IP Library › Granted Patent US 12,281,313
Granted Patent B2
US 12,281,313 · App. 17/010,556 · Granted Apr 22, 2025

Compositions and methods for delivering nucleic acids to cochlear and vestibular cells

Inventors: Jeffrey R. Holt (Boston, MA); Yukako Asai (Boston, MA); Paola Andrea Solanes Vega (Lausanne, CH); Bernard Schneider (Lausanne, CH)
Assignee: Children's Medical Center Corporation
C12N15/64A61P27/16
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Quick Facts
Patent No.
US 12,281,313
App. No.
17/010,556
Granted
Apr 22, 2025
Kind
B2
Abstract

Provided herein are materials and methods for efficiently delivering nucleic acids to cochlear and vestibular cells, and methods of treating sensory transduction disorders associated with a genetic defect.

Claims (20)

1. An AAV vector, wherein the vector comprises:

a polynucleotide encoding:

a capsid comprising amino acid sequence: TLAVPFK (SEQ ID NO: 27); and

a polypeptide selected from the group consisting of TMC1, TMC2, MYO7A, USH1C, CDH23, PCDH15, SANS, CIB2, USH2A, VLGR1, WHRN, CLRN1, PDZD7, KCNQ4, TMPRSS3, STRC, EYA4, harmonin-a, b, and c, OTOF, GPR98, MYO6, MYO15A, LOXHD1, POU3F4, EYA1, WFS1, ACTG1, TMIE, PJVK, SYNE4, and FAM65B; and

a promoter that directs expression of the polynucleotide encoding the polypeptide.

2. The vector of claim 1 , wherein the AAV vector is AAV9-php.b vector.

3. A cell comprising the AAV9-php.b vector of claim 2 .

4. The cell of claim 3 , wherein the cell is an outer or inner hair cell, vestibular hair cell, a spiral ganglion, or a vestibular ganglion.

5. The vector of claim 1 , wherein the promoter is selected from the group consisting of an Espin promoter, a PCDH15 promoter, a PTPRQ promoter, a Myo6 promoter, a KCNQ4 promoter, a Myo7a promoter, a synapsin promoter, a GFAP promoter, a CMV promoter, a CAG promoter, a CBH promoter, a CBA promoter, a U6 promoter, and a TMHS (LHFPL5) promoter.

6. A method, comprising: administering the AAV vector of claim 1 to an inner ear of a subject having a recessive mutation in a gene selected from the group consisting of: TMC1, TMC2, MYO7A, USH1C, CDH23, PCDH15, SANS, CIB2, USH2A, VLGR1, WHRN, CLRN1, PDZD7, KCNQ4, TMPRSS3, STRC, EYA4, harmonin-a, harmonin-b, harmonin-c, OTOF, GPR98, MYO6, MYO15A, LOXHD1, POU3F4, EYA1, WFS1, ACTG1, TMIE, PJVK, SYNE4, and FAM65B, thereby forming an AAV vector-encoded transgene, wherein the AAV vector-encoded transgene is a wild-type form of the mutated gene in the subject,

thereby expressing the polypeptide in the inner ear.

7. The method of claim 6 , wherein the inner ear disorder is Usher Syndrome.

8. The method of claim 6 , wherein administering transduces at least 70% of inner hair cells and outer hair cells of the inner ear.

9. The method of claim 6 , wherein the cell is a cell of the inner ear.

10. The method of claim 6 , wherein the administering improves or maintains auditory and/or vestibular function in the subject.

11. The method of claim 10 , wherein increase in auditory function is associated with preservation of hair bundle morphology and/or restoration of mechanotransduction.

12. The method of claim 6 , wherein the recessive mutation is associated with partial hearing loss, complete deafness, or partial or complete vestibular dysfunction.

