 1 and 2 which correspond to UniProtKB Accession No. P20783 and to CCDS 8538.1 , respectively. These sequences are shown in Table 2, below.
  • the amino acid sequence of isoform 2 of wild-type human NT-3 and its corresponding cDNA sequence (SEQ ID NOs: 21 and 48), the amino acid sequence of the mature form of wild-type human NT-3 (SEQ ID NO: 8), and amino acid sequences of variants of the mature form of wild-type human NT-3 (SEQ ID NOs: 34-46) are provided in Table 3, herein. Table 2.
  • NT-3 neurotrophin-3 and its abbreviation, “NT-3,” as used herein include, for example, forms of the human NT-3 protein that have an amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NOs: 1 , 7, or 8 (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, or 100% identical to the amino acid sequence of SEQ ID NO:
  • NT-3 protein 1 , 7, or 8 and/or forms of the human NT-3 protein that contain one or more substitutions, insertions, and/or deletions (e.g., one or more conservative and/or nonconservative amino acid substitutions, such as up to 5, 10, 15, 20, 25, or more, conservative or nonconservative amino acid substitutions) relative to a wild-type NT-3 protein.
  • substitutions, insertions, and/or deletions e.g., one or more conservative and/or nonconservative amino acid substitutions, such as up to 5, 10, 15, 20, 25, or more, conservative or nonconservative amino acid substitutions
  • NT-3 neurotrophin-3 and its abbreviation, “NT-3,” as used herein include, for example, forms of the human NT-3 gene that correspond to a cDNA having a nucleic acid sequence that is at least 85% identical to the nucleic acid sequence of SEQ ID NO: 16 or 48 (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, or 100% identical to the amino acid sequence of SEQ ID NO: 2 or 48).
  • the term “dose” refers to the quantity of a therapeutic agent, such as a neurotrophin described herein (e.g., NT-3) that is administered to a subject for the treatment of a disorder or condition, such as to treat or prevent sensory hair cell loss).
  • a therapeutic agent as described herein may be administered in the form of an auricular dosage form in a single dose or in multiple doses for the treatment of a particular indication. In each case, the auricular dosage form agent may be administered using one or more unit dosage forms.
  • a single dose of 1 mg of a therapeutic agent may be administered using, e.g., two 0.5 mg unit dosage forms of the therapeutic agent, four 0.25 mg unit dosage forms of the therapeutic agent, one single 1 mg unit dosage form of the therapeutic agent, and the like.
  • endogenous describes a molecule (e.g., a metabolite, polypeptide, nucleic acid, or cofactor) that is found naturally in a particular organism (e.g., a human) or in a particular location within an organism (e.g., an organ, a tissue, or a cell, such as a human cell).
  • a molecule e.g., a metabolite, polypeptide, nucleic acid, or cofactor
  • exogenous describes a molecule (e.g., a small molecule, polypeptide, nucleic acid, or cofactor) that is not found naturally in a particular organism (e.g., a human) or in a particular location within an organism (e.g., an organ, a tissue, or a cell, such as a human cell).
  • a particular organism e.g., a human
  • a particular location within an organism e.g., an organ, a tissue, or a cell, such as a human cell.
  • Exogenous materials include those that are provided from an external source to an organism or to cultured matter extracted there from.
  • interfering RNA refers to a RNA, such as a short interfering RNA (siRNA), micro RNA (miRNA), or short hairpin RNA (shRNA) that suppresses the expression of a target RNA transcript, for example, by way of (i) annealing to the target RNA transcript, thereby forming a nucleic acid duplex; and (ii) promoting the nuclease-mediated degradation of the RNA transcript and/or (iii) slowing, inhibiting, or preventing the translation of the RNA transcript, such as by sterically precluding the formation of a functional ribosome-RNA transcript complex or otherwise attenuating formation of a functional protein product from the target RNA transcript.
  • siRNA short interfering RNA
  • miRNA micro RNA
  • shRNA short hairpin RNA
  • Interfering RNAs as described herein may be provided to a patient, such as a human patient having a neurological disorder described herein, in the form of, for example, a single- or double-stranded oligonucleotide, or in the form of a vector (e.g., a viral vector) containing a transgene encoding the interfering RNA.
  • a vector e.g., a viral vector
  • Exemplary interfering RNA platforms are described, for example, in Lam et al. , Molecular Therapy - Nucleic Acids 4:e252 (2015); Rao et al. , Advanced Drug Delivery Reviews 61 :746-769 (2009); and Borel et al., Molecular Therapy 22:692-701 (2014), the disclosures of each of which are incorporated herein by reference in their entirety.
  • Percent (%) sequence complementarity with respect to a reference polynucleotide sequence is defined as the percentage of nucleic acids in a candidate sequence that are complementary to the nucleic acids in the reference polynucleotide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence complementarity.
  • a given nucleotide is considered to be “complementary” to a reference nucleotide as described herein if the two nucleotides form canonical Watson-Crick base pairs.
  • Watson-Crick base pairs in the context of the present disclosure include adenine-thymine, adenine-uracil, and cytosine-guanine base pairs.
  • a proper Watson-Crick base pair is referred to in this context as a “match,” while each unpaired nucleotide, and each incorrectly paired nucleotide, is referred to as a “mismatch.”
  • Alignment for purposes of determining percent nucleic acid sequence complementarity can be achieved in various ways that are within the capabilities of one of skill in the art, for example, using publicly available computer software such as BLAST, BLAST-2, or Megalign software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal complementarity over the full length of the sequences being compared.
  • the percent sequence complementarity of a given nucleic acid sequence, A, to a given nucleic acid sequence, B, is calculated as follows:
  • a query nucleic acid sequence is considered to be “completely complementary” to a reference nucleic acid sequence if the query nucleic acid sequence has 100% sequence complementarity to the reference nucleic acid sequence.
  • Percent (%) sequence identity with respect to a reference polynucleotide or polypeptide sequence is defined as the percentage of nucleic acids or amino acids in a candidate sequence that are identical to the nucleic acids or amino acids in the reference polynucleotide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent nucleic acid or amino acid sequence identity can be achieved in various ways that are within the capabilities of one of skill in the art, for example, using publicly available computer software such as BLAST, BLAST-2, or Megalign software.
  • percent sequence identity values may be generated using the sequence comparison computer program BLAST.
  • percent sequence identity of a given nucleic acid or amino acid sequence, A, to, with, or against a given nucleic acid or amino acid sequence, B, (which can alternatively be phrased as a given nucleic acid or amino acid sequence, A that has a certain percent sequence identity to, with, or against a given nucleic acid or amino acid sequence, B) is calculated as follows:
  • auricular dosage form refers to a composition containing a therapeutic agent to be administered auricularly (e.g., intratympanically or transtympanically) to a patient, such as a mammal, e.g., a human, in order to prevent, treat or control a particular disease or condition affecting the mammal, e.g., diseases and conditions described herein.
  • the term “pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms, which are suitable for contact with the tissues of a patient, such as a mammal (e.g., a human) without excessive toxicity, irritation, allergic response and other problem complications commensurate with a reasonable benefit/risk ratio.
  • the terms “provide” and “providing” refer to the delivery of a therapeutic agent to a subject (e.g., a mammalian subject, such as a human) in need of treatment, such as a subject experiencing or at risk of developing a neurological disorder described herein.
  • a therapeutic agent may be provided to a subject in need thereof, for instance, by direct administration of the therapeutic agent to the subject, or by administration of a prodrug that is converted in vivo to the therapeutic agent upon administration of the prodrug to the subject.
  • exemplary prodrugs include, without limitation, esters, phosphates, and other chemical functionalities susceptible to hydrolysis upon administration to a subject.
  • Prodrugs include those known in the art, such as those described, for instance, in Vig et al. , Adv. Drug Deliv. Rev. 65:1370-1385 (2013), and Huttunen et al. , Pharmacol. Rev. 63:750-771 (2011 ), the disclosures of each of which are incorporated herein by reference in their entirety.
  • sample refers to a specimen (e.g., blood, blood component (e.g., serum or plasma), urine, saliva, amniotic fluid, cerebrospinal fluid, tissue (e.g., placental or myometrial), pancreatic fluid, chorionic villus sample, and cells) isolated from a patient.
  • a specimen e.g., blood, blood component (e.g., serum or plasma), urine, saliva, amniotic fluid, cerebrospinal fluid, tissue (e.g., placental or myometrial), pancreatic fluid, chorionic villus sample, and cells
  • the phrases “specifically binds” and “binds” refer to a binding reaction which is determinative of the presence of a particular protein in a heterogeneous population of proteins and other biological molecules that is recognized, e.g., by a ligand with particularity.
  • a ligand e.g., a protein, proteoglycan, or glycosaminoglycan
  • a ligand that specifically binds to a protein will bind to the protein, e.g., with a KD of less than 100 nM.
  • a ligand that specifically binds to a protein may bind to the protein with a KD of up to 100 nM (e.g., between 1 pM and 100 nM).
  • a ligand that does not exhibit specific binding to a protein or a domain thereof will exhibit a KD of greater than 100 nM (e.g., greater than 200 nM, 300 nM, 400 nM, 500 nM, 600 nm, 700 nM, 800 nM, 900 nM, 1 mM, 100 mM, 500 mM, or 1 mM) for that particular protein or domain thereof.
  • a variety of assay formats may be used to determine the affinity of a ligand for a specific protein. For example, solid-phase ELISA assays are routinely used to identify ligands that specifically bind a target protein.
  • the terms “subject’ and “patient” are used interchangeably and refer to an organism, such as a mammal (e.g., a human) that receives therapy for the treatment or prevention of a disease or condition described herein, for example, for an otic disease or condition, such as ear pruritus, otitis externa, otalgia, tinnitus, vestibular dysfunction (e.g., vertigo, dizziness, loss of balance), ear fullness, hearing loss, Meniere's disease, sensorineural hearing loss (e.g., noise-induced hearing loss, age-related hearing loss (presbycusis), ototoxic drug-induced hearing loss, hearing loss related to head trauma, hearing loss related to infection), autoimmune ear disease, ototoxicity, excitotoxicity, hidden hearing loss, cochlear synaptopathy, endolymphatic hydrops, labyrinthitis, Ramsay Hunt's Syndrome, vestibular neuronitis, or microvascular compression syndrome
  • the terms “increasing” and “decreasing” refer to modulating resulting in, respectively, greater or lesser amounts, of function, expression, or activity of a metric relative to a reference.
  • the amount of a marker of a metric e.g., hearing, such as hearing measured using standard clinical tests
  • the amount of a marker of a metric may be increased or decreased in a subject by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 98% or more relative to the amount of the marker prior to administration.
  • the metric is measured subsequent to administration at a time that the administration has had the recited effect, e.g., at least one week, one month, 3 months, or 6 months, after a treatment regimen has begun.
  • the terms “effective amount,” “therapeutically effective amount,” and a “sufficient amount” of an auricular dosage form, polypeptide, small molecule, or viral vector described herein refer to a quantity sufficient to, when administered to the subject, including a mammal, for example a human, effect beneficial or desired results, including clinical results, and, as such, an “effective amount” or synonym thereto depends upon the context in which it is being applied.
  • the auricular dosage form in the context of treating sensorineural hearing loss or vestibular dysfunction, it is an amount of the auricular dosage form sufficient to achieve a treatment response as compared to the response obtained without administration of the auricular dosage form.
  • the amount of a given auricular dosage form described herein that will correspond to such an amount will vary depending upon various factors, such as the given agent, the pharmaceutical formulation, the route of administration, the type of disease or disorder, the identity of the subject (e.g. age, sex, weight) or host being treated, and the like, but can nevertheless be routinely determined by one skilled in the art.
  • a “therapeutically effective amount” of an auricular dosage form of the present disclosure is an amount which results in a beneficial or desired result in a subject as compared to a control.
  • a therapeutically effective amount of an auricular dosage form of the present disclosure may be readily determined by one of ordinary skill by routine methods known in the art. Dosage regimen may be adjusted to provide the optimum therapeutic response.
  • locally or “local administration” means administration at a particular site of the body intended for a local effect and not a systemic effect.
  • local administration are epicutaneous, inhalational, intra-articular, intrathecal, intravaginal, intravitreal, intrauterine, intra-lesional administration, lymph node administration, intratumoral administration, administration to the inner ear (e.g., transtympanic or intratympanic injection), and administration to a mucous membrane of the subject, wherein the administration is intended to have a local and not a systemic effect.
