IP Library › Granted Patent US 12,264,317
Granted Patent B2
US 12,264,317 · App. 18/777,187 · Granted Apr 1, 2025

Compositions and methods for treating non-age-associated hearing impairment in a human subject

Inventors: Emmanuel John Simons (Brookline, MA); Ellen Reisinger (Dußlingen, DE); Sebastian Kügler (Göttingen, DE); Hanan Al-Moyed (Göttingen, DE)
Assignee: Akouos, Inc.
C12N15/52A01K67/0276A61K38/1709A61K48/0075A61P27/16C07K14/47C12N5/062C12N9/16C12N15/65C12N15/86C12N15/902A01K2217/075A01K2227/103A01K2267/03C12N2310/20C12N2750/14143C12N2830/008C12Y301/03001
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,264,317
App. No.
18/777,187
Granted
Apr 1, 2025
Kind
B2
Abstract

Provided herein are compositions that include at least two different nucleic acid vectors, where each of the at least two different vectors includes a coding sequence that encodes a different portion of an otoferlin protein, and the use of these compositions to treat hearing loss in a subject.

Claims (40)

1. A method of treating otoferlin related hearing loss in a subject, comprising administering to the subject a plurality of AAV vectors comprising:

a) a first AAV vector comprising a 5′ inverted terminal repeat (ITR), a 3′ ITR, a F1 phage recombinogenic region, and a promoter operably linked to a portion of a gene encoding an otoferlin polypeptide; and

b) a second AAV vector comprising a 5′ ITR, a 3′ ITR, a F1 phage recombinogenic region, and a portion of the gene encoding an otoferlin polypeptide;

wherein the first AAV vector and the second AAV vector are capable of constituting a full-length otoferlin messenger RNA in the subject;

wherein the first and second AAV vectors each include a total number of nucleotides of up to about 5kb; and

wherein the otoferlin related hearing loss is associated with reduced expression, lack of expression, or dysfunction of otoferlin.

2. The method of claim 1 , wherein the otoferlin polypeptide is an otoferlin isoform 5 polypeptide.

3. The method of claim 2 , wherein the otoferlin polypeptide is the human otoferlin isoform 5 polypeptide.

4. The method of claim 1 , wherein the F1 phage recombinogenic region is a 77 base pair recombinogenic region from the F1 phage genome.

5. The method of claim 1 , wherein the F1 phage recombinogenic region comprises the nucleotide sequence at positions 2-78 of SEQ ID NO: 39.

6. The method of claim 1 , wherein the first AAV vector further comprises a splicing donor signal sequence and the second AAV vector further comprises a splicing acceptor signal sequence and a polyadenylation signal.

7. The method of claim 6 , wherein the first AAV vector comprises the portion of the gene encoding the otoferlin polypeptide positioned 3′ to the promoter, the splicing donor signal sequence is positioned at the 3′ end of the first coding sequence, and the F1 phage recombinogenic region is positioned 3′ to the splicing donor signal sequence; and the second AAV vector comprises the splicing acceptor signal sequence positioned 3′ to the F1 phage recombinogenic region, the portion of the gene encoding an otoferlin polypeptide is positioned at the 3′ end of the splicing acceptor signal sequence, and the polyadenylation sequence is positioned at the 3′ end of the second coding sequence.

8. The method of claim 6 , wherein the method comprises ITR-mediated recombination and splicing between the splicing donor signal sequence and the splicing acceptor signal sequence to generate the full-length otoferlin messenger RNA.

9. The method of claim 6 , wherein the method comprises F1 phage recombinogenic region-induced recombination and splicing between the splicing donor signal sequence and the splicing acceptor signal sequence to generate the full-length otoferlin messenger RNA.

10. The method of claim 1 , wherein the otoferlin coding sequence is split at the exon 21-exon 22 junction.

11. The method of claim 1 , wherein the 5′ and 3′ ITRs are AAV2 serotype ITRs.

12. The method of claim 1 , wherein the first and second AAV vectors are encapsulated by AAV capsids and wherein the AAV capsids are AAV serotype 1, 2, 3, 4, 5, 6, 7, 8, 9, rh8, rh10, rh39, rh43, or Anc80.

13. The method of claim 12 , wherein the first and second AAV vectors are encapsulated by Anc80 capsids which are Anc80L65 capsids.

14. The method of claim 1 , wherein the plurality of AAV vectors is administered into a cochlea of the subject.

15. The method of claim 1 , wherein the full-length otoferlin messenger RNA is expressed in a cochlear inner hair cell.

16. The method of claim 1 , wherein the subject is a human.

17. The method of claim 1 , wherein each portion of the gene encoding the otoferlin polypeptide encodes up to 70% of SEQ ID NO: 5.

18. The method of claim 1 , wherein the plurality of AAV vectors is formulated in a composition for intracochlear administration and the composition further comprises a synthetic perilymph solution.

19. A method of treating otoferlin related hearing loss in a subject, comprising administering to the subject a plurality of AAV vectors comprising:

a) a first AAV vector comprising (i) a promoter, (ii) a portion of a gene encoding an otoferlin polypeptide, (iii) a splicing donor signal sequence, (iv) a 77 base pair F1 phage recombinogenic region, and (v) 5′ and 3′ ITRs; and

b) a second AAV vector comprising (i) a 77 base pair F1 phage recombinogenic region, (ii) a splicing acceptor signal sequence, (iii) a portion of the gene encoding an otoferlin polypeptide, (iv) a polyadenylation signal, and (v) 5′ and 3′ ITRs;

wherein the first AAV vector and the second AAV vector are capable of constituting a full-length otoferlin messenger RNA in the subject;

wherein the first and second AAV vectors each include a total number of nucleotides of up to about 5 kb; and

wherein the otoferlin related hearing loss is associated with reduced expression, lack of expression, or dysfunction of otoferlin.