13. A method of transducing an outer hair cell, an inner hair cell, a vestibular hair cell, a spiral ganglion, or a vestibular ganglion in a subject having a defective gene, the method comprising:

injecting the AAV vector of claim 1 into an inner ear of the subject, thereby forming an AAV vector-encoded transgene, wherein the AAV vector-encoded transgene is a wild-type form of the defective gene of the subject,

thereby expressing the polypeptide in the outer hair cell, the inner hair cell, the vestibular hair cell, the spiral ganglion, or the vestibular ganglion, wherein the defective gene comprises a recessive mutation.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 18, 2020
From: HOLT, JEFFREY R.; ASAI, YUKAKO
To: CHILDREN'S MEDICAL CENTER CORPORATION
Reel/Frame 054693/0459 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 18, 2020
From: SOLANES VEGA, PAOLA ANDREA; SCHNEIDER, BERNARD
To: ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Reel/Frame 054693/0488 →
Continuity (3)
Continuation PCTUS2019020794 · Mar 5, 2019
Provisional Application 62638697 · Mar 5, 2018
Related Publication 20200392516A1 · Dec 17, 2020
References Cited (63)
US 11730827B2 · Holt et al. · 2023 [cited by applicant]
US 20050287127A1 · Li et al. · 2005 [cited by applicant]
US 20130095071A1 · Bance et al. · 2013 [cited by applicant]
US 20170166926A1 · Deverman et al. · 2017 [cited by applicant]
US 20170204144A1 · Deverman et al. · 2017 [cited by applicant]
US 20180055908A1 · Petit et al. · 2018 [cited by applicant]
US 20190351072A1 · Holt et al. · 2019 [cited by applicant]
US 20230330268A1 · Holt et al. · 2023 [cited by applicant]
JP 2016536011A · 2016 [cited by applicant]
JP 2018536420A · 2018 [cited by applicant]
WO 2006026570A2 · 2006 [cited by applicant]
WO 2011075838A1 · 2011 [cited by applicant]
WO 2015054653A2 · 2015 [cited by applicant]
WO 2015089462A1 · 2015 [cited by applicant]
WO 2017100791A1 · 2017 [cited by applicant]
WO 2017136764A1 · 2017 [cited by applicant]
WO 2017189964A2 · 2017 [cited by applicant]
WO 2018017834A1 · 2018 [cited by applicant]
WO 2019200016A1 · 2019 [cited by applicant]
Sekerkova, et al. (2006) “Espins and the actin cytoskeleton of hair cell stereocilia and sensory cell microvilli”, Cell and Molecular Life Sciences, 63: 2329-41. (Year: 2006). [cited by examiner]
Zheng, et al. (2008) “Evaluation of Promoters for Use in Tissue-Specific Gene Delivery”, in Meths Mol Bio, Gene Ther Prot, vol. 2: Design and Charact Gene Trans Vects, 3rd Ed, Ed by J M. Le Doux, Humana Press, Springer … [cited by examiner]
Gyorgy, et al. (Nov. 20, 2018) “Gene Transfer with AAV9-PHP.B rescues Hearing a Mouse Model of Usher Syndrome 3A and Transduces Hair Cells in a Non-human Primate”, Molecular Therapy, 13: 1-13. (Year: 2018). [cited by examiner]
Kawashima, et al. (2011) “Mechanotransduction in mouse inner ear hair cells requires transmembrane channel-like genes”, 121(12): 4796-4809. (Year: 2011). [cited by examiner]
Nakanishi, et al. (2014) “Mutations of TMC1 cause deafness by disrupting mechanoelectrical transduction”, Auris Nasus Larynx, 41(5): 399-408. (Year: 2014). [cited by examiner]
Gao, et al. (2018) “Treatment of autosomal dominant hearing loss by in vivo delivery of genome editing agents”, 553: 217, 21 pages long. (Year: 2018). [cited by examiner]