  • plasmid refers to a to an extrachromosomal circular double stranded DNA molecule into which additional DNA segments may be ligated.
  • a plasmid is a type of vector, a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked.
  • Certain plasmids are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial plasmids having a bacterial origin of replication and episomal mammalian plasmids).
  • Other vectors e.g., non-episomal mammalian vectors
  • Certain plasmids are capable of directing the expression of genes to which they are operably linked.
  • SGN spiral ganglion neuron
  • CNS central nervous system
  • Type II SGNs which innervate outer hair cells and are not required for the transmission of sound information to the CNS.
  • vestibular hair cell refers to group of specialized cells in the inner ear that are involved in sensing movement and contribute to the sense of balance and spatial orientation.
  • Vestibular hair cells are located in the semicircular canals and otolith organs (e.g., utricle and saccule) of the inner ear. Damage to vestibular hair cells and genetic mutations that disrupt vestibular hair cell function are implicated in vestibular dysfunction such as vertigo and imbalance disorders.
  • wild-type refers to a genotype with the highest frequency for a particular gene in a given organism.
  • treat or “treatment” refer to therapeutic treatment, in which the object is to slow, delay, or halt the progression or development of an otic disease or condition, e.g., in a human subject.
  • amino acid As used herein, the terms “amino acid,” “amino acid monomer,” and “amino acid residue” are used interchangeably and refer to naturally-occurring alpha-amino acid molecules, such as those set forth in Table 1 , herein.
  • amino acid As used herein, the terms “amino acid,” “amino acid monomer,” and “amino acid residue” additionally refer to variants of the amino acid molecules set forth in Table 1 , such as beta-amino acids and gamma- amino acids, as well as amino acids in which the side chain is located on the amino nitrogen (such as the amino acid monomers that comprise peptoids, described, for example, in Kwon and Kodedk, J. Am. Chem. Soc.
  • amino acid amino acid monomer
  • amino acid residue additionally refer to variants of the amino acid molecules set forth in Table 1 in which the amino nitrogen atom is modified, for example, by way of N-alkylation (e.g., N-methylation). Examples of N-methylated amino acids are described in Chatterjee et al., Acc. Chem. Res. 41 :1331 -1342 (2008), the disclosure of which is incorporated herein by reference).
  • amino acid amino acid
  • amino acid monomer amino acid residue
  • peptide and “polypeptide” are used interchangeably and refer to polymers containing repeating amino acid molecules covalently bound to one another by way of amide bonds (also referred to as peptide bonds) or peptide bond isosteres).
  • antibody refers to an immunoglobulin molecule that specifically binds to, or is immunologically reactive with, a particular antigen, and includes polyclonal, monoclonal, genetically engineered, and otherwise modified forms of antibodies, including, but not limited to, chimeric antibodies, humanized antibodies, heteroconjugate antibodies (e.g., bi- tri- and quad-specific antibodies, diabodies, triabodies, and tetrabodies), and antigen-binding fragments of antibodies, including e.g., Fab', F(ab')2, Fab, Fv, rlgG, and scFv fragments.
  • two or more portions of an immunoglobulin molecule are covalently bound to one another, e.g., via an amide bond, a thioether bond, a carbon-carbon bond, a disulfide bridge, or by a linker, such as a linker described herein or known in the art.
  • Antibodies also include antibody-like protein scaffolds, such as the tenth fibronectin type III domain ( 10 Fn3), which contains BC, DE, and FG structural loops similar in structure and solvent accessibility to antibody complementarity-determining regions (CDRs).
  • the tertiary structure of the 10 Fn3 domain resembles that of the variable region of the IgG heavy chain, and one of skill in the art can graft, e.g., the CDRs of a reference antibody onto the fibronectin scaffold by replacing residues of the BC, DE, and FG loops of 10 Fn3 with residues from the CDR-H1 , CDR-H2, or CDR-H3 regions, respectively, of the reference antibody.
  • antigen-binding fragment refers to one or more fragments of an antibody that retain the ability to specifically bind to a target antigen.
  • the antigen-binding function of an antibody can be performed by fragments of a full-length antibody.
  • the antibody fragments can be a Fab, F(ab’)2, scFv, SMIP, diabody, a triabody, an affibody, a nanobody, an aptamer, or a domain antibody.
  • binding fragments encompassed of the term “antigen-binding fragment” of an antibody include, but are not limited to: (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb including VH and VL domains; (vi) a dAb fragment (Ward et al., Nature 341 :544-546, 1989), which consists of a VH domain; (vii) a dAb which consists of a VH or a VL domain; (viii) an isolated CDR; and (ix) a combination of two or more isolated CDR
  • the two domains of the Fv fragment, VL and VH are coded for by separate genes, they can be joined, using recombinant methods, by a linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single-chain Fv (scFv); see, e.g., Bird et al., Science 242:423-426, 1988, and Fluston et al., Proc. Natl. Acad. Sci. USA 85:5879-5883, 1988).
  • scFv single-chain Fv
  • These antibody fragments can be obtained using conventional techniques known to those of skill in the art, and the fragments can be screened for utility in the same manner as intact antibodies.
  • Antigen-binding fragments can be produced by recombinant DNA techniques, enzymatic or chemical cleavage of intact immunoglobulins, or, in some embodiments, by chemical peptide synthesis procedures known in the art.
  • bispecific antibodies refers to monoclonal, often human or humanized antibodies that have binding specificities for at least two different antigens.
  • chimeric antibody refers to an antibody having variable domain sequences (e.g., CDR sequences) derived from an immunoglobulin of one source organism, such as rat or mouse, and constant regions derived from an immunoglobulin of a different organism (e.g., a human, another primate, pig, goat, rabbit, hamster, cat, dog, guinea pig, member of the bovidae family (such as cattle, bison, buffalo, elk, and yaks, among others), cow, sheep, horse, or bison, among others).
  • variable domain sequences e.g., CDR sequences
  • CDR complementarity-determining region
  • FRs framework regions
  • amino acid positions that delineate a hypervariable region of an antibody can vary, depending on the context and the various definitions known in the art. Some positions within a variable domain may be viewed as hybrid hypervariable positions in that these positions can be deemed to be within a hypervariable region under one set of criteria while being deemed to be outside a hypervariable region under a different set of criteria. One or more of these positions can also be found in extended hypervariable regions.
  • variable domains of native heavy and light chains each comprise four framework regions that primarily adopt a b-sheet configuration, connected by three CDRs, which form loops that connect, and in some cases form part of, the b-sheet structure.
  • the CDRs in each chain are held together in close proximity by the FR regions in the order FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4 and, with the CDRs from the other antibody chains, contribute to the formation of the target binding site of antibodies (see Kabat et al, Sequences of Proteins of Immunological Interest (National Institute of Health, Bethesda, Md. 1987; incorporated herein by reference).
  • numbering of immunoglobulin amino acid residues is done according to the immunoglobulin amino acid residue numbering system of Kabat et al, unless otherwise indicated.
  • the term “derivatized antibodies” refers to antibodies that are modified by a chemical reaction so as to cleave residues or add chemical moieties not native to an isolated antibody. Derivatized antibodies can be obtained by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization by addition of known chemical protecting/blocking groups, proteolytic cleavage, linkage to a cellular ligand or other protein. Any of a variety of chemical modifications can be carried out by known techniques, including, without limitation, specific chemical cleavage, acetylation, formylation, metabolic synthesis of tunicamycin, etc. using established procedures. Additionally, the derivative can contain one or more non-natural amino acids, e.g., using amber suppression technology (see, e.g., US Patent No. 6,964,859; incorporated herein by reference).
  • diabodies refers to bivalent antibodies comprising two polypeptide chains, in which each polypeptide chain includes VH and VL domains joined by a linker that is too short (e.g., a linker composed of five amino acids) to allow for intramolecular association of VH and VL domains on the same peptide chain. This configuration forces each domain to pair with a complementary domain on another polypeptide chain so as to form a homodimeric structure.
  • triabodies refers to trivalent antibodies comprising three peptide chains, each of which contains one VH domain and one VL domain joined by a linker that is exceedingly short (e.g., a linker composed of 1 -2 amino acids) to permit intramolecular association of VH and VL domains within the same peptide chain.
  • a linker that is exceedingly short (e.g., a linker composed of 1 -2 amino acids) to permit intramolecular association of VH and VL domains within the same peptide chain.
  • peptides configured in this way typically trimerize so as to position the VH and VL domains of neighboring peptide chains spatially proximal to one another to permit proper folding (see Holliger et al., Proc. Natl. Acad. Sci. USA 90:6444-48, 1993; incorporated herein by reference).
  • FW region includes amino acid residues that are adjacent to the CDRs. FW region residues may be present in, for example, human antibodies, rodent- derived antibodies (e.g., murine antibodies), humanized antibodies, primatized antibodies, chimeric antibodies, antibody fragments (e.g., Fab fragments), single-chain antibody fragments (e.g., scFv fragments), antibody domains, and bispecific antibodies, among others.
  • rodent- derived antibodies e.g., murine antibodies
  • humanized antibodies e.g., primatized antibodies
  • chimeric antibodies e.g., antibody fragments (e.g., Fab fragments), single-chain antibody fragments (e.g., scFv fragments), antibody domains, and bispecific antibodies, among others.
  • heterospecific antibodies refers to monoclonal, preferably human or humanized, antibodies that have binding specificities for at least two different antigens.
  • the recombinant production of heterospecific antibodies is based on the co-expression of two immunoglobulin heavy chain-light chain pairs, where the two heavy chains have different specificities (Milstein et al., Nature 305:537, 1983). Similar procedures are disclosed, e.g., in WO 93/08829, U.S. Pat. Nos.
  • Heterospecific antibodies can include Fc mutations that enforce correct chain association in multi-specific antibodies, as described by Klein et al, mAbs 4(6):653-663, 2012; incorporated herein by reference.
  • human antibody refers to an antibody in which substantially every part of the protein (e.g., CDR, framework, CL, CH domains (e.g., CH1 , CH2, CH3), hinge, (VL, VH)) is substantially non-immunogenic in humans, with only minor sequence changes or variations.
  • a human antibody can be produced in a human cell (e.g., by recombinant expression), or by a non-human animal or a prokaryotic or eukaryotic cell that is capable of expressing functionally rearranged human immunoglobulin (e.g., heavy chain and/or light chain) genes.
  • a human antibody when a human antibody is a single chain antibody, it can include a linker peptide that is not found in native human antibodies.
  • an Fv can comprise a linker peptide, such as two to about eight glycine or other amino acid residues, which connects the variable region of the heavy chain and the variable region of the light chain.
  • linker peptides are considered to be of human origin.
  • Fluman antibodies can be made by a variety of methods known in the art including phage display methods using antibody libraries derived from human immunoglobulin sequences. See U.S. Patent Nos.
  • Fluman antibodies can also be produced using transgenic mice that are incapable of expressing functional endogenous immunoglobulins, but which can express human immunoglobulin genes. See, e.g., PCT publications WO 98/24893; WO 92/01047; WO 96/34096; WO 96/33735; U.S. Patent Nos. 5,413,923; 5,625, 126; 5,633,425; 5,569,825; 5,661 ,016; 5,545,806;
  • humanized antibodies refers to forms of non-human (e.g., murine) antibodies that are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab', F(ab')2 or other target-binding subdomains of antibodies) which contain minimal sequences derived from non-human immunoglobulin.
  • the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin. All or substantially all of the FR regions may also be those of a human immunoglobulin sequence.
  • the humanized antibody can also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin consensus sequence.
  • Fc immunoglobulin constant region
  • Methods of antibody humanization are known in the art. See, e.g., Riechmann et al., Nature 332:323-7, 1988; U.S. Patent Nos: 5,530,101 ; 5,585,089; 5,693,761 ; 5,693,762; and 6,180,370 to Queen et al; EP239400; PCT publication WO 91/09967; U.S. Patent No. 5,225,539; EP592106; and EP519596; incorporated herein by reference.
  • the term “monoclonal antibody” refers to an antibody that is derived from a single clone, including any eukaryotic, prokaryotic, or phage clone, and not the method by which it is produced.
  • multi-specific antibodies refers to antibodies that exhibit affinity for more than one target antigen.
  • Multi-specific antibodies can have structures similar to full immunoglobulin molecules and include Fc regions, for example IgG Fc regions.
  • Such structures can include, but not limited to, IgG-Fv, lgG-(scFv)2, DVD-lg, (scFv)2-(scFv)2-Fc and (scFv)2-Fc-(scFv)2.