20. The method of claim 19 , wherein the otoferlin polypeptide is the human otoferlin isoform 5 polypeptide.

21. The method of claim 19 , wherein each portion of the gene encoding the otoferlin polypeptide encodes up to 70% of SEQ ID NO: 5.

22. The method of claim 19 , wherein the otoferlin coding sequence is split at the exon 21-exon 22 junction.

23. The method of claim 19 , wherein the F1 phage recombinogenic region is the nucleotide sequence at positions 2-78 of SEQ ID NO: 39.

24. The method of claim 19 , wherein the method comprises ITR-mediated recombination and splicing between the splicing donor signal sequence and the splicing acceptor signal sequence to generate the full-length otoferlin messenger RNA.

25. The method of claim 19 , wherein the method comprises F1 phage recombinogenic region-induced recombination and splicing between the splicing donor signal sequence and the splicing acceptor signal sequence to generate full-length otoferlin messenger RNA.

26. The method of claim 19 , wherein the first and second AAV vectors are encapsulated by AAV capsids, and wherein the AAV capsids are AAV serotype 1, 2, 3, 4, 5, 6, 7, 8, 9, rh8, rh10, rh39, rh43, or Anc80.

27. The method of claim 26 , wherein the first and second AAV vectors are encapsulated by Anc80 capsids, which are Anc80L65 capsids.

28. The method of claim 19 , wherein the plurality of AAV vectors is administered into a cochlea of the subject.

29. The method of claim 19 , wherein the full-length otoferlin messenger RNA is expressed in a cochlear inner hair cell.

30. The method of claim 19 , wherein the plurality of AAV vectors is formulated in a composition for intracochlear administration and the composition further comprises a synthetic perilymph solution.

Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 24, 2024
From: SIMONS, EMMANUEL JOHN
To: AKOUOS, INC.
Reel/Frame 068679/0445 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 24, 2024
From: REISINGER, ELLEN; AL-MOYED, HANAN; KÜGLER, SEBASTIAN
To: GEORG-AUGUST-UNIVERSITÄT GÖTTINGEN STIFTUNG ÖFFENTLICHEN RECHTS, UNIVERSITÄTSMEDIZIN
Reel/Frame 068679/0594 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 24, 2024
From: GEORG-AUGUST-UNIVERSITÄT GÖTTINGEN STIFTUNG ÖFFENTLICHEN RECHTS, UNIVERSITÄTSMEDIZIN
To: AKOUOS, INC.
Reel/Frame 068679/0605 →
Continuity (6)
Continuation 18458752 · Aug 30, 2023
Continuation 17929647 · Sep 2, 2022
Continuation 17378606 · Jul 16, 2021
Continuation 16327396
Provisional Application 62494866 · Aug 23, 2016
Related Publication 20240384276A1 · Nov 21, 2024
References Cited (365)
US 4075196A · Badertscher et al. · 1978 [cited by applicant]
US 5122458A · Post et al. · 1992 [cited by applicant]
US 5168062A · Stinski et al. · 1992 [cited by applicant]
US 5510118A · Bosch et al. · 1996 [cited by applicant]
US 5552157A · Yagi et al. · 1996 [cited by applicant]
US 5565213A · Nakamori et al. · 1996 [cited by applicant]
US 5567434A · Szoka, Jr. · 1996 [cited by applicant]
US 5651991A · Sugiyama et al. · 1997 [cited by applicant]
US 5656016A · Ogden · 1997 [cited by applicant]
US 5697899A · Hillman et al. · 1997 [cited by applicant]
US 5738868A · Shinkarenko · 1998 [cited by applicant]
US 5741516A · Webb et al. · 1998 [cited by applicant]
US 5770219A · Chiang et al. · 1998 [cited by applicant]
US 5779708A · Wu · 1998 [cited by applicant]
US 5783208A · Venkateshwaran et al. · 1998 [cited by applicant]
US 5795587A · Gao et al. · 1998 [cited by applicant]
US 5797898A · Santini, Jr. et al. · 1998 [cited by applicant]
US 5851452A · Vallet Mas et al. · 1998 [cited by applicant]
US 6007856A · Cox et al. · 1999 [cited by applicant]
US 6265180B1 · Zuelli et al. · 2001 [cited by applicant]
US 6274150B1 · Simonnet et al. · 2001 [cited by applicant]
US 7419817B2 · Chiorini et al. · 2008 [cited by applicant]
US 7851196B2 · Schaffer et al. · 2010 [cited by applicant]
US 8236557B2 · Dongsheng et al. · 2012 [cited by applicant]
US 8507270B2 · Yamaguchi et al. · 2013 [cited by applicant]
US 8591457B2 · Gilbert · 2013 [cited by applicant]
US 9249417B2 · Yamaguchi et al. · 2016 [cited by applicant]
US 9695220B2 · Vandenberghe et al. · 2017 [cited by applicant]
US 9719070B2 · Vandenberghe et al. · 2017 [cited by applicant]
US 10119125B2 · Vandenberghe et al. · 2018 [cited by applicant]
US 10494645B2 · Auricchio et al. · 2019 [cited by applicant]
US 10526584B2 · Vandenberghe et al. · 2020 [cited by applicant]
US 11525139B2 · Simons et al. · 2022 [cited by applicant]
US 11781145B2 · Simons · 2023 [cited by examiner]
US 11807867B2 · Simons · 2023 [cited by examiner]
US 11993777B2 · Simons · 2024 [cited by examiner]
US 12071627B2 · Simons · 2024 [cited by examiner]
US 12077773B2 · Simons · 2024 [cited by examiner]
US 20030194412A1 · Baker et al. · 2003 [cited by applicant]
US 20040005370A1 · Breton · 2004 [cited by applicant]
US 20040048836A1 · Wilmott · 2004 [cited by applicant]
US 20040115159A1 · Tadlock et al. · 2004 [cited by applicant]
US 20040116512A1 · Naguib et al. · 2004 [cited by applicant]
US 20040127661A1 · Kaspar et al. · 2004 [cited by applicant]
US 20050096340A1 · Zhang et al. · 2005 [cited by applicant]
US 20050184275A1 · Mora-Gutierrez et al. · 2005 [cited by applicant]
US 20060040354A1 · Okeefe · 2006 [cited by applicant]
US 20130095071A1 · Bance et al. · 2013 [cited by applicant]
US 20160076054A1 · Auricchio et al. · 2016 [cited by applicant]
US 20180055908A1 · Petit et al. · 2018 [cited by applicant]
US 20180369414A1 · Stankovic et al. · 2018 [cited by applicant]
US 20190076623A1 · Mackay et al. · 2019 [cited by applicant]
US 20190100560A1 · Vandenberghe et al. · 2019 [cited by applicant]
US 20190185864A1 · Simons et al. · 2019 [cited by applicant]
US 20200101122A1 · Cheng et al. · 2020 [cited by applicant]
US 20200123504A1 · Vandenberghe et al. · 2020 [cited by applicant]
US 20200390905A1 · Simons et al. · 2020 [cited by applicant]
US 20210095313A1 · Bartolome · 2021 [cited by applicant]
US 20210363534A1 · Simons et al. · 2021 [cited by applicant]
US 20220040327A1 · Simons et al. · 2022 [cited by applicant]
US 20230090286A1 · Simons et al. · 2023 [cited by applicant]
US 20230108913A1 · Simons et al. · 2023 [cited by applicant]
US 20230407315A1 · Simons et al. · 2023 [cited by applicant]
US 20240011039A1 · Simons et al. · 2024 [cited by applicant]
US 20240093237A1 · Simons et al. · 2024 [cited by applicant]
EP 1249232A1 · 2002 [cited by applicant]
JP H07285863A · 1995 [cited by applicant]
JP H08507515A · 1996 [cited by applicant]
JP 2001513331A · 2001 [cited by applicant]
JP 2003527411A · 2003 [cited by applicant]
JP 2004532214A · 2004 [cited by applicant]
JP 2012511307A · 2012 [cited by applicant]
WO WO9810088A1 · 1998 [cited by applicant]
WO WO9960146A1 · 1999 [cited by applicant]
WO WO0032233A2 · 2000 [cited by applicant]
WO WO0046354A1 · 2000 [cited by applicant]
WO WO0055342A1 · 2000 [cited by applicant]
WO WO0125253A2 · 2001 [cited by applicant]
WO WO0149829A1 · 2001 [cited by applicant]
WO WO0166782A1 · 2001 [cited by applicant]
WO WO0170972A2 · 2001 [cited by applicant]
WO WO0202175A1 · 2002 [cited by applicant]
WO WO0212455A1 · 2002 [cited by applicant]
WO WO0212525A2 · 2002 [cited by applicant]