Zincarelli, et al. (2008) “Analysis of AAV Serotypes 1-9 Mediated Gene Expression and Tropism in Mice After Systemic Injection”, Molecular Therapy, 16(6): 1073-80. (Year: 2008). [cited by examiner]
Arnold et al., “Novel Slow- and Fast-Type Drug Release Round-Window Microimplants for Local Drug Application to the Cochlea: An Experimental Study in Guinea Pigs,” Audiology & Neuro-Otology, 2005, vol. 10, pp. 53-63. [cited by applicant]
Deverman et al., “Cre-dependent selection yields AAV variants for widespread gene transfer to the adult brain,” Nature Biotechnology, Feb. 2016, vol. 34, No. 2, pp. 204-209. [cited by applicant]
Landegger et al., “A synthetic AAV vector enables safe and efficient gene transfer to the mammalian inner ear,” Nature Biotechnology, Mar. 2017, vol. 35, No. 3, pp. 280-284. [cited by applicant]
Mathur et al., “Usher syndrome: Hearing loss, retinal degeneration and associated abnormalities,” Biochimica et Biophysica Acta, 2015, vol. 1852, No. 3, pp. 406-420. [cited by applicant]
Extended European Search Report dated Dec. 3, 2021 in corresponding European Patent Application No. 19764479.2 (7 pages). [cited by applicant]
Alagramam et al., “Promoter, alternative splice forms, and genomic structure of protocadherin 15,” Genomics, 2007, vol. 90, pp. 482-492. [cited by applicant]
Durymanov et al., “Non-viral Delivery of Nucleic Acids: Insight Into Mechanisms of Overcoming Intracellular Barriers,” Frontiers in Pharmacology, 2018, vol. 9, Article No. 971, pp. 1-15. [cited by applicant]
Géléoc et al., “35 Gene Therapy Restores Auditory and Vestibular Function in a Mouse Model of Usher Syndrome, Type 1C,” Symposium—New horizons in hearing rehabilitation, Abstract Book, Inner Ear Biology 2016, Montpellie… [cited by applicant]
GenBank Accession No. AKU89595.1. [cited by applicant]
Goodyear et al., “A Receptor-Like Inositol Lipid Phosphatase Is Required for the Maturation of Developing Cochlear Hair Bundles,” The Journal of Neuroscience, Oct. 8, 2003, vol. 23, No. 27, pp. 9208-9219. [cited by applicant]
Grimm et al., “Helper Virus-Free, Optically Controllable, and Two-Plasmid-Based Production of Adeno-associated Virus Vectors of Serotypes 1 to 6,” Molecular Therapy, Jun. 2003, vol. 7, No. 6, pp. 839-850. [cited by applicant]
György et al., “Rescue of Hearing by Gene Delivery to Inner-Ear Hair Cells Using Exosome-Associated AAV,” Molecular Therapy, 2017, vol. 25, No. 2, pp. 379-391. [cited by applicant]
Kawashima et al., “Mechanotransduction in mouse inner ear hair cells requires transmembrane channel-like genes,” The Journal of Clinical Investigation, 2011, vol. 121, No. 12, pp. 4796-4809. [cited by applicant]
Kotterman et al., “Engineering adeno-associated viruses for clinical gene therapy,” Nature Reviews Genetics, 2014, vol. 15, pp. 445-451. [cited by applicant]
Landegger et al., “269. Novel Synthetic AAV Efficiently Transduces Neurosensory Hair Cells in the Cochlea,” Molecular Therapy, May 1, 2016, vol. 24, Suppl. 1, p. S107. [cited by applicant]
Lenzi et al., NCBI Bookshelf, A Service of the National Library of Medicine, National Institute of Health, Oversight and Review of Clinical Gene Transfer Protocols: Assessing the Role of the Recombinant DNA Advisory Com… [cited by applicant]
Longo-Guess et al., “Targeted knockout and lacZ reporter expression of the mouse Tmhs deafness gene and characterization of the hscy-2J mutation,” Mammalian Genome, 2007, vol. 18, pp. 646-656. [cited by applicant]