  • the scFv can be attached to either the N-terminal or the C- terminal end of either the heavy chain or the light chain.
  • antibody fragments can be components of multi-specific molecules without Fc regions, based on fragments of IgG or DVD or scFv.
  • Exemplary multi-specific molecules that lack Fc regions and into which antibodies or antibody fragments can be incorporated include scFv dimers (diabodies), trimers (triabodies) and tetramers (tetrabodies), Fab dimers (conjugates by adhesive polypeptide or protein domains) and Fab trimers (chemically conjugated), are described by Fludson and Souriau, 2003, Nature Medicine 9:129- 134; incorporated herein by reference.
  • primary antibody refers to an antibody comprising framework regions from primate-derived antibodies and other regions, such as CDRs and/or constant regions, from antibodies of a non-primate source. Methods for producing primatized antibodies are known in the art.
  • a primatized antibody or antigen-binding fragment thereof described herein can be produced by inserting the CDRs of a non-primate antibody or antigen-binding fragment thereof into an antibody or antigen-binding fragment thereof that contains one or more framework regions of a primate.
  • scFv refers to a single-chain Fv antibody in which the variable domains of the heavy chain and the light chain from an antibody have been joined to form one chain.
  • scFv fragments contain a single polypeptide chain that includes the variable region of an antibody light chain (VL) (e.g., CDR-L1 , CDR-L2, and/or CDR-L3) and the variable region of an antibody heavy chain (VH) (e.g., CDR-H1 , CDR-H2, and/or CDR-H3) separated by a linker.
  • VL antibody light chain
  • VH variable region of an antibody heavy chain
  • the linker that joins the VL and VH regions of a scFv fragment can be a peptide linker composed of proteinogenic amino acids.
  • linkers can be used to so as to increase the resistance of the scFv fragment to proteolytic degradation (e.g., linkers containing D-amino acids), in order to enhance the solubility of the scFv fragment (e.g., hydrophilic linkers such as polyethylene glycol-containing linkers or polypeptides containing repeating glycine and serine residues), to improve the biophysical stability of the molecule (e.g., a linker containing cysteine residues that form intramolecular or intermolecular disulfide bonds), or to attenuate the immunogenicity of the scFv fragment (e.g., linkers containing glycosylation sites).
  • linkers containing D-amino acids e.g., hydrophilic linkers such as polyethylene glycol-containing linkers or polypeptides containing repeating glycine and serine residues
  • hydrophilic linkers such as polyethylene glycol-containing linkers or polypeptides containing repeating
  • scFv molecules are known in the art and are described, e.g., in US patent 5,892,019, Flo et al. , (Gene 77:51 , 1989); Bird et al., (Science 242:423, 1988); Pantoliano et al., (Biochemistry 30:10117, 1991 ); Milenic et al., (Cancer Research 51 :6363, 1991 ); and Takkinen et al., (Protein Engineering 4:837, 1991 ).
  • the VL and VH domains of a scFv molecule can be derived from one or more antibody molecules.
  • variable regions of the scFv molecules described herein can be modified such that they vary in amino acid sequence from the antibody molecule from which they were derived.
  • nucleotide or amino acid substitutions leading to conservative substitutions or changes at amino acid residues can be made (e.g., in CDR and/or framework residues).
  • mutations are made to CDR amino acid residues to optimize antigen binding using art recognized techniques.
  • scFv fragments are described, for example, in WO 2011/084714; incorporated herein by reference.
  • solvate means a compound as described herein wherein molecules of a suitable solvent are incorporated in the crystal lattice.
  • a suitable solvent is physiologically tolerable at the dosage administered.
  • solvates may be prepared by crystallization, recrystallization, or precipitation from a solution that includes organic solvents, water, or a mixture thereof.
  • solvents examples include ethanol, water (for example, mono-, di-, tri-, tetra-, and penta-hydrates), A/-methylpyrrolidinone (NMP), dimethyl sulfoxide (DMSO), A/,A/-dimethylformamide (DMF), A/,A/-dimethylacetamide (DMAC), 1 ,3-dimethyl-2-imidazolidinone (DMEU), 1 ,3-dimethyl-3, 4,5,6- tetrahydro-2-(1 H)-pyrimidinone (DMPU), acetonitrile (ACN), propylene glycol, ethyl acetate, benzyl alcohol, 2-pyrrolidone, benzyl benzoate, and the like.
  • the solvate is water-based, the solvate is referred to as a hydrate.
  • alkaline salt represents a sodium or potassium salt of a compound.
  • Alkaline salts may be monobasic or, if the number of acidic moieties (e.g., -COOH, -SO3H, or -P(0)(0H) n moieties) permits, dibasic or tribasic.
  • alkoxy refers to a group -OR, where R is alkyl as described herein.
  • alkyl refers to an acyclic straight or branched chain saturated hydrocarbon group, which, has from 1 to 25 carbons, unless otherwise specified. Typically, an alkyl group in an alkyl glycoside has 6 to 25 carbons (e.g., 9 to 18 carbons). Alkyl groups are exemplified by hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, and the like.
  • alkyl glycoside refers to a mono-, di-, or tri-saccharide in which at least one hydroxyl is replaced with an alkoxy.
  • alkyl glycosides include hexyl-, heptyl-, octyl-, nonyl-, decyl-, undecyl-, dodecyl-, tridecyl-, tetradecyl-, pentadecyl-, hexadecyl-, heptadecyl-, and octadecyl a- or b-D-maltoside; hexyl-, heptyl-, octyl-, nonyl-, decyl-, undecyl-, dodecyl-, tridecyl-, tetradecyl, pentadecyl-, hexadecyl-, hexadecyl-, h
  • an alkyl glycoside is an alkyl maltoside, e.g., tridecyl maltoside or dodecyl maltoside.
  • the at least one replaced hydroxyl is a glycosidic hydroxyl.
  • sucrose fatty ester represents sucrose in which at least one hydroxyl is replaced with -OR, where R is a fatty acid acyl.
  • the fatty acid acyl is a long chain fatty acid acyl.
  • a long chain fatty acid acyl is a C13-C21 fatty acid acyl.
  • the fatty acid acyl may be a medium chain fatty acid acyl.
  • a medium chain fatty acid acyl is a C6-C12 fatty acid acyl.
  • ammonium salt represents an NHV salt of a compound.
  • Ammonium salts may be monobasic or, if the number of acidic moieties (e.g., -COOH, -SO3H, or -P(0)(OH) n moieties) permits, dibasic or tribasic.
  • platinum-based antineoplastic agent represents a coordination compound of Pt(ll) or Pt(IV).
  • Platinum-based antineoplastic agents are known in the art as platins.
  • platinum-based antineoplastic agents include at least two coordination sites at the platinum center that are occupied by nitrogenous spectator ligand(s).
  • the nitrogenous spectator ligands are monodentate or bidentate ligands, in which the donor atom is an sp 3 - or sp 2 -hybridized nitrogen atom within the ligand.
  • Non-limiting examples of nitrogenous spectator ligands are ammonia, 1 ,2- cyclohexanediamine, a picoline, phenanthrin, or 1 ,6-hexanediamine.
  • Non-limiting examples of platinum- based antineoplastic agents include cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, and satraplatin.
  • substantially neutral refers to a pH level of 5.5 to about 8.5, as measured at 20 °C.
  • gelling agent refers to pharmaceutically acceptable excipient known in the art to produce a gel upon mixing with a solvent (e.g., an aqueous solvent).
  • a solvent e.g., an aqueous solvent
  • gelling agents include hyaluronan, a polyoxyethylene-polyoxypropylene block copolymer (e.g., a poloxamer), poly(lactic-co-glycolic) acid, polylactic acid, polycaprolactone, alginic acid or a salt thereof, polyethylene glycol, a cellulose, a cellulose ether, a carbomer (e.g., CARBOPOL®), agar-agar, gelatin, glucomannan, galactomannan (e.g., guar gum, locust bean gum, or tara gum), xanthan gum, chitosan, pectin, starch, tragacanth, carrageenan, polyvinylpyrrolidone, polyvin
  • hypothalamic represents an auricular dosage form having a calculated osmolarity of 300 mOsm/L to 7,000 mOsm/L (e.g., 300 mOsm/L to 2,500 mOsm/L), which corresponds to 300 mmol to 7,000 mmol (e.g., 300 mOsm/L to 2,500 mmol) of ions and/or neutral molecules produced by dissolution of platinum-deactivating agent and any ionic, non-polymeric excipients in 1 L of solvent having calculated osmolarity of 0 mOsm/L.
  • the calculated osmolarity does not include ions and/or neutral molecules produced from polymeric excipients (e.g., from a gelling agent).
  • polymeric excipients e.g., a gelling agents
  • polymeric excipients are deemed as not contributing to the calculated osmolarity of the auricular dosage forms disclosed herein.
  • tonicity agent refers to a class of pharmaceutically acceptable excipients that are used to control osmolarity of auricular dosage forms.
  • a tonicity agent include substantially neutral buffering agents (e.g., phosphate buffered saline, tris buffer, or artificial perilymph), dextrose, mannitol, glycerin, potassium chloride, and sodium chloride (e.g., as a hypertonic, isotonic, or hypotonic saline).
  • Artificial perilymph is an aqueous solution containing NaCI (120-130 mM), KCI (3.5 mM), CaCI 2 (1 .3-1 .5 mM), MgCI 2 (1 .2 mM), glucose (5.0-11 mM), and buffering agents (e.g., NaHCCb (25 mM) and NaH 2 PC>4 (0.75 mM), or HEPES (20 mM) and NaOH (adjusted to pH of about 7.5)).
  • buffering agents e.g., NaHCCb (25 mM) and NaH 2 PC>4 (0.75 mM
  • HEPES (20 mM) and NaOH (adjusted to pH of about 7.5)
  • injection means delivery to the round window by injection or infusion through an ear canal with a temporarily removed or lifted tympanic membrane or through a port created through an auditory bulla into the middle ear of a subject.
  • transtympanic in reference to a route of administration, means delivery to the round window by injection or infusion across tympanic membrane.
  • a transtympanic injection may be performed directly through the tympanic membrane or through a tube embedded in the tympanic membrane (e.g., through a tympanostomy tube or grommet).
  • inner ear injection refers to the direct injection of drug into the inner ear space.
  • FIG. 1 is a schematic diagram illustrating the experimental setup of the in vitro round window membrane penetration experiments described in Example 1 , below.
  • FIG. 2 is a graph showing the calculated round window membrane permeability (Papp) of NT-3, atenolol, metoprolol, and lucifer yellow.
  • Hollow squares denote Papp values obtained in artificial perilymph (AP+) solution.
  • Squares filled with “X” denote values obtained upon 30 minutes of pre treatment with EDTA.
  • Triangles denote values obtained in 20% poloxamer.
  • PBS 2x phosphate buffered saline
  • TDM tridecylmaltoside
  • FIG. 13 is a schematic diagram illustrating the experimental setup of the in vitro round window membrane penetration experiments designed to evaluate the permeability of NT-3 with 0.25%, 1%, or 1% TDM. Tight and adherens junctions were evaluated after 3.5 hrs of incubation with NT-3 and 0.25%, 1%, or 1 % TDM at 37 S C.
  • FIG. 14 is a series of images showing immunohistochemical staining for cell junction proteins after 3.5 hours of incubation with NT-3 in vehicle (control condition). Adherens junctions appeared normal after 3.5 hours of incubation with NT-3 in vehicle.
  • FIG. 15 is a series of images showing immunohistochemical staining for tight junction proteins after 3.5 hours of incubation with NT-3 and 0.25% TDM. Adherens and tight junctions appeared normal after 3.5 hours of incubation with NT-3 in 0.25% TDM.
  • FIG. 16 is a series of images showing immunohistochemical staining for tight junction proteins after 3.5 hours of incubation with NT-3 and 1% TDM. After incubation with NT-3 and 1% TDM, gaps were observed between cells (asterisks in merged image on bottom right).
  • FIG. 17 is a series of images showing immunohistochemical staining for tight junction proteins after 3.5 hours of incubation with NT-3 and 3% TDM. After incubation with NT-3 and 3% TDM, larger open patches were visible in the membrane.
  • FIG. 18 is a graph showing the flux profiles for NT-3 in vehicle with a 3 pm pore filter (control) and NT-3 and 0.25%, 1%, or 3% TDM.
  • FIG. 19 is a graph showing the apparent permeability (Papp) of NT-3 in different conditions (vehicle with 0.4 pm pore filter, EDTA with 0.4 pm pore filter, vehicle with 3 pm pore filter, 0.25% TDM.