WO WO03014367A1 · 2003 [cited by applicant]
WO WO03093295A2 · 2003 [cited by applicant]
WO WO2004113494A2 · 2004 [cited by applicant]
WO WO2005009287A2 · 2005 [cited by applicant]
WO WO2005013938A1 · 2005 [cited by applicant]
WO WO2005020962A1 · 2005 [cited by applicant]
WO WO2005027872A2 · 2005 [cited by applicant]
WO WO2005042539A1 · 2005 [cited by applicant]
WO WO2005073384A2 · 2005 [cited by applicant]
WO WO2005118792A1 · 2005 [cited by applicant]
WO WO2006012414A2 · 2006 [cited by applicant]
WO WO2006033689A2 · 2006 [cited by applicant]
WO WO2007046703A2 · 2007 [cited by applicant]
WO WO2007127264A2 · 2007 [cited by applicant]
WO WO2007148971A2 · 2007 [cited by applicant]
WO WO2008030485A2 · 2008 [cited by applicant]
WO WO2008045242A2 · 2008 [cited by applicant]
WO WO2009014445A2 · 2009 [cited by applicant]
WO WO2009021017A2 · 2009 [cited by applicant]
WO WO2010148143A1 · 2010 [cited by applicant]
WO WO2011094198A1 · 2011 [cited by applicant]
WO WO2011112089A2 · 2011 [cited by applicant]
WO WO2012022920A1 · 2012 [cited by applicant]
WO WO2012123430A1 · 2012 [cited by applicant]
WO WO2013063379A1 · 2013 [cited by applicant]
WO WO2013075008A1 · 2013 [cited by applicant]
WO WO2013123503A1 · 2013 [cited by applicant]
WO WO2014145599A2 · 2014 [cited by applicant]
WO WO2014170480A1 · 2014 [cited by applicant]
WO WO2015031686A9 · 2015 [cited by applicant]
WO WO2015054653A2 · 2015 [cited by applicant]
WO WO2015137802A1 · 2015 [cited by applicant]
WO WO2016004319A1 · 2016 [cited by applicant]
WO WO2016114992A2 · 2016 [cited by applicant]
WO WO2016128407A1 · 2016 [cited by applicant]
WO WO2016139321A1 · 2016 [cited by applicant]
WO WO2016144892A1 · 2016 [cited by applicant]
WO WO2017019994A2 · 2017 [cited by applicant]
WO WO2017096039A1 · 2017 [cited by applicant]
WO WO2017100791A1 · 2017 [cited by applicant]
WO WO2017108931A1 · 2017 [cited by applicant]
WO WO2017132530A1 · 2017 [cited by applicant]
WO WO2017136764A1 · 2017 [cited by applicant]
WO WO2017223193A1 · 2017 [cited by applicant]
WO WO2018011599A2 · 2018 [cited by applicant]
WO WO2018017956A2 · 2018 [cited by applicant]
WO WO2018022608A2 · 2018 [cited by applicant]
WO WO2018039375A1 · 2018 [cited by applicant]
WO WO2018089192A1 · 2018 [cited by applicant]
WO WO2018128688A1 · 2018 [cited by applicant]
WO WO2018204734A1 · 2018 [cited by applicant]
WO WO2018204786A1 · 2018 [cited by applicant]
WO WO2018204797A1 · 2018 [cited by applicant]
WO WO2018204803A1 · 2018 [cited by applicant]
WO WO2018232055A1 · 2018 [cited by applicant]
WO WO2019028306A2 · 2019 [cited by applicant]
WO WO2019084145A1 · 2019 [cited by applicant]
WO WO2019157370A1 · 2019 [cited by applicant]
WO WO2019162396A1 · 2019 [cited by applicant]
WO WO2019165292A1 · 2019 [cited by applicant]
WO WO2019173367A1 · 2019 [cited by applicant]
WO WO2018145111A9 · 2019 [cited by applicant]
WO WO2019210181A1 · 2019 [cited by applicant]
WO WO2019222328A1 · 2019 [cited by applicant]
WO WO2019222329A1 · 2019 [cited by applicant]
WO WO2020014479A1 · 2020 [cited by applicant]
WO WO2020023612A1 · 2020 [cited by applicant]
WO WO2020069320A1 · 2020 [cited by applicant]
WO WO2020097372A1 · 2020 [cited by applicant]
Akil, O., et al., “Dual AAV-mediated Gene Therapy Restores Hearing in a Dfnb9 Mouse Model,” Proceedings of the National Academy of Sciences of the United States of America 116(10):4496-4501,: National Academy of Science… [cited by applicant]
Akil, O., et al., “Restoration of Hearing in the VGLUT3 Knockout Mouse Using Virally Mediated Gene Therapy,” Neuron 75(2):283-293, Cell Press, United States (Jul. 2012). [cited by applicant]
Alemi, A., “AOS Research Grant: Restoration of Hearing in the Otoferlin Knockout Mouse Using Viral Gene Therapy”, American Otological Society INC 145th Annual Meeting, Manchester Grand Hyatt, San Diego, United States (A… [cited by applicant]
Al-Moyed, H., et al., “A Dual-AAV Approach Restores Fast Exocytosis and Partially Rescues Auditory Function in Deaf Otoferlin Knock-out Mice,” EMBO Molecular Medicine 11(1):e9396, Wiley-Blackwell, United Kingdom (Jan. 2… [cited by applicant]
Ame, J.C., et al., “A Bidirectional Promoter Connects the Poly(Adp-ribose) Polymerase 2 (Parp-2) Gene to the Gene for Rnase P Rna. Structure and Expression of the Mouse Parp-2 Gene,” The Journal of Biological Chemistry … [cited by applicant]
Andersen, J.K., et al., “Herpesvims-mediated Gene Delivery Into the Rat Brain: Specificity and Efficiency of the Neuron-specific Enolase Promoter,” Cellular and Molecular Neurobiology 13(5):503-515, Kluwer Academic/Plen… [cited by applicant]
Arbuthnot, P.B., et al., “In Vitro and in Vivo Hepatoma Cell-specific Expression of a Gene Transferred With an Adenoviral Vector,” Human Gene Therapy 7(13):1503-1514, Mary Ann Liebert Inc., United States (Aug. 1996). [cited by applicant]
Asai, H., et al., “Depletion of Microglia and Inhibition of Exosome Synthesis Halt Tau Propagation,” Nature Neuroscience 18(11):1584-1593, Nature America Inc., United States (Nov. 2015). [cited by applicant]
Asokan, A., et al., “The AAV Vector Toolkit: Poised at the Clinical Crossroads,” Molecular Therapy 20(4):699-708, Cell Press, United States (Apr. 2012). [cited by applicant]
Azaiez, H., et al., “Genotype-phenotype Correlations for SLC26A4-related Deafness,” Human Genetics 122(5):451-457, Springer Verlag, Germany (Dec. 2007). [cited by applicant]