Maison et al., “Muscarinic Signaling in the Cochlea: Presynaptic and Postsynaptic Effects on Efferent Feedback and Afferent Excitability,” The Journal of Neuroscience, May 12, 2010, vol. 30, No. 19, pp. 6751-6762. [cited by applicant]
MedlinePlus “Usher syndrome,” National Institute of Health / National Library of Medicine, 2022, pp. 1-8. [cited by applicant]
Parker et al., “Genetic investigations in childhood deafness,” Archives of Disease in Childhood, 2015, vol. 100, No. 3, pp. 271-278. [cited by applicant]
Shim et al., “Nonviral Delivery Systems for Cancer Gene Therapy: Strategies and Challenges,” Current Gene Therapy, 2017, vol. 17, No. 5, pp. 1-18. [cited by applicant]
Shu et al., “Identification of Adeno-Associated Viral Vectors That Target Neonatal and Adult Mammalian Inner Ear Cell Subtypes,” Human Gene Therapy, Sep. 1, 2016, vol. 27, No. 9, pp. 687-699. [cited by applicant]
Office Action dated Jul. 5, 2023 in corresponding Japanese Patent Application No. 2020-570406 (4 pages). [cited by applicant]
English translation of Office Action dated Jul. 5, 2023 in corresponding Japanese Patent Application No. 2020-570406 (4 pages). [cited by applicant]
Askew et al., “Tmc gene therapy restores auditory function in deaf mice,” Science Translational Medicine, Jul. 8, 2015, vol. 7, No. 295, 295ra108, pp. 1-28. [cited by applicant]
Shibata et al., “Intravenous rAAV2/9 injection for murine cochlear gene delivery,” Scientific Reports, 2017, vol. 7, No. 9609, pp. 1-11. [cited by applicant]
Xia et al., “Inner Ear Gene Transfection in Neonatal Mice Using Adeno-Associated Viral Vector: A Comparison of Two Approaches,” PLoS One, Aug. 2012, vol. 7, No. 8, e43218, pp. 1-8. [cited by applicant]
Office Action dated Feb. 1, 2023 in corresponding Japanese Patent Application No. 2020-570406 (4 pages). [cited by applicant]
English translation of the Office Action dated Feb. 1, 2023 in corresponding Japanese Patent Application No. 2020-570406 (5 pages). [cited by applicant]
György et al., “Gene Transfer with AAV9-PHP.B Rescues Hearing in a Mouse Model of Usher Syndrome 3A and Transduces Hair Cells in a Non-human Primate,” Molecular Therapy: Methods & Clinical Development, Nov. 19, 2018, vo… [cited by applicant]
Morabito et al., “AAV-PHP.B-Mediated Global-Scale Expression in the Mouse Nervous System Enables GBA1 Gene Therapy for Wide Protection from Synucleinopathy,” Molecular Therapy, Aug. 10, 2017, vol. 25, pp. 2727-2742. [cited by applicant]
Pan et al., “Gene Therapy Restores Auditory and Vestibular Function in a Mouse Model of Usher Syndrome Type 1c,” Nature Biotechnology, Feb. 6, 2017, vol. 35, pp. 264-272. [cited by applicant]
International Search Report and Written Opinion issued in corresponding International Patent Application No. PCT/US2019/020794, mailed Jul. 5, 2019 (12 pages). [cited by applicant]
Office Action dated Feb. 8, 2024 in corresponding Chinese Patent Application No. 201980030614.5 (10 pages). [cited by applicant]
English translation of Office Action dated Feb. 8, 2024 in corresponding Chinese Patent Application No. 201980030614.5 (9 pages). [cited by applicant]
Office Action dated Nov. 25, 2024 in corresponding Japanese Patent Application No. 2023-186434 (2 pages). [cited by applicant]
English translation of Office Action dated Nov. 25, 2024 in corresponding Japanese Patent Application No. 2023-186434 (2 pages). [cited by applicant]