  • the invention provides auricular dosage forms and methods of their use.
  • the auricular dosage forms described herein include a therapeutic agent, a gelling agent, and a permeation enhancing amount of a permeabilizer selected from the group consisting of alkyl glycosides and sucrose fatty esters.
  • the alkyl glycosides and/or sucrose fatty esters used in the auricular dosage forms described herein may be superior relative to other permeabilizers for delivery of a therapeutic agent to an inner ear, e.g., by mediating permeation of the therapeutic agent across the round window membrane.
  • the auricular dosage forms and methods described herein address the problem of the therapeutic agent delivery across the round window membrane.
  • the delivery of therapeutic agents through the round window membrane and into the inner ear is a longstanding challenge, particularly for larger molecular weight agents, such as proteins, antibodies, nucleic acids, viral vectors, and nanoparticles, among others.
  • larger molecular weight agents such as proteins, antibodies, nucleic acids, viral vectors, and nanoparticles, among others.
  • the auricular dosage forms and methods described herein may be used to control not only the passage of therapeutic agents across the round window membrane but also to control release profiles of the therapeutic agents to the inner ear.
  • alkyl glycosides e.g., tridecyl maltoside (TDM)
  • sucrose fatty esters may modulate tight junctions between epithelial cells of the round window membrane, facilitating the permeation of therapeutic agents across this barrier.
  • otic diseases or conditions such as ceruminosis or ceruminosis associated with an otic disease or condition, ear pruritus, otitis externa, otalgia, tinnitus, vestibular dysfunction (e.g., vertigo, dizziness, or loss of balance), ear fullness, hearing loss, Meniere's disease, sensorineural hearing loss (e.g., noise-induced hearing loss, age-related hearing loss (presbycusis), ototoxic drug-induced hearing loss, hearing loss related to head trauma, hearing loss related to infection), autoimmune ear disease, ototoxicity, excitotoxicity, hidden hearing loss, cochlear synaptopathy, endolymphatic hydrops, labyrinthitis, Ramsay Hunt's Syndrome, vestibular
  • the auricular dosage forms described herein may additionally be used to prevent or mitigate sensory hair cell death.
  • Particular embodiments of the auricular dosage forms that can be used for this purpose include those in which the therapeutic agent is a neurotrophin, an immunomodulating agent, an aural pressure modulating agent, a corticosteroid, an antimicrobial agent, an antagonist of truncated TrkC or truncated TrkB, a non-natural TrkB or TrkC agonist, a TrkB receptor agonist antibody, a TrkB receptor agonist compound, a TrkC receptor agonist antibody, a TrkC receptor agonist compound, a WNT modulator, or an anti-platinum chemoprotectant agent.
  • auricular dosage forms that are particularly suited for this indication are those in which the therapeutic agent is a neurotrophin selected from NT-3, NGF, BDNF, CNTF, GDNF, NT-4, FGF, IGF, EGF, PGF, MANF, CDNF, a pan-neurotrophin (PNT-1 ), a chimeric neurotrophin (e.g., an NGF/BDNF chimera), or a combination thereof, or an anti-platinum chemoprotectant agent, such as sodium thiosulfate or N-acetylcysteine.
  • the therapeutic agent is a neurotrophin selected from NT-3, NGF, BDNF, CNTF, GDNF, NT-4, FGF, IGF, EGF, PGF, MANF, CDNF, a pan-neurotrophin (PNT-1 ), a chimeric neurotrophin (e.g., an NGF/BDNF chimera), or a combination thereof, or an
  • the sections that follow provide a description of the structural features of the permeabilizers that may be incorporated into the auricular dosage forms of the present disclosure, as well as therapeutic agents that may be co-formulated with such peptides and exemplary pathologies that may be treated, prevented, and/or mitigated using these auricular dosage forms.
  • Auricular dosage forms disclosed herein include a permeabilizer selected from the group consisting of alkyl glycosides and sucrose fatty esters.
  • An alkyl glycoside is a mono-, di-, or tri-saccharide in which at least one hydroxyl is replaced with an alkoxy.
  • an alkyl glycoside is an alkyl maltoside, e.g., tridecyl maltoside or dodecyl maltoside.
  • the at least one replaced hydroxyl is a glycosidic hydroxyl.
  • a sucrose fatty ester is sucrose in which at least one hydroxyl is replaced with -OR, where R is a fatty acid acyl.
  • the fatty acid acyl is a long chain fatty acid acyl.
  • a long chain fatty acid acyl is a C13-C21 fatty acid acyl.
  • the fatty acid acyl may be a medium chain fatty acid acyl.
  • a medium chain fatty acid acyl is a C6-C12 fatty acid acyl.
  • An auricular dosage form described herein may include, e.g., at least 0.01% (w/v) (e.g., at least 0.025% (w/v), at least 0.05% (w/v), at least 0.1% (w/v), at least 0.25% (w/v), at least 0.5% (w/v), or at least 1% (w/v); e.g., 5% (w/v) or less, 3% (w/v) or less, 1% (w/v) or less, 0.5% (w/v) or less, 0.25% (w/v) or less, or 0.1% (w/v) or less; e.g., 0.01% (w/v) to 5% (w/v), 0.025% (w/v) to 5% (w/v), 0.05% (w/v) to 5% (w/v), 0.1% (w/v) to 5% (w/v), 0.25% (w/v) to 5% (w/v), 0.5% (w/v) to
  • therapeutic agents that may be incorporated into the auricular dosage forms described herein are neurotrophins, immunomodulating agents, aural pressure modulating agents, corticosteroids, antimicrobial agents, antagonists of truncated TrkC or truncated TrkB, non-natural TrkB or TrkC agonists, TrkB receptor agonist antibodies or antigen-binding fragments thereof, TrkB receptor agonist compounds, TrkC receptor agonist antibodies or antigen-binding fragments thereof, TrkC receptor agonist compounds, neuroprotection agents, Atohl modulators (e.g., an Atohl polypeptide or a nucleic acid vector engineered to express Atohl , e.g., human Atohl (Hathl )), WNT modulators, and anti platinum chemoprotectant agents (e.g., sodium thiosulfate or N-acetylcysteine).
  • Atohl modulators e.g., an Atoh
  • the therapeutic agent may be, for example, a neurotrophin selected from neurotrophin-3 (NT-3), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), glial cell-line derived neurotrophic factor (GDNF), neurotrophin-4 (NT-4), fibroblast growth factor (FGF), insulin-like growth factor (IGF), epidermal growth factor (EGF), platelet-derived growth factor (PGF), mesencephalic astrocyte-derived neurotrophic factor (MANF), cerebral dopamine neurotrophic factor (CDNF), a pan-neurotrophin (e.g., PNT-1 ), a chimeric neurotrophin (e.g., an NGF/BDNF chimera), and combinations thereof.
  • NT-3 neurotrophin-3
  • NGF nerve growth factor
  • BDNF brain-derived neurotrophic factor
  • CNTF ciliary neurotrophic factor
  • FGF fibroblast growth factor
  • IGF insulin-like growth factor
  • EGF
  • the neurotrophic factor is NT-3.
  • the NT-3 may have an amino acid sequence having at least 85% sequence identity (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NOs: 1 , 7, or 8.
  • the NT-3 may have, for example, an amino acid sequence that differs from the amino acid sequence of any one of SEQ ID NOs: 1 , 7, or 8 by only one or more conservative amino acid substitutions, such as by up to 25, up to 20, up to 15, up to 10, or up to 5 conservative amino acid substitutions.
  • the NT-3 may be an NT-3 variant having an amino acid sequence with one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs: 1 , 7, or 8.
  • the NT-3 variant may have, for example, the sequence of any one of SEQ ID NOs: 34-46.
  • the NT-3 variant has the sequence of SEQ ID NO: 35.
  • the NT-3 variant has the sequence of SEQ ID NO: 43.
  • the NT-3 variant has the sequence of SEQ ID NO: 44.
  • the NT-3 may be encoded by a nucleic acid having the sequence of SEQ ID NO: 2 or SEQ ID NO: 56.
  • the neurotrophic factor is NGF.
  • the NGF may have an amino acid sequence having at least 85% sequence identity (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NOs: 5 or 6.
  • the NGF may have, for example, an amino acid sequence that differs from the amino acid sequence of SEQ ID NOs: 5 or 6 by only one or more conservative amino acid substitutions, such as by up to 11 , up to 20, up to 15, up to 10, or up to 5 conservative amino acid substitutions.
  • the NGF may be an NGF variant having an amino acid sequence with one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) amino acid substitutions relative to the amino acid sequence of SEQ ID NOs: 5 or 6.
  • the NGF variant has the sequence any one of SEQ ID NOs: 20- 23.
  • the NGF may be an NGF variant having an amino acid sequence with one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) amino acid substitutions relative to the amino acid sequence of SEQ ID NOs: 5 or 6 and one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) deleted amino acids relative to the amino acid sequence of SEQ ID NOs: 5 or 6.
  • the NGF variant has the sequence of SEQ ID NO: 24.
  • the NGF may be encoded by a nucleic acid having the sequence of SEQ ID NO: 55 or SEQ ID NO: 62.
  • the neurotrophic factor is NT-4.
  • the NT-4 may have an amino acid sequence having at least 85% sequence identity (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NOs: 9 or 10.
  • the NT-4 may have, for example, an amino acid sequence that differs from the amino acid sequence of SEQ ID NOs: 9 or 10 by only one or more conservative amino acid substitutions, such as by up to 25, up to 20, up to 15, up to 10, or up to 5 conservative amino acid substitutions.
  • the NT-4 may be an NT-4 variant having an amino acid sequence with one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) amino acid substitutions relative to the amino acid sequence of SEQ ID NOs: 9 or 10.
  • the NT-4 may be encoded by a nucleic acid having the sequence of SEQ ID NO: 57.
  • the neurotrophic factor is BDNF.
  • the BDNF may have an amino acid sequence having at least 85% sequence identity (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of any one of SEQ ID NOs: 11 -16.
  • the BDNF may have, for example, an amino acid sequence that differs from the amino acid sequence of any one of SEQ ID NOs: 11 -16 by only one or more conservative amino acid substitutions, such as by up to 25, up to 20, up to 15, up to 10, or up to 5 conservative amino acid substitutions.
  • the BDNF may be a BDNF variant having an amino acid sequence with one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs: 11 -16.
  • the BDNF may be encoded by a nucleic acid having the sequence of any one of SEQ ID NOs: 58-61 .
  • the neurotrophin is a pan-neurotrophin, such as PNT-1 .
  • the PNT-1 may have an amino acid sequence having at least 85% sequence identity (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 17.
  • the PNT-1 may have, for example, an amino acid sequence that differs from the amino acid sequence of SEQ ID NO: 17 by only one or more conservative amino acid substitutions, such as by up to 25, up to 20, up to 15, up to 10, or up to 5 conservative amino acid substitutions.
  • the PNT-1 may be a PNT-1 variant having an amino acid sequence with one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 17.
  • the PNT-1 variant has the sequence any one of SEQ ID NOs: 25-28 or 31 -33.
  • the neurotrophin is a chimeric neurotrophin.
  • the chimeric neurotrophin is an NGF/BDNF chimera.
  • the chimeric neurotrophin may have an amino acid sequence having at least 85% sequence identity (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of any one of SEQ ID NOs: 18, 19, 29, or 30.
  • the chimeric neurotrophin may have, for example, an amino acid sequence that differs from the amino acid sequence of any one of SEQ ID NOs: 18, 19, 29, or 30 by only one or more conservative amino acid substitutions, such as by up to 25, up to 20, up to 15, up to 10, or up to 5 conservative amino acid substitutions.
  • the chimeric neurotrophin may be a chimeric neurotrophin variant having an amino acid sequence with one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs: 18, 19, 29, or 30.
  • the neurotrophic factor is CNTF.
  • the CNTF may have an amino acid sequence having at least 85% sequence identity (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 47.
  • the CNTF may have, for example, an amino acid sequence that differs from the amino acid sequence of SEQ ID NO: 47 by only one or more conservative amino acid substitutions, such as by up to 25, up to 20, up to 15, up to 10, or up to 5 conservative amino acid substitutions.
  • the CNTF may be a CNTF variant having an amino acid sequence with one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 47.
  • the CNTF may be encoded by a nucleic acid having the sequence of SEQ ID NO: 63.
  • the neurotrophic factor is IGF.