Baker, K., et al., “Repair of the Vestibular System via Adenovector Delivery of Atohl: a Potential Treatment for Balance Disorders,” Advances in oto-rhino-laryngology 66:52-63, Basel : Karger, Switzerland (2009). [cited by applicant]
Banasik, M.B., and McCray Jr., P.B., “Integrase-defective Lentiviral Vectors: Progress and Applications,” Gene Therapy 17(2):150-157, Nature Publishing Group, United Kingdom (Oct. 2009). [cited by applicant]
Bartoli, M., et al., “Noninvasive Monitoring of Therapeutic Gene Transfer in Animal Models of Muscular Dystrophies,” Gene Therapy 13(1):20-28, Nature Publishing Group, United Kingdom (Jan. 2006). [cited by applicant]
Basu, J., et al., “Human Artificial Chromosomes: Potential Applications and Clinical Considerations,” Pediatric Clinics of North America 53(5):843-853, W.B. Saunders, United States (Oct. 2006). [cited by applicant]
Batt, D.B. and Carmichael, G.G., “Characterization of the Polyomavims Late Polyadenylation Signal,” Molecular and Cellular Biology 15(9):4783-4790, American Society for Microbiology, United States (Sep. 1995). [cited by applicant]
Batzer, M.A., et al., “Enhanced evolutionary PCR using oligonucleotides with inosine at the 3′-terminus,” Nucleic Acids Research 19(18):5081, Oxford University Press, United Kingdom (Sep. 1991). [cited by applicant]
Bellec, J., et al., “CFTR Inactivation by Lentiviral Vector-mediated RNA Interference and CRISPR-Cas9 Genome Editing in Human Airway Epithelial Cells,” Current Gene Therapy 15(5):447-459, Bentham Science Publishers, Uni… [cited by applicant]
Bermingham, N.A., et al., “Mathl: an Essential Gene for the Generation of Inner Ear Hair Cells,” Science 284(5421):1837-1841, American Association for the Advancement of Science, United States (Jun. 1999). [cited by applicant]
Boeda, B., et al., “A Specific Promoter of the Sensory Cells of the Inner Ear Defined by Transgenesis,” Human Molecular Genetics 10(15):1581-1589, Oxford University Press, United Kingdom (Jul. 2001). [cited by applicant]
Boshart, M., et al., “A Very Strong Enhancer Is Located Upstream of an Immediate Early Gene of Human Cytomegalovims,” Cell 41(2):521-530, Cell Press, United States (Jun. 1985). [cited by applicant]
Bourlais, C.L., et al., “Ophthalmic Drug Delivery Systems—Recent Advances,” Progress in Retinal and Eye Research 17(1):33-58, Pergamon Press, United Kingdom (Jan. 1998). [cited by applicant]
Brene, S., et al., “Regulation of GluR2 Promoter Activity by Neurotrophic Factors via a Neuron-restrictive Silencer Element,” The European Journal of Neuroscience 12(5):1525-1533, Wiley-Blackwell, France (May 2000). [cited by applicant]
Budenz, C.L., et al., “Differential Effects of AAV.BDNF and AAV.Ntf3 in the Deafened Adult Guinea Pig Ear,” Scientific Reports 5:8619, Nature Publishing Group, United Kingdom (Mar. 2015). [cited by applicant]
Carter, B.J., “Handbook of Parvovimses,” ed., P. Tijsser, CRC Press, pp. 155-168, United States (1990). [cited by applicant]
Chatterjee, P., et al., “Otoferlin Deficiency in Zebrafish Results in Defects in Balance and Hearing: Rescue of the Balance and Hearing Phenotype With Full-length and Truncated Forms of Mouse Otoferlin,” Molecular and C… [cited by applicant]
Chen, C.Y., et al., “mRNA Decay Mediated by Two Distinct AU-rich Elements From C-fos and Granulocyte-macrophage Colony-stimulating Factor Transcripts: Different Deadenylation Kinetics and Uncoupling From Translation,” M… [cited by applicant]
Chen, J., et al., “Expression of Rat Bone Sialoprotein Promoter in Transgenic Mice,” Journal of Bone and Mineral Research 11(5):654-664, : American Society for Bone and Mineral Research, United States (May 1996). [cited by applicant]
Chen, Z., et al., “Inner Ear Drug Delivery via a Reciprocating Perfusion System in the Guinea Pig,” Journal of Controlled Release 110(1):1-19, Elsevier Science Publishers, Netherlands (Dec. 2005). [cited by applicant]
Choi, B.Y., et al., “Identities and Frequencies of Mutations of the Otoferlin Gene (OTOF) Causing DFNB9 Deafness in Pakistan,” Clinical Genetics 75(3):237-243, Copenhagen, Demnark (Mar. 2009). [cited by applicant]
Choi, J., et al., “Optimization of Aav Expression Cassettes to Improve Packaging Capacity and Transgene Expression in Neurons,” Molecular Brain 7:17, BioMed Central, United Kingdom (Mar. 2014). [cited by applicant]
Cong L., et al., “Multiplex Genome Engineering Using CRISPR/Cas Systems,” Science, 339(6121):819- 823, American Association for the Advancement of Science, United States (2013). [cited by applicant]
Crispo, M., et al., “Embryo Development, Fetal Growth and Postrtatal Phenotype of eGFP Lambs Generated by Lentiviral Transgenesis,” Transgenic Research 24(1):31-41, Kluwer Academic Publishers, Netherlands (Feb. 2015). [cited by applicant]
Cunningham, S.C., et al., “Gene Delivery to the Juvenile Mouse Liver Using AAV2/8 Vectors,” Molecular Therapy 16(6):1081-1088, Cell Press, United States (Jun. 2008). [cited by applicant]
Dalgleish, D.G., et al., “The Characterization of Small Emulsion Droplets Made From Milk Proteins and Triglyceride Oil,” Colloids and Surfaces 123-124: 145-153, Elsevier, Netherlands (1997). [cited by applicant]
De Campo, L., et al., “Five-Component Food-Grade Microemulsions: Structural Characterizations by SANS,” Journal of Colloid and Interface Science 274(1):251-267, Academic Press, United States (Jun. 2004). [cited by applicant]
De Felipe, P and Izquierdo, M., “Tricistronic and Tetracistronic Retroviral Vectors for Gene Transfer,” Human Gene Therapy 11(13):1921-1931, Mary Ann Liebert Inc., United States (Sep. 2000). [cited by applicant]