  • the IGF may have an amino acid sequence of IGF1 and have at least 85% sequence identity (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of any one of SEQ ID NOs: 48-51 .
  • the IGF may have an amino acid sequence of IGF2 and have at least 85% sequence identity (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or 100% sequence identity) to the amino acid sequence of any one of SEQ ID NOs: 52-54.
  • the IGF e.g., IGF1
  • the IGF may have, for example, an amino acid sequence that differs from the amino acid sequence of any one of SEQ ID NOs: 48-51 by only one or more conservative amino acid substitutions, such as by up to 25, up to 20, up to 15, up to 10, or up to 5 conservative amino acid substitutions.
  • the IGF may have, for example, an amino acid sequence that differs from the amino acid sequence of any one of SEQ ID NOs: 52-54 by only one or more conservative amino acid substitutions, such as by up to 25, up to 20, up to 15, up to 10, or up to 5 conservative amino acid substitutions.
  • the IGF may be an IGF1 variant having an amino acid sequence with one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs: 48-51 .
  • the IGF may be an IGF2 variant having an amino acid sequence with one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs: 52-54.
  • the IGF may be IGF1 and may be encoded by a nucleic acid having the sequence of any one of SEQ ID NOs: 64-66.
  • the IGF may be IGF2 and may be encoded by a nucleic acid having the sequence of SEQ ID NO: 67 or SEQ ID NO: 68.
  • the therapeutic agent is a glial cell line-derived neurotrophic factor family ligand, a neuropoietic cytokine, an anti-inflammatory cytokine, a neuroprotection agent, growth differentiation factor 11 , erythropoietin (EPO), granulocyte-colony stimulating factor, granulocyte- macrophage colony stimulating factor, growth differentiation factor-9, thrombopoietin, transforming growth factor alpha (TGF-a), stromal cell-derived factor 1 , myostatin (growth differentiation factor 8), parathyroid hormone, parathyroid hormone related peptide, interleukin 1 receptor antagonist, fibroblast growth factor 18, high-mobility group protein 2, glucocorticoid receptor, fibroblast growth factor 9, hepatocyte growth factor, or a TGFp-superfamily protein.
  • the therapeutic agent is a glial cell line-derived neurotrophic factor family ligand selected from glial cell line-derived neurotrophic factor (GDNF), neurturin, artemin, and persephin.
  • GDNF glial cell line-derived neurotrophic factor
  • neurturin glial cell line-derived neurotrophic factor
  • artemin artemin
  • persephin persephin
  • neurotrophin sequences are provided in Table 3, below. Table 3. Neurotrophin Sequences
  • Therapeutic agents that may be incorporated into the auricular dosage forms and methods described herein include neuropoietic cytokines, such as interleukin-6, interleukin-11 , inteleukin-27, leukemia inhibitory factor, cardiotrophin 1 , neuropoietin, cardiotrophin-like cytokine, and fibroblast growth factor 2.
  • neuropoietic cytokines such as interleukin-6, interleukin-11 , inteleukin-27, leukemia inhibitory factor, cardiotrophin 1 , neuropoietin, cardiotrophin-like cytokine, and fibroblast growth factor 2.
  • Therapeutic agents that may be incorporated into the auricular dosage forms and methods described herein include anti-inflammatory cytokines.
  • anti-inflammatory cytokines useful in conjunction with the auricular dosage forms and methods described herein are interleukin-4 and interleukin-10.
  • Therapeutic agents that may be incorporated into the auricular dosage forms and methods described herein include neuroprotection agents.
  • the auricular dosage forms described herein may contain a neuroprotection agent selected from neuregulin-1 and vascular endothelial growth factor (VEGF).
  • VEGF vascular endothelial growth factor
  • Therapeutic agents that may be incorporated into the auricular dosage forms and methods described herein include TGFp superfamily member proteins.
  • the auricular dosage forms described herein may contain a TGFp-superfamily protein selected from TGFp, TGFp3, BMP2, and BMP7.
  • Therapeutic agents that may be incorporated into the auricular dosage forms and methods described herein include immunomodulating agents.
  • the auricular dosage forms described herein may contain an immunomodulating agent selected from the group including anti-TNF agents (e.g., anti-TNF antibodies, such as infliximab adalimumab, and golimumab; fusion proteins, such as etanercept; TACE inhibitors; IKK inhibitors; or calcineurin inhibitors) and toll-like receptor inhibitors.
  • Therapeutic agents that may be incorporated into the auricular dosage forms and methods described herein include anti-platinum chemoprotectant agents.
  • anti-platinum chemoprotectant agents are believed to reduce or eliminate the toxicity of platin-based antineoplastic agents by competitively ligating and substantially coordinatively saturating the platinum centers present in the platinum-based antineoplastic agents.
  • the concentration of an anti-platinum chemoprotectant agent in an auricular dosage form (e.g., a pharmaceutical dosage form) of the invention may be, e.g., at least 0.05M (e.g., at least 0.1 M, at least 0.2M, at least 0.3M, at least 0.4M, at least 0.5M, or at least 1 M).
  • concentration of an anti-platinum chemoprotectant agent in an auricular dosage form (e.g., an auricular unit dosage form) of the invention may be, e.g., about 2.5M or less (e.g., 2.0M or less,
  • Non-limiting examples of the concentrations of an anti-platinum chemoprotectant agent in an auricular dosage form (e.g., an auricular unit dosage form) of the invention may be, e.g., about 0.05M to about 1 .5 M, about 0.05M to about 0.5M, about 0.05M to about 0.2M, about 0.05M to about 0.1 M, about 0.1 M to about 1 .5M, about 0.1 M to about 0.5M, about 0.1 M to about 0.2M, about 0.2M to about 1 .5M, about 0.2M to about
  • the concentration of an anti-platinum chemoprotectant agent in an auricular dosage form (e.g., an auricular unit dosage form) of the invention is 1 .0M to about 1 .5M.
  • Anti-platinum chemoprotectant agents are known in the art.
  • Non-limiting examples of anti platinum chemoprotectant agents include an alkaline or ammonium thiosulfate salt (e.g., sodium thiosulfate, potassium thiosulfate, or ammonium thiosulfate) or a solvate thereof (e.g., sodium thiosulfate pentahydrate), an alkaline diethyldithiocarbamate salt, amifostine, methionine, N-acetylcysteine, cysteine, 2-aminoethanethiol, glutathione (GSH) or a C1-C6 alkyl ester thereof (e.g., glutathione ethyl ester: y-Glu- Cys-Gly-OEt) or a salt thereof, lysine or a salt thereof, histidine or a salt thereof, arginine or a salt thereof,
  • Viral genomes provide a rich source of vectors that can be used for the efficient delivery of a gene of interest into the genome of a target cell (e.g., a mammalian cell, such as a human cell). Viral genomes are particularly useful vectors for gene delivery because the polynucleotides contained within such genomes are typically incorporated into the genome of a target cell by generalized or specialized transduction. These processes occur as part of the natural viral replication cycle, and do not require added proteins or reagents to induce gene integration.
  • a target cell e.g., a mammalian cell, such as a human cell.
  • Viral genomes are particularly useful vectors for gene delivery because the polynucleotides contained within such genomes are typically incorporated into the genome of a target cell by generalized or specialized transduction. These processes occur as part of the natural viral replication cycle, and do not require added proteins or reagents to induce gene integration.
  • viral vectors examples include adeno-associated viral (AAV) vectors (e.g., AAV1 , AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, rh10, rh39, rh43, rh74, Anc80, Anc80L65, DJ/8, DJ/9, 7m8, PHP.B, PHP.eb, and PHP.S), retrovirus, adenovirus (e.g., Ad5,
  • Ad26, Ad34, Ad35, and Ad48 parvovirus (e.g., adeno-associated viruses), coronavirus, negative strand RNA viruses such as orthomyxovirus (e.g., influenza virus), rhabdovirus (e.g., rabies and vesicular stomatitis virus), paramyxovirus (e.g.
  • parvovirus e.g., adeno-associated viruses
  • coronavirus e.g., coronavirus
  • negative strand RNA viruses such as orthomyxovirus (e.g., influenza virus), rhabdovirus (e.g., rabies and vesicular stomatitis virus), paramyxovirus (e.g.
  • RNA viruses such as picornavirus and alphavirus
  • double stranded DNA viruses including adenovirus, herpesvirus (e.g., Herpes Simplex virus types 1 and 2, Epstein-Barr virus, cytomegalovirus), and poxvirus (e.g., vaccinia, modified vaccinia Ankara (MVA), fowlpox and canarypox).
  • Herpesvirus e.g., Herpes Simplex virus types 1 and 2, Epstein-Barr virus, cytomegalovirus
  • poxvirus e.g., vaccinia, modified vaccinia Ankara (MVA), fowlpox and canarypox
  • Other examples of viral vectors that may be used in conjunction with the auricular dosage forms and methods described herein are Norwalk virus, togavirus, flavivirus, reoviruses, papovavirus, hepadnavirus, and hepatitis virus, among others.
  • retroviruses examples include: avian leukosis-sarcoma, mammalian C-type, B-type viruses, D-type viruses, HTLV-BLV group, lentivirus, spumavirus (Coffin, J. M., Retroviridae: The viruses and their replication, In Fundamental Virology, Third Edition, B. N. Fields, et al ., Eds., Lippincott-Raven Publishers, Philadelphia,
  • murine leukemia viruses include murine leukemia viruses, murine sarcoma viruses, mouse mammary tumor virus, bovine leukemia virus, feline leukemia virus, feline sarcoma virus, avian leukemia virus, human T-cell leukemia virus, baboon endogenous virus, Gibbon ape leukemia virus, Mason Pfizer monkey virus, simian immunodeficiency virus, simian sarcoma virus, Rous sarcoma virus and lentiviruses.
  • vectors are described, for example, in US Patent No. 5,801 ,030, the disclosure of which is incorporated herein by reference as it pertains to viral vectors for use in gene therapy.
  • the therapeutic agent is an antibody or antigen-binding fragment thereof, such as an antibody or antigen-binding fragment thereof that binds TrkB, TrkC, or a receptor thereof.
  • the antibody or antigen-binding fragment thereof may be, for example, a monoclonal antibody or antigen binding fragment thereof, a polyclonal antibody or antigen-binding fragment thereof, a humanized antibody or antigen-binding fragment thereof, a bispecific antibody or antigen-binding fragment thereof, a dual-variable immunoglobulin domain, a single-chain Fv molecule (scFv), a diabody, a triabody, a nanobody, an antibody-like protein scaffold, a Fv fragment, a Fab fragment, a F(ab’)2 molecule, or a tandem di-scFv.
  • scFv single-chain Fv molecule
  • TrkB- and TrkC-binding antibodies useful in conjunction with the auricular dosage forms and methods described herein are those produced by the cell lines shown in Table 4, below.
  • Other TrkB- and TrkC-binding antibodies that may be used in conjunction with the auricular dosage forms and methods described herein are recited in WO 2017/019907.
  • Therapeutic agents that may be incorporated into the auricular dosage forms described herein further include liposomes, vesicles, synthetic vesicles, exosomes, synthetic exosomes, dendrimers, and nanoparticles. Additional examples of therapeutic agents that may be used in conjunction with the auricular dosage forms and methods described herein are small molecules, such as those that are not naturally round window membrane-penetrant. Further examples of such therapeutic agents are interfering RNA molecules, such as a short interfering RNA (siRNA), a short hairpin RNA (shRNA), and a micro RNA (miRNA). Exemplary interfering RNA molecules are those at are at least 85% complementary to, and/or that anneal to, a target nucleic acid of interest, thereby suppressing the expression of the target nucleic acid.
  • siRNA short interfering RNA
  • shRNA short hairpin RNA
  • miRNA micro RNA
  • therapeutic agents that may be incorporated into the auricular dosage forms and methods described herein are, without limitation, antimicrobial agents, an arylcycloalkylamine, an elipticine derivative, anti-apoptotic agents, c-JNK inhibitors, antioxidants, NSAIDs, analgesics, neuroprotection agents, glutamate modulators, interleukin 1 modulators, interleukin-1 antagonists, corticosteroids, anti-TNF agents, calcineurin Inhibitors, IKK inhibitors, Interleukin inhibitors, platelet activating factor antagonists, TNF-a converting enzyme (TACE) inhibitors, Toll-like receptor inhibitors, autoimmune agents, IL-1 modulators, RNA interference agents, aquaporin modulators, estrogen-related receptor beta modulators, GAP junction proteins, vasopressin receptor modulators, NMDA receptor modulators, ENaC receptor modulators, osmotic diuretics, progesterone receptors, prostaglandins, cytofluor
  • the auricular dosage forms described herein may be administered to a subject (e.g., a mammalian subject, such as a human patient) to treat and/or prevent one or more of a variety of pathologies.
  • the auricular dosage forms described herein may be used to deliver a therapeutic agent across the round window membrane of a subject (e.g., a mammalian subject, such as a human patient) so as to treat an otic disease, such as ceruminosis or ceruminosis associated with an otic disease or condition, ear pruritus, otitis externa, otalgia, tinnitus, vestibular dysfunction (e.g., vertigo, dizziness, or loss of balance), ear fullness, hearing loss, Meniere's disease, sensorineural hearing loss (e.g., noise-induced hearing loss, age-related hearing loss (presbycusis), ototoxic drug-induced hearing loss, hearing loss related to head trauma, hearing loss related to infection
  • Subjects that may be treated as described herein are subjects having or at risk of developing sensorineural hearing loss, deafness, auditory neuropathy, tinnitus, and/or vestibular dysfunction (e.g., subjects having or at risk of developing hearing loss, vestibular dysfunction, or both).
  • the auricular dosage forms and methods described herein can be used to treat subjects having or at risk of developing damage to cochlear hair cells (e.g., damage related to acoustic trauma, disease or infection, head trauma, ototoxic drugs, or aging), subjects having or at risk of developing damage to vestibular hair cells (e.g., damage related to disease or infection, head trauma, ototoxic drugs, or aging), subjects having or at risk of developing damage to spiral ganglion neurons (SGNs) (e.g., damage related to acoustic trauma, disease or infection, head trauma, ototoxic drugs, or aging), subjects having or at risk of developing SGN degeneration, subjects having or at risk of developing sensorineural hearing loss, deafness, auditory neuropathy, or tinnitus, subjects having or at risk of developing vestibular dysfunction (e.g., dizziness, vertigo, or imbalance), subjects having tinnitus (e.g., tinnitus alone, or tin
  • the subject has hearing loss and/or vestibular dysfunction that is associated with or results from damage to or loss of hair cells (e.g., cochlear or vestibular hair cells) or SGNs.
  • the methods described herein may include a step of screening a subject for one or more mutations in genes known to be associated with hearing loss or vestibular dysfunction prior to treatment with or administration of the auricular dosage forms described herein.
  • a subject can be screened for a genetic mutation using standard methods known to those of skill in the art (e.g., genetic testing).
  • the methods described herein may also include a step of assessing hearing and/or vestibular function in a subject prior to treatment with or administration of the auricular dosage forms described herein.
  • Hearing can be assessed using standard tests, such as audiometry, auditory brainstem response (ABR), electrochocleography (ECOG), and otoacoustic emissions.
  • ABR auditory brainstem response
  • ECOG electrochocleography
  • Vestibular function may be assessed using standard tests, such as eye movement testing (e.g., electronystagmogram (ENG) or videonystagmogram (VNG)), posturography, rotary-chair testing, ECOG, vestibular evoked myogenic potentials (VEMP), and specialized clinical balance tests, such as those described in Mancini and Horak, Eur J Phys Rehabil Med, 46:239 (2010). These tests can also be used to assess hearing and/or vestibular function in a subject after treatment with or administration of the auricular dosage forms described herein.
  • eye movement testing e.g., electronystagmogram (ENG) or videonystagmogram (VNG)
  • ECOG vestibular evoked myogenic potentials
  • VEMP vestibular evoked myogenic potentials
  • specialized clinical balance tests such as those described in Mancini and Horak, Eur J Phys Rehabil Med, 46:239 (2010).
  • auricular dosage forms and methods described herein may also be administered as a preventative treatment to patients at risk of developing hearing loss and/or vestibular dysfunction, e.g., patients who have a family history of hearing loss or vestibular dysfunction (e.g., inherited hearing loss or vestibular dysfunction), patients carrying a genetic mutation associated with hearing loss or vestibular dysfunction who do not yet exhibit hearing impairment or vestibular dysfunction or patients exposed to risk factors for acquired hearing loss (e.g., acoustic trauma, disease or infection, head trauma, ototoxic drugs, or aging) or vestibular dysfunction (e.g., disease or infection, head trauma, ototoxic drugs, or aging).
  • acoustic trauma, disease or infection, head trauma, ototoxic drugs, or aging or vestibular dysfunction
  • auricular dosage forms and methods described herein can be used to promote or induce hair cell regeneration in a subject (e.g., cochlear and/or vestibular hair cell regeneration) and/or SGN regeneration in a subject.
  • Subjects that may benefit from auricular dosage forms that promote or induce hair cell regeneration and/or SGN regeneration include subjects suffering from hearing loss or vestibular dysfunction as a result of loss of hair cells and/or SGNs (e.g., loss of hair cells and/or SGNs related to trauma (e.g., acoustic trauma or head trauma), disease or infection, ototoxic drugs, or aging), and subjects with abnormal hair cells and/or SGNs (e.g., hair cells and/or SGNs that do not function properly when compared to normal hair cells), damaged hair cells and/or SGNs (e.g., hair cell and/or SGN damage related to trauma (e.g., acoustic trauma or head trauma), disease or infection, ototoxic drugs, or aging), or
  • the auricular dosage forms and methods described herein can also be used to promote or increase hair cell survival and/or SGN survival (e.g., increase survival of damaged hair cells and/or SGNs, promote repair of damaged hair cells and/or SGNs, or preserve hair cells and/or SGNs in a subject at risk of loss of hair cells and/or SGNs (e.g., loss of hair cells and/or SGNs due to age, exposure to loud noise, disease or infection, head trauma, or ototoxic drugs)).
  • hair cell survival and/or SGN survival e.g., increase survival of damaged hair cells and/or SGNs, promote repair of damaged hair cells and/or SGNs, or preserve hair cells and/or SGNs in a subject at risk of loss of hair cells and/or SGNs (e.g., loss of hair cells and/or SGNs due to age, exposure to loud noise, disease or infection, head trauma, or ototoxic drugs)).
  • the auricular dosage forms and methods described herein can also be used to prevent or reduce hair cell and/or SGN damage or death (e.g., cochlear hair cell and/or vestibular hair cell damage or death and/or SGN damage or death).
  • the methods prevent or reduce ototoxic drug- induced hair cell and/or SGN damage or death.
  • the methods prevent or reduce ototoxic drug-induced hair cell and/or SGN damage or death in subjects who have been treated with ototoxic drugs, or who are currently undergoing or soon to begin treatment with ototoxic drugs.
  • Ototoxic drugs are toxic to the cells of the inner ear (e.g., hair cells and SGNs), and can cause sensorineural hearing loss, vestibular dysfunction (e.g., vertigo, dizziness, or imbalance), tinnitus, or a combination of these symptoms.
  • Drugs that have been found to be ototoxic include aminoglycoside antibiotics (e.g., gentamycin, neomycin, streptomycin, tobramycin, kanamycin, vancomycin, and amikacin), viomycin, antineoplastic drugs (e.g., platinum-containing chemotherapeutic agents, such as cisplatin, carboplatin, and oxaliplatin), loop diuretics (e.g., ethacrynic acid and furosemide), salicylates (e.g., aspirin, particularly at high doses), and quinine.
  • aminoglycoside antibiotics e.g., gentamycin, neomycin, streptomycin, tobramycin, kanamycin, vancomycin, and amikacin
  • viomycin e.g., antineoplastic drugs (e.g., platinum-containing chemotherapeutic agents, such as cisplatin, carboplatin, and ox
  • the methods described herein prevent or reduce hair cell and/or SGN damage or death (e.g., cochlear hair cell and/or vestibular hair cell damage or death and/or SGN damage or death) related to acoustic trauma, disease or infection, head trauma, or aging.
  • hair cell and/or SGN damage or death e.g., cochlear hair cell and/or vestibular hair cell damage or death and/or SGN damage or death
  • auricular dosage forms that are particularly suited for these indications are those in which the therapeutic agent is a neurotrophin selected from NT-3, NGF, BDNF, CNTF, GDNF, NT-4, FGF, IGF, EGF, PGF, MANF, CDNF, a pan-neurotrophin (e.g., PNT-1), a chimeric neurotrophin (e.g., an NGF/BDNF chimera), or a combination thereof.
  • the therapeutic agent is a neurotrophin selected from NT-3, NGF, BDNF, CNTF, GDNF, NT-4, FGF, IGF, EGF, PGF, MANF, CDNF, a pan-neurotrophin (e.g., PNT-1), a chimeric neurotrophin (e.g., an NGF/BDNF chimera), or a combination thereof.
  • auricular dosage forms that are suited for preventing or reducing ototoxic-drug induced hair cell and/or SGN damage or death, in particular, for preventing or mitigating platinum-induced ototoxicity, are those in which the therapeutic agent is an anti-platinum chemoprotectant agent (e.g., an alkaline or ammonium thiosulfate salt or a solvate thereof, an alkaline diethyldithiocarbamate salt, amifostine, methionine, N- acetylcysteine, cysteine, 2-aminoethanethiol, glutathione (GSH) or a C1-C6 alkyl ester thereof, lysine, histidine, arginine, ethylene diamine tetraacetic acid, dimercaprol, dimercaptosuccinic acid, dimercapto- propane sulfonate salt, penicillamine, a-lipoic acid, or fur
  • the auricular dosage forms described herein are administered in an amount sufficient to improve hearing, improve vestibular function (e.g., improve balance or reduce dizziness or vertigo), treat, prevent, reduce or slow the development of tinnitus, treat, prevent, reduce, or delay the development of hearing loss, slow the progression of hearing loss, treat, prevent, reduce, or delay the development of vestibular dysfunction, slow the progression of vestibular dysfunction, prevent or reduce hair cell damage (e.g., hair cell damage related to acoustic trauma, head trauma, ototoxic drugs, disease or infection, or aging), prevent, slow, or reduce hair cell death (e.g., ototoxic drug-induced hair cell death, noise-related hair cell death, age-related hair cell death, disease or infection-related hair cell death, or head trauma-related hair cell death), promote or increase hair cell development, increase hair cell numbers (e.g., promote or induce hair cell regeneration), promote or increase hair cell survival, improve hair cell function, prevent or reduce SGN damage, prevent, slow, or reduce
  • Flearing may be evaluated using standard hearing tests (e.g., audiometry, ABR, electrochocleography (ECOG), and otoacoustic emissions) and may be improved by 5% or more (e.g., 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 200% or more) compared to hearing measurements obtained prior to treatment.
  • standard hearing tests e.g., audiometry, ABR, electrochocleography (ECOG), and otoacoustic emissions
  • 5% or more e.g., 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 200% or more
  • Vestibular function may be evaluated using standard tests for balance and vertigo (e.g., eye movement testing (e.g., ENG or VNG), posturography, rotary-chair testing, ECOG, VEMP, and specialized clinical balance tests) and may be improved by 5% or more (e.g., 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 200% or more) compared to measurements obtained prior to treatment.
  • the auricular dosage forms are administered in an amount sufficient to improve the subject’s ability to understand speech.
  • the auricular dosage forms described herein may also be administered in an amount sufficient to slow or prevent the development or progression of sensorineural hearing loss and/or vestibular dysfunction (e.g., in subjects who carry a genetic mutation associated with hearing loss or vestibular dysfunction, who have a family history of hearing loss or vestibular dysfunction (e.g., hereditary hearing loss or vestibular dysfunction), or who have been exposed to risk factors associated with hearing loss or vestibular dysfunction (e.g., ototoxic drugs, head trauma, disease or infection, or acoustic trauma) but do not exhibit hearing impairment or vestibular dysfunction (e.g., vertigo, dizziness, or imbalance), or in subjects exhibiting mild to moderate hearing loss or vestibular dysfunction).
  • a genetic mutation associated with hearing loss or vestibular dysfunction who have a family history of hearing loss or vestibular dysfunction (e.g., hereditary hearing loss or vestibular dysfunction), or who have been exposed to risk factors associated with hearing loss or vestibular dysfunction (e.g., oto
  • Hair cell numbers, hair cell function, SGN numbers, or SGN function may be evaluated indirectly based on hearing tests or tests of vestibular function, and may be increased by 5% or more (e.g., 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 200% or more) compared to hair cell numbers, hair cell function, SGN numbers, or SGN function prior to administration of the auricular dosage forms described herein.