De Felipe, P., et al., “Use of the 2A Sequence From Foot-and-mouth Disease Vims in the Generation of Retroviral Vectors for Gene Therapy,” Gene Therapy 6(2):198-208, Nature Publishing Group, United Kingdom (Feb. 1999). [cited by applicant]
De Fougerolles, A.R., “Delivery Vehicles for Small Interfering RNA in Vivo,” Human Gene Therapy 19(2):125-132, Mary Ann Liebert Inc., United States (2008). [cited by applicant]
Di Domenico, M., et al., “Towards Gene Therapy for Deafness,” Journal of Cellular Physiology 226(10):2494-2499, Wiley-Liss, United States (Oct. 2011). [cited by applicant]
Dirren, E., et al., “Intracerebroventricular Injection of Adeno-associated Vims 6 and 9 Vectors for Cell Type-specific Transgene Expression in the Spinal Cord,” Human Gene Therapy 25(2):109-120, Mary Ann Liebert Inc., U… [cited by applicant]
Dmitriev, I., et al., “An Adenovims Vector With Genetically Modified Fibers Demonstrates Expanded Tropism via Utilization of a Coxsackievims and Adenovims Receptor-Independent Cell Entry Mechanism,” Journal of Virology … [cited by applicant]
Duan, D., et al., “Expanding AAV Packaging Capacity With Trans-splicing or Overlapping Vectors: a Quantitative Comparison,” Molecular Therapy 4(4):383-391, Cell Press, United States (Oct. 2001). [cited by applicant]
Duman, D., et al., “Screening of 38 Genes Identifies Mutations in 62% of Families With Nonsyndromic Deafness in Turkey,” Genetic Testing and Molecular Biomarkers 15(1-2):29-33, Mary Ann Liebert Inc., United States (Jan.… [cited by applicant]
Duncker, S.V., et al., “Otoferlin Couples to Clathrin-mediated Endocytosis in Mature Cochlear Inner Hair Cells,” The Journal of neuroscience 33(22):9508-9519, Society for Neuroscience, United States (May 2013). [cited by applicant]
Engel, J., et al., “Two Classes of Outer Hair Cells Along the Tonotopic Axis of the Cochlea,” Neuroscience 143(3):837-849, Elsevier Science, United States (Dec. 2006). [cited by applicant]
Evans, G. A. and Lewis, K. A., “Physical Mapping of Complex Genomes by Cosmid Multiplex Analysis,” Proceedings of the National Academy of Sciences of the United States of America 86(13):5030-5034, National Academy of Sc… [cited by applicant]
Fisher, K.J., et al., “Transduction With Recombinant Adeno-associated Vims for Gene Therapy Is Limited by Leading-strand Synthesis,” Journal of Virology 70(1):520-532, American Society For Microbiology, United States (J… [cited by applicant]
Furler, S., et al., “Recombinant AAV Vectors Containing the Foot and Mouth Disease Vims 2A Sequence Confer Efficient Bicistronic Gene Expression in Cultured Cells and Rat Substantia Nigra Neurons,” Gene Therapy 8(11):86… [cited by applicant]
Gait, M. J., “Oligonucleotide Synthesis: a Practical Approach,” Practical Approach Series, Oxford, United States (1984). [cited by applicant]
GenBank, “ [cited by applicant]
GenBank, “ [cited by applicant]
GenBank, “ [cited by applicant]
GenBank, “ [cited by applicant]
GenBank, “ [cited by applicant]
GenBank, “ [cited by applicant]
GenBank, “ [cited by applicant]
GenBank, “Human Elongation Factor EF-1-alpha Gene, Complete Cds,” Accession No. J046 17.1, accessed at https://www.ncbi.nlm.nih.gov/nuccore/J0461 7. 1, accessed on Jul. 20, 2021, 3 pages. [cited by applicant]
GenBank, “Human gene for H1 RNA,” Accession No. X16612.1, accessed at https://www.ncbi.nlm.nih.gov/nuccore/X16612.1. accessed on Jul. 20, 2021, 2 pages. [cited by applicant]
GenBank, “Mus Musculus Myosin Viia Gene, Promoter and Partial Cds,” Accession No. AF384559.1, accessed at https://www.ncbi.nlm.nih.gov/nuccore/AF384559.1. accessed on Jul. 20, 2021, 2 pages. [cited by applicant]
GenBank, “Mus Musculus Poly (Adp-ribose) Polymerase 2 (Parp2) Gene, Complete Cds,” Accession No. AF191547.1, accessed at https://www.ncbi.nlm.nih.gov/nuccore/AF191547.1, accessed on Jul. 20, 2021, 5 pages. [cited by applicant]
GenBank, “Mus Musculus Strain C57BL/6J Chromosome 5, GRCm38.p6 C57BL/6J,” NCBI Reference Sequence: NC_000071.6, accessed at https://www.ncbi.nlm.nih.gov/nuccore/NC_000071.6, accessed on Jul. 22, 2021, 2 pages. [cited by applicant]
GenBank, “Neurotrophin 3, Isoform CRA_b [ [cited by applicant]
GenBank: Neurotrophin 3, Isoform CRA_b [ [cited by applicant]
Gene ID: 459083, “OTOF otoferlin [ [cited by applicant]
Gene ID: 557476, “otofa otoferlin a [ [cited by applicant]
Gene ID: 696717 “OTOF otoferlin [ [cited by applicant]
Gene ID: 83762 “Otof otoferlin [ [cited by applicant]
GenPept, “HMus musculus otoferlin (Otof), transcript variant 4, mRNA,” Accession No. NM_001313767. 1, accessed at https://www.ncbi.nlm.nih.gov/nuccore/NM_001313767.1, accessed on Jul. 20, 2021, 7 pages. [cited by applicant]
GenPept, “otoferlin [ [cited by applicant]
GenPept, “otoferlin isoform 4 [Mus musculus],” Accession No. NP_001300696.1, accessed at https://www.ncbi.nlm.nih.gov/protein/NP_001300696.1, accessed on Jul. 20, 2021, 4 pages. [cited by applicant]
GenPept, “otoferlin isoform b [ [cited by applicant]
GenPept, “otoferlin isoform c [ [cited by applicant]
GenPept, “otoferlin isoform d [ [cited by applicant]
GenPept, “otoferlin isoform e [ [cited by applicant]
Ghosh, A., et al., “A Hybrid Vector System Expands Adeno-Associated Viral Vector Packaging Capacity in a Transgene-Independent Manner,” Molecular Therapy : The Journal of the American Society of Gene Therapy 16(1):124-1… [cited by applicant]