  • 5% or more e.g., 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 200% or more
  • Hair cell damage or death and/or SGN damage or death may be reduced by 5% or more (e.g., 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 200% or more) compared to hair cell damage or death and/or SGN damage or death typically observed in untreated subjects, and can be evaluated indirectly based on standard hearing tests.
  • These effects may occur, for example, within 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 15 weeks, 20 weeks, 25 weeks, or more, following administration of the auricular dosage forms described herein.
  • the patient may be evaluated 1 month, 2 months, 3 months, 4 months, 5 months, 6 months or more following administration of the auricular dosage form depending on the dose and route of administration used for treatment. Depending on the outcome of the evaluation, the patient may receive additional treatments.
  • Auricular dosage forms may be administered once, or more than once (e.g., once annually, twice annually, three times annually, bi-monthly, or monthly).
  • Auricular dosage forms are administered auricularly.
  • the auricular dosage form is administered intratympanically or transtympanically.
  • a needle is used to pierce the tympanic membrane to instill drug into the middle ear space or traverse an existing PE tube or perforation of the ear drum to instill drug.
  • a separate ventilation hole in the tympanic membrane may or may not be created to allow air to escape the middle ear space.
  • the instilled drug may then target middle ear structures, cells or be designed to enter the inner ear via the round and oval membranes to affect specific targets. This may be accomplished, e.g., by instilling drug through the round window membrane, the oval window, a cochleostomy, or labrinthotomy approach.
  • tympanomeatal flap lifting up the ear drum
  • exposing the round window, stapes/oval window and promontory A stapedotomy hole may be created in the footplate and the drug instilled into the vestibule by pump, injection, or some other method.
  • the bony lip of the round window (RW) is removed (typically by drill) to expose the RW.
  • the RW may then be pierced with a needle and the drug infused or the RW may be fenestrated and the drug instilled directly through the fenestration.
  • an entirely separate entrance hole to the cochlea may be opened by drilling a cochleostomy hole into the cochlea and drug instilled.
  • a mastoidectomy may be performed and the facial recess opened to provide direct access to the oval and round windows as well as the promontory and the semicircular canals.
  • the labyrinth may be opened, much like a cochleostomy, for the instillation of drug.
  • a separate opening into the RW or OW may be created to allow for excess perilymph to leak out.
  • the amount of the auricular dosage form administered to the subject is, or the auricular unit dosage form has a volume of, at least 0.05 ml_ (e.g., at least 0.1 ml_, at least 0.2 ml_, at least 0.3 ml_, at least 0.4 ml_, at least 0.5 ml_, at least 0.6 ml_, at least 0.7 ml_, at least 0.8 ml_, at least 0.9 ml_, or at least 1 ml_; e.g., 1 .1 ml_ or less, 1 ml_ or less, 0.9 ml_ or less, 0.8 ml_ or less, 0.7 ml_ or less, 0.6 ml_ or less, 0.5 ml_ or less, 0.4 ml_ or less, 0.3 ml_ or less, or 0.2 ml_ or less; e.g., 0.05 ml_ to 1 .1
  • 0.3 mL to 0.4 mL 0.05 mL to 0.3 mL, 0.1 mL to 0.3 mL, or 0.2 mL to 0.3 mL).
  • the auricular dosage form is configured to control the release profile of the therapeutic agent.
  • the release profile of the therapeutic agent is controlled in part by the physical and chemical interactions of the agent with the other components of the auricular dosage form, e.g., pH, solubility, hydration, complexation, and diffusivity.
  • the auricular dosage form may allow for the immediate release of the therapeutic agent. In some embodiments, the auricular dosage form may allow for sustained release of the therapeutic agent.
  • the release of the therapeutic agent may be sustained from about 1 day to about 6 weeks, or more (e.g., for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, 14 days, 21 days, 28 days, 35 days, 42 days, 48 days, or more).
  • the sustained release of the therapeutic agent may occur in a continuous matter, pulsatile manner, or a combination of both.
  • the auricular dosage form may be configured for both an immediate release and controlled release of the therapeutic agent, and may further be dependent on the environmental or physiological conditions of the administration.
  • the auricular dosage forms described herein may contain pharmaceutically acceptable diluents, carriers, and/or excipients.
  • the auricular dosage forms described herein may contain, e.g., liquid solvents, buffering agents, viscosity agents, and/or coloring agents.
  • Certain excipients may perform multiple roles.
  • a liquid solvent in addition to its function as a carrier, may be used as a buffering agent.
  • solvents are known in the art, e.g., salines (e.g., hypertonic saline, hypotonic saline, isotonic saline, or phosphate-buffered saline) and artificial perilymph.
  • Liquid solvents that may be used in conjunction with the auricular dosage forms described herein include water, mineral oil, salines (e.g., hypertonic saline, hypotonic saline, isotonic saline, or phosphate- buffered saline), artificial perilymph, and tris buffer.
  • salines e.g., hypertonic saline, hypotonic saline, isotonic saline, or phosphate- buffered saline
  • artificial perilymph e.g., phosphate- buffered saline
  • Artificial perilymph is an aqueous solution containing NaCI (120-130 mM), KCI (3.5 mM), CaCI 2 (1 .3-1 .5 mM), MgCI 2 (1 .2 mM), glucose (5.0-11 mM), and buffering agents (e.g., NaHC03 (25 mM) and NaH 2 P04 (0.75 mM), or HEPES (20 mM) and NaOH (adjusted to pH of about 7.5)).
  • buffering agents e.g., NaHC03 (25 mM) and NaH 2 P04 (0.75 mM
  • HEPES (20 mM) and NaOH (adjusted to pH of about 7.5)
  • Buffering agents may be used to adjust the pH of an auricular dosage form (e.g., a pharmaceutical dosage form) of the invention a substantially neutral pH level.
  • buffering agents that may be used in the auricular dosage forms and methods described herein are known in the art, and include, without limitation, phosphate buffers and Good’s buffers (e.g., tris, MES, MOPS, TES, HEPES, HEPPS, tricine, and bicine).
  • buffering agents may be used to control the osmolarity of the auricular dosage form.
  • Viscosity agents can be used to increase or decrease the dynamic viscosity of the auricular dosage form prior to administration or to control the dynamic viscosity post administration. Viscosity agents may further control the release profile of the compound of the auricular dosage form.
  • viscosity agents examples include, without limitation, sodium stearate, bladderwrack, bentonite, eratonia, chondrus, dextrose, furcellaran, Ghatti gum, hectorite, lactose, sucrose, sucralose, maltodextrin, mannitol, sorbitol, honey, cellulose and its derivatives (e.g., ethyl cellulose, ethylhydroxyethyl cellulose, ethylmethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl-cellulose (HPMC), sodium carboxymethyl-cellulose (CMC)), pectin, chondroitin sulfate, or a combination thereof.
  • HPMC sodium carboxymethyl-cellulose
  • Example 1 Identification of TDM as a round window membrane permeabilizing agent
  • NT-3 neurotrophin-3
  • NT-3 is a non-covalent homodimer protein of about 27 kDa. Each chain of NT-3 has three disulfide bonds.
  • the protein has a pi of 9.5 and is positively charged at physiological pH. Although the protein has an ECso of less than 20 ng/ml, the protein experiences difficulty in penetrating the round window membrane.
  • TDM neurotrophin-3
  • an in vitro permeability assay was designed to test the apparent permeability of NT-3 against that of other compounds, the experimental design of which is shown in FIG. 1 .
  • TEER transepithelial electrical resistance
  • 100 mI_ artificial perilymph (AP+) with API was added to the insert, and 500 mI_ AP+ was added to the bath.
  • Cultures were incubated at 37 S C and 20 mI_ samples were collected at various time points. As evidenced by the results shown in FIG. 2, NT-3 is poorly round window membrane-penetrant.
  • TDM intratympanic administration of TDM was capable of not only significantly elevating cochlear NT-3 exposure, but was also able to effectuate a sustained residence of NT-3 in guinea pig perilymph for an extended period of time (FIGS. 12A-12B).
  • TDM was substantially superior to other permeation enhancers tested, which had little to no effect on NT-3 round window membrane penetration (see, e.g., FIGS. 3 - 11 ).
  • the in vitro permeability assay was used to evaluate administration of NT-3 in either vehicle or 0.25%, 1%, or 3% TDM, as depicted in FIG. 13 (all solutions were 20% (w/v) poloxamer 407 in phosphate buffered saline with 5 mM Lucifer Yellow).
  • all solutions were 20% (w/v) poloxamer 407 in phosphate buffered saline with 5 mM Lucifer Yellow).
  • cultures were incubated at 37 S C and 50 pL samples were collected at various time points. After 3.5 hours of incubation, the top and bottom media were collected separately and the insert was fixed for immunohistochemical staining to evaluate tight and adherens junctions.
  • FIG. 14 adherens junctions appeared normal after incubation with NT-3 and vehicle, exhibiting an organized honeycomb network. Adherens junctions and tight junctions also appeared normal after incubation with NT-3 in 0.25% TDM (FIG. 15). After incubation with NT-3 in 1% TDM, gaps could be observed between cells, denoted using asterisks in the merged image in FIG. 16. After incubation with NT-3 in 3% TDM, larger open patches could be observed, as shown in FIG. 17. NT-3 also exhibited greater flux (FIG. 18) and apparent permeability (FIG. 19) when incubated with 1 % and 3% TDM compared to control.
  • Example 2 Auricular dosage forms containing sodium thiosulfate and a permeabilizer
  • Hyaluronan (30.68 mg; Pharma Grade 80, Kikkoman Biochemifa company) was added to 3 mL of distilled water. The resulting mixture was stirred at 4 °C for 30 min. Sodium thiosulfate pentahydrate (744.90 mg) was added to the solution. The pH was adjusted to pH 7.21 by addition of NaOH (0.1 M, 2 pL). The resulting solution was filtered through 0.22 pm Millex-GV sterile filter with 1820 mOsmol/kg. Gel 2 (1M, 1% (w/v) hyaluronan, with 1% TDM)
  • Hyaluronan (29.96 mg; Pharma Grade 80, Kikkoman Biochemifa company) and TDM (30.03 mg, Aldrich) were added to 3 ml_ of distilled water. The resulting mixture was stirred at 4 °C for 30 min. Sodium thiosulfate pentahydrate (744.38 mg) was added to the solution. The pH was adjusted to pH 7.08 by addition of NaOH (0.1 M, 2 mI_). The resulting solution was filtered through 0.22 pm Millex-GV sterile filter with 1958 mOsmol/kg. Gels 7, 8, 9, 10, and 11 were prepared using a similar protocol.
  • Hyaluronan (15.22 mg; Pharma Grade 80, Kikkoman Biochemifa company) was added to distilled water (1 .50 ml_), and the resulting mixture was stirred for 30 min at 4 °C.
  • Peptide KLALKLALKALKLAALKLA (15.10 mg) was added to the solution, and the mixture was stirred for 20 min at 4 °C.
  • Sodium thiosulfate pentahydrate (373.05 mg) was added to the solution. The pH was adjusted to pH 7.10 by addition of NaOH (0.1 M, 9 mI_). The resulting solution was filtered through 0.22 pm Millex- GV sterile filter with 1902 mOsmol/kg.
  • Hyaluronan (30.15 mg; Pharma Grade 80, Kikkoman Biochemifa company) was added to distilled water (3 ml_), and the resulting mixture was stirred for 30 min at 4 °C.
  • EDTA (30.27 mg) was added to the solution, and the mixture was stirred for 20 min at 4 °C.
  • Sodium thiosulfate pentahydrate (744.74 mg) was added to the solution, and the solution was stirred for 15 min at 4 °C.
  • the pH was measured as 7.04.
  • the resulting solution was filtered through 0.22 pm Millex-GV sterile filter with 1830 mOsmol/kg.
  • Hyaluronan 29.85 mg; Pharma Grade 80, Kikkoman Biochemifa company
  • dipotassium Glycyrrhizinate 30.16 mg
  • distilled water 3 ml_
  • Sodium thiosulfate pentahydrate 743.87 mg was added to the solution.
  • the pH was adjusted to pH 7.18 by addition of NaOH (0.1 M, 2 pL).
  • the resulting solution was filtered through 0.22 pm Millex-GV sterile filter with 1960 mOsmol/kg.
  • Hyaluronan (40.00 mg; Pharma Grade 80, Kikkoman Biochemifa company) and n-Dodecyl b-D- maltoside (1 .04 mg, NDM) were added to distilled water (4 ml_), and the resulting mixture was stirred for 30 min at 4 °C.