Ghosh, A., et al., “Efficient Transgene Reconstitution with Hybrid Dual AAV Vectors Carrying the Minimized Bridging Sequences,” Human Gene Therapy 22(1):77-83, Mary Ann Liebert Inc., United States (Jan. 2011). [cited by applicant]
Gossen, M. and Bujard, H., “Tight Control of Gene Expression in Mammalian Cells by Tetracycline-Responsive Promoters,” Proceedings of the National Academy of Sciences of the United States of America 89(12):5547-5551, Na… [cited by applicant]
Gossen, M., “Transcriptional Activation by Tetracyclines in Mammalian Cells,” Science 268:1766-1769, American Association for the Advancement of Science, United States (Jun. 1995). [cited by applicant]
Gray, S. J., “Optimizing Promoters for Recombinant Adeno-Associated Vims-Mediated Gene Expression in the Peripheral and Central Nervous System Using Self-Complementary Vectors,” Human Gene Therapy 22(9):1143-1153, Mary … [cited by applicant]
Halpin, C., et al., “Self-Processing 2A-Polyproteins—a System for Co-ordinate Expression of Multiple Proteins in Transgenic Plants,” Plant Journal for Cell and Molecular Biology 17(4):453-459, Blackwell Scientific Publi… [cited by applicant]
Hansal, S. A., et al., “Induction of Antigen-Specific Hyporesponsiveness by Transplantation of Hemopoietic Cells Containing an MHC Class I Transgene Regulated by a Lymphocyte-Specific Promoter,” Journal of Immunology 16… [cited by applicant]
Harvey, D. M. and Caskey, C. T., “Inducible Control of Gene Expression: Prospects for Gene Therapy,” Current Opinion in Chemical Biology 2(4):512-518, Elsevier, United Kingdom (Aug. 1998). [cited by applicant]
Heidel, J.D., et al., “Administration in Non-Human Primates of Escalating Intravenous Doses of Targeted Nanoparticles Containing Ribonucleotide Reductase Subunit M2 siRNA,” Proceedings of the National Academy of Science… [cited by applicant]
Heidrych, P., et al., “Otoferlin Interacts with Myosin VI: Implications for Maintenance of the Basolateral Synaptic Structure of the Inner Hair Cell,” Human Molecular Genetics 18(15):2779-2790, IRL Press at Oxford Unive… [cited by applicant]
Heidrych, P., et al., “Rab8b GTPase, a Protein Transport Regulator, is an Interacting Partner of Otoferlin, Defective in a Human Autosomal Recessive Deafness Form,” Human Molecular Genetics 17(23):3814-3821, IRL Press a… [cited by applicant]
Hellen, C. U. and Sarnow, P., “Internal Ribosome Entry Sites in Eukaryotic mRNA Molecules,” Genes & Development 15(13):1593-1612, Cold Spring Harbor Laboratory Press, United States (Jul. 2001). [cited by applicant]
Hu-Lieskovan, S. et al., “Sequence-Specific Knockdown ofEWS-FLil by Targeted, Non viral Delivery of Small Interfering RNA Inhibits Tumor Growth in a Murine Model of Metastatic Ewing's Sarcoma”, Cancer Research 65: 8984-… [cited by applicant]
Husseman, J. and Raphael, Y., “Gene Therapy in the Inner Ear Using Adenovirus Vectors,” Advances in Oto-rhino-laryngology 66:37-51, Karger, Switzerland (2009). [cited by applicant]
Ikeno, M., et al., “Construction of YAC-based Mammalian Artificial Chromosomes,” Nature Biotechnology 16(5):431-439, Nature America Publishing, United States (May 1998). [cited by applicant]
Written Opinion for PCT/US17/048257 (Compositions and Methods for Treating Non-Age-Associated Hearing Impairment in a Human Subject, filed Aug. 23, 2017), received by ISA/KR, 11 pages (Dec. 27, 2017). [cited by applicant]
Written Opinion for PCT/US2019/019268 (Compositions and Methods for Treating Non-Age-Associated Hearing Impairment in a Human Subject, filed Feb. 22, 2019), received from ISA/KR, 13 pages (Jun. 13, 2019). [cited by applicant]
Iwamoto, M., et al., “A General Chemical Method to Regulate Protein Stability in the Mammalian Central Nervous System,” Chemistry & Biology 17(9):981-988, Elsevier, United States (Sep. 2010). [cited by applicant]
Iwasa, Y., et al., “OTOF Mutation Screening in Japanese Severe to Profound Recessive Hearing Loss Patients,” BMC Medical Genetics 14:95, BioMed Central, United Kingdom (Sep. 2013). [cited by applicant]
Izumikawa, M., et al., “Response of the Flat Cochlear Epithelium to Forced Expression of Atohl,” 240(1-2):52-56, Hearing Research, Netherlands (Jun. 2008). [cited by applicant]
Jing, Z., et al., “Disruption of the Presynaptic Cytomatrix Protein Bassoon Degrades Ribbon Anchorage, Multiquantal Release, and Sound Encoding at the Hair Cell Afferent Synapse,” The Journal of Neuroscience 33(10):4456… [cited by applicant]
Johnson, C.P. and Chapman, E.R., “Otoferlin Is a Calcium Sensor That Directly Regulates SNARE-mediated Membrane Fusion,” The Journal of Cell Biology 191(1):187-197, Rockefeller University Press, United States (Oct. 2010… [cited by applicant]
Jung, S., et al., “Disruption of Adaptor Protein 2mu (AP-2mu) in Cochlear Hair Cells Impairs Vesicle Reloading of Synaptic Release Sites and Hearing,” The EMBO Journal 34(21):2686-2702, Wiley Blackwell, United Kingdom (… [cited by applicant]
Katoh, M., et al., “Construction of a Novel Human Artificial Chromosome Vector for Gene Delivery,” Biochemical and Biophysical Research Communications 321(2):280-290, Elsevier, United States (Aug. 2004). [cited by applicant]
Kawamoto, K., et al., “Math 1 Gene Transfer Generates New Cochlear Hair Cells in Mature Guinea Pigs in Vivo,” The Journal of Neuroscience 23(11):4395-4400, Society for Neuroscience, United States (Jun. 2003). [cited by applicant]