  • Sodium thiosulfate pentahydrate (992.86 mg) was added to the solution, and the mixture was stirred for 20 min at 4 °C.
  • the pH was adjusted to pH 6.86 by addition of NaOH (0.1 M, 2 pL).
  • the resulting solution was filtered through 0.22 pm Millex-GV sterile filter.
  • Albino guinea pigs (Hartley), body weight at 250-350 g, were used for the studies.
  • the animal was placed on its shoulder with the surgery ear up and auditory bulla was first exposed using retroauricular approach. A hole of 2-3 mm in diameter was drilled on the bulla to provide direct visualization of the round window niche.
  • 10 pL of an aqueous composition of 0.5 M sodium thiosulfate / 2% (w/v) hyaluronan (STS Composition) were applied onto the RWM using a 10 pL Hamilton syringe and a 26-gauge needle. After application, guinea pigs remained at this position for 30 min to allow compound to diffuse into the cochlea. The bulla opening was sealed with a muscle graft and the incision closed with sutures.
  • Sampling procedures are as follows, in brief. All sampling procedures were terminal. Animals were euthanized with CO2. 0.5 ml_ samples of blood were collected by cardiac puncture. Plasma was separated by centrifugation at 5,000 rpm at 4 °C for 10 min and collected in a separate tube. 50 mI_ of cerebrospinal fluid were collected through the cisterna magma. Perilymph was collected ex vivo to avoid contamination from the cerebrospinal fluid influx via the cochlear aqueduct. The temporal bone was rapidly isolated, and the bulla was removed to expose the cochlea. Any visible remaining dosed compositions were carefully removed with absorbent points under the surgical microscope before perilymph sampling.
  • TDM tridecyl maltoside
  • NDM n-Dodecyl b-D-maltoside
  • 19aa KLALKLALKALKLAALKLA
  • HA sodium hyaluronate All percentages in Table 5 are (w/w).
  • the hair was shaved around the left ear using an electric razor and the skin was cleaned using 75% ethanol.
  • a self-retaining retractor was placed prior to creating a small hole (0.5mm diameter) either with a drilling in the posterior part of the bulla.
  • the bulla bone was uncapped in a dorsal and caudal direction using a pair of jeweler's tip forceps.
  • the bone was removed in a piecemeal fashion under high magnification. Care was exercised not to puncture the stapedial artery, which lies directly beneath the bulla cap, as bleeding from this artery may compromise the procedure.
  • the amount of bone removed was kept to a minimum to prevent excessive fluid entry to the middle ear while still allowing excellent visualization and access to the round window niche.
  • the delivered agent was allowed to rest within the round window niche for up to 30 min.
  • the small hole was covered with muscular tissue and tissue glue.
  • a TDT RZ6 system was used to record the ABR.
  • a computer-controlled TDT RZ6 System was used to generate the auditory pure tone and power amplified before being fed to a closed-field speaker to deliver sound stimuli.
  • the same pure tone stimuli was repeated 512 times, the sound pressure levels were increased in a step of 10 dB SPL (5 dB around threshold) from 20 dB SPL to 90 dB SPL after every 512 repeated trials.
  • the lowest sound level which induced a brainstem response was regarded as the threshold.
  • Hearing threshold was measured at 4, 24, and 32 kHz.
  • ABR recording was performed before surgery or dosing and on the 7 th and 21 st day after auricular dosage form dosing. The ABR was recorded first from the left ear and then from the right ear.
  • Example 5 Delivery of a therapeutic agent across the round window membrane of a human patient
  • a physician can deliver a therapeutic agent into the inner ear of a subject (e.g., a mammalian subject, such as a human).
  • a physician may administer an auricular dosage form containing a permeabilizer described herein (e.g., TDM) to a human patient so as to effectuate the passage of a therapeutic agent into the inner ear of the patient (e.g., through the round window membrane).
  • a permeabilizer described herein e.g., TDM
  • the auricular dosage form may be administered so as to treat or mitigate one or more of a variety of otic disorders, such as ceruminosis or ceruminosis associated with an otic disease or condition, ear pruritus, otitis externa, otalgia, tinnitus, vestibular dysfunction (e.g., vertigo, dizziness, or loss of balance), ear fullness, hearing loss, Meniere's disease, sensorineural hearing loss (e.g., noise-induced hearing loss, age-related hearing loss (presbycusis), ototoxic drug-induced hearing loss, hearing loss related to head trauma, hearing loss related to infection), autoimmune ear disease, ototoxicity, excitotoxicity, hidden hearing loss, cochlear synaptopathy, endolymphatic hydrops, labyrinthitis, Ramsay Hunt's Syndrome, vestibular neuronitis, or microvascular compression syndrome, hyperacusis, presbystasis, central auditory processing disorder, auditory
  • the physician may administer the auricular dosage form to the patient by way of one or more routes of administration described herein.
  • the physician may administer the auricular dosage forms to the patient auricularly, e.g., by intratympanic or transtympanic administration (e.g., injection).
  • the physician may determine the optimal quantity of the auricular dosage form to administer to the patient.
  • the physician may choose to administer at least 0.05 mL of the auricular dosage form to the round window of the subject.
  • Exemplary amounts of the auricular dosage form that may be administered to the subject are, without limitation, at least 0.05 ml_ (e.g., at least 0.1 ml_, at least 0.2 ml_, at least 0.3 ml_, at least 0.4 ml_, at least 0.5 ml_, at least 0.6 ml_, at least 0.7 ml_, at least 0.8 ml_, at least 0.9 ml_, or at least 1 ml_; e.g., 1 .1 ml_ or less, 1 ml_ or less, 0.9 ml_ or less, 0.8 ml_ or less, 0.7 ml_ or less, 0.6 ml_ or less, 0.5 ml_ or less, 0.4 ml_ or less, 0.3 ml_ or less, or 0.2 ml_ or less; e.g., 0.05 ml_ to 1 .1 ml_, 0.1 ml_ to
  • the physician may conduct an analysis to determine whether the therapeutic agent is still present in vivo at an effective level.
  • the physician may obtain a sample from the patient, such as a blood sample or perilymph sample, and may determine whether the subject is a candidate for a subsequent administration of the therapeutic agent based, for example, on the concentration of the therapeutic agent remaining in the sample and the time from the initial administration at which the sample was obtained.
  • Example 6 Delivery of a neurotrophin across the round window membrane of a human patient to prevent or reduce sensory hair cell damage or death
  • a physician may administer an auricular dosage form containing one or more of the permeabilizers described herein (e.g., TDM) to a human patient in order to treat, prevent, or reduce sensory hair cell damage or death in the subject.
  • a neurotrophin e.g., neurotrophin-3 (NT- 3), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), glial cell-line derived neurotrophic factor (GDNF), neurotrophin-4 (NT-4), fibroblast growth factor (FGF), insulin-like growth factor (IGF), epidermal growth factor (EGF), platelet-derived growth factor (PGF), mesencephalic astrocyte-derived neurotrophic factor (MANF), cerebral dopamine neurotrophic factor (CDNF), a pan-neurotrophic factor (e.g., PNT-1 ), a chimeric neurotrophin (e.g., a NGF/BDNF chimera), or combinations thereof) may be admi
  • the physician may determine the optimal quantity of the auricular dosage form to administer to the patient. For example, the physician may choose to administer at least 0.05 mL of the auricular dosage form to the round window of the subject.
  • Exemplary amounts of the auricular dosage form that may be administered to the subject are, without limitation, at least 0.1 mL, at least 0.2 mL, at least 0.3 mL, at least 0.4 mL, at least 0.5 mL, at least 0.6 mL, at least 0.7 mL, at least 0.8 mL, at least 0.9 mL, or at least 1 mL; e.g., 1 .1 mL or less, 1 mL or less, 0.9 mL or less, 0.8 mL or less, 0.7 mL or less, 0.6 mL or less, 0.5 mL or less, 0.4 mL or less, 0.3 mL or less, or 0.2 mL or less; e.g., 0.05
  • the physician may conduct an analysis to determine whether the therapeutic agent is still present in vivo at an effective level.
  • the physician may obtain a sample from the patient, such as a blood sample or perilymph sample, and may determine whether the subject is a candidate for a subsequent administration of the therapeutic agent based, for example, on the concentration of the therapeutic agent remaining in the sample and the time from the initial administration at which the sample was obtained.
  • Example 7 Delivery of an anti-platinum chemoprotectant agent across the round window membrane of a human patient to mitigate platinum-induced ototoxicity
  • a physician may administer an auricular dosage form containing one or more of the permeabilizers described herein (e.g., TDM) to a human patient in order to treat, prevent, or reduce sensory hair cell damage or death in the subject.
  • a thiosulfate salt or a pharmaceutically acceptable solvate thereof may be admixed with a permeabilizer described herein, optionally in combination with a gelling agent (e.g., hyaluronan), and administered to the patient so as to treat, prevent, or reduce sensory hair cell damage or death.
  • the resulting auricular dosage form may be administered to the patient by way, for example, of local administration, e.g., by intratympanic or transtympanic administration.
  • the physician may determine the optimal quantity of the auricular dosage form to administer to the patient. For example, the physician may choose to administer at least 0.05 mL of the auricular dosage form to the round window of the subject.
  • Exemplary amounts of the auricular dosage form that may be administered to the subject are, without limitation, at least 0.1 mL, at least 0.2 mL, at least 0.3 mL, at least 0.4 mL, at least 0.5 mL, at least 0.6 mL, at least 0.7 mL, at least 0.8 mL, at least 0.9 mL, or at least 1 mL; e.g., 1 .1 mL or less, 1 mL or less, 0.9 mL or less, 0.8 mL or less, 0.7 mL or less, 0.6 mL or less, 0.5 mL or less, 0.4 mL or less, 0.3 mL or less, or 0.2 mL or less; e.g., 0.05
  • the physician may conduct an analysis to determine whether the therapeutic agent is still present in vivo at an effective level.
  • the physician may obtain a sample from the patient, such as a blood sample or perilymph sample, and may determine whether the subject is a candidate for a subsequent administration of the therapeutic agent based, for example, on the concentration of the therapeutic agent remaining in the sample and the time from the initial administration at which the sample was obtained.

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Abstract

L'invention concerne des formes posologiques auriculaires contenant des glycosides d'alkyle ou des activateurs de perméation d'esters gras de saccharose pour une administration d'agent thérapeutique à l'oreille interne par l'intermédiaire de la membrane de fenêtre ronde. Des exemples d'affections qui peuvent être traitées et/ou prévenues à l'aide des formes posologiques auriculaires décrites dans la présente invention sont, sans limitation, les maladies otiques, la céruminose, le prurit auriculaire, l'otite externe, l'otalgie, l'acouphène, le dysfonctionnement vestibulaire, la plénitude de l'oreille, la maladie de Ménière, la neuropathie auditive, l'ototoxicité induite par le platine, et la surdité neurosensorielle, entre autres.
PCT/US2020/045954 2019-08-14 2020-08-12 Activateurs de perméation, compositions les contenant, et leurs procédés d'utilisation WO2021030452A1 (fr)

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WO2023288115A1 (fr) * 2021-07-15 2023-01-19 Sio2 Medical Products, Inc. Composition de conservation pour acides nucléiques et échantillons biologiques et procédés d'utilisation
EP4316462A1 (fr) * 2022-08-05 2024-02-07 Dompé farmaceutici S.p.a. Administration intranasale de bdnf pour le traitement de la perte auditive neurosensorielle
WO2024054494A1 (fr) * 2022-09-06 2024-03-14 Sio2 Medical Products, Inc. Composition de conservation pour marqueurs biologiques et échantillons biologiques et méthodes d'utilisation

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023288115A1 (fr) * 2021-07-15 2023-01-19 Sio2 Medical Products, Inc. Composition de conservation pour acides nucléiques et échantillons biologiques et procédés d'utilisation
EP4316462A1 (fr) * 2022-08-05 2024-02-07 Dompé farmaceutici S.p.a. Administration intranasale de bdnf pour le traitement de la perte auditive neurosensorielle
WO2024028483A1 (fr) * 2022-08-05 2024-02-08 Dompé Farmaceutici Spa Administration intranasale de bdnf pour le traitement de la surdité neurosensorielle
WO2024054494A1 (fr) * 2022-09-06 2024-03-14 Sio2 Medical Products, Inc. Composition de conservation pour marqueurs biologiques et échantillons biologiques et méthodes d'utilisation

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