Kazuki, Y. and Oshimura, M., “Human Artificial Chromosomes for Gene Delivery and the Development of Animal Models,” Molecular Therapy 19(9):1591-1601, Cell Press, United States (Sep. 2011). [cited by applicant]
Kazuki, Y., et al., “Refined Human Artificial Chromosome Vectors for Gene Therapy and Animal Transgenesis,” Gene Therapy 18(4):384-393, Nature Publishing Group, United Kingdom (Apr. 2011). [cited by applicant]
Klump, H., et al., “Retroviral Vector-mediated Expression of HoxB4 in Hematopoietic Cells Using a Novel Coexpression Strategy,” Gene Therapy 8(10):811-817, Nature Publishing Group, United Kingdom (May 2001). [cited by applicant]
Kouprina, N., et al., “Human Artificial Chromosome-based Gene Delivery Vectors for Biomedicine and Bioteclmology,” Expert Opinion on Drug Delivery 11(4):517-535, Informa Healthcare, United Kingdom (Apr. 2014). [cited by applicant]
Kral, A. and O'Donoghue, G.M., “Profound Deafness in Childhood,” The New United Kingdom Journal of Medicine 363(15):1438-1450, Massachusetts Medical Society, United States (Oct. 2010). [cited by applicant]
Kugler, S., et al., “Differential Transgene Expression in Brain Cells in Vivo and in Vitro From AAV-2 Vectors With Small Transcriptional Control Units,” Virology 311(1):89-95, Academic Press, United States (Jun. 2003). [cited by applicant]
Lai, Y., et al., “Efficient in Vivo Gene Expression by Trans-splicing Adeno-associated Viral Vectors,” Nature Biotechnology 23(11):1435-1439, Nature America Publishing, United States (Nov. 2005). [cited by applicant]
Landegger, L.D., et al., “A Synthetic AAV Vector Enables Safe and Efficient Gene Transfer to the Mammalian Inner Ear,” Nature Biotechnology 35(3):280-284, Nature America Publishing, United States (Mar. 2017). [cited by applicant]
Levitt, N., et al., “Definition of an Efficient Synthetic Poly(A) Site,” Genes & Development 3(7):1019-1025, Cold Spring Harbor Laboratory Press, United States (Jul. 1989). [cited by applicant]
Li, L., et al., “Production and Characterization of Novel Recombinant Adeno-associated Vims Replicative-form Genomes: A Eukaryotic Source of DNA for Gene Transfer,” PloS One 8(8):e69879, Public Library of Science, Unite… [cited by applicant]
Liu, Y., et al., “Promoter Effects of Adeno-associated Viral Vector for Transgene Expression in the Cochlea in Vivo,” Experimental & Molecular Medicine 39(2):170-175, Nature Publishing Group, United States (Apr. 2007). [cited by applicant]
Longo-Guess, C., et al., “A Missense Mutation in the Conserved C2B Domain of Otoferlin Causes Deafness in a New Mouse Model of DFNB9,” Hearing Research 234(1-2):21-28, Elsevier/North-Holland Biomedical Press, Netherland… [cited by applicant]
Lostal, W., et al., “Efficient Recovery of Dysferlin Deficiency by Dual Adeno-Associated Vector-Mediated Gene Transfer,” Human Molecular Genetics 19(10):1897-1907, IRL Press at Oxford University Press, United Kingdom (M… [cited by applicant]
Magari, S.R., et al., “Pharmacologic Control of a Humanized Gene Therapy System Implanted Into Nude Mice,” The Journal of Clinical Investigation 100(11):2865-2872, American Society for Clinical Investigation, United Sta… [cited by applicant]
Maier, P., et al., “Retroviral Vectors for Gene Therapy,” Future Microbiology 5(10):1507-1523, Future Medicine, United Kingdom (Oct. 2010). [cited by applicant]
Marlin, S., et al., “Temperature-sensitive Auditory Neuropathy Associated With an Otoferlin Mutation: Deafening Fever!,” Biochemical and Biophysical Research Communications 394(3):737-742, Elsevier, United States (Apr. … [cited by applicant]
Matrai, J., et al., “Recent Advances in Lentiviral Vector Development and Applications,” Molecular Therapy 18(3):477-490, Cell Press, United States (Mar. 2010). [cited by applicant]
Mattion, N.M., et al., “Foot-and-mouth Disease Vims 2a Protease Mediates Cleavage in Attenuated Sabin 3 Poliovims Vectors Engineered for Delivery of Foreign Antigens,” Journal of Virology 70(11):8124-8127, American Soci… [cited by applicant]
Menchaca, A. and Rubianes, E., “New Treatments Associated With Timed Artificial Insemination in Small Ruminants,” Reproduction, Fertility, and Development 16(4):403-413, Commonwealth Scientific and Industrial Research O… [cited by applicant]
Menoret, et al., “Advanced protocols for Animal Transgenesis,” An ISTT Manual, Heidelberg: Springer, pp. 117-136, Germany (2011). [cited by applicant]
Migliosi, V., et al., “Q829X, A Novel Mutation in the Gene Encoding Otoferlin (OTOF), Is Frequently Found in Spanish Patients With Prelingual Non-syndromic Hearing Loss,” Journal of Medical Genetics 39(7):502-506, Briti… [cited by applicant]
Milone, M.C., et al., “Chimeric Receptors Containing CD137 Signal Transduction Domains Mediate Enhanced Survival of T Cells and Increased Antileukemic Efficacy in Vivo,” Molecular Therapy 17(8):1453-1464, Cell Press, Un… [cited by applicant]
Mirghomizadeh, F., et al., “Substitutions in the Conserved C2C Domain of Otoferlin Cause DFNB9, a Form of Nonsyndromic Autosomal Recessive Deafness,” Neurobiology of Disease 10(2):157-164, Academic Press, United States … [cited by applicant]
Moser, T and Beutner, D., “Kinetics of Exocytosis and Endocytosis at the Cochlear Inner Hair Cell Afferent Synapse of the Mouse,” Proceedings of the National Academy of Sciences of the United States of America 97(2):883… [cited by applicant]
Murray, A. W. and Szostak, J.W., “Construction of Artificial Chromosomes in Yeast,” Nature 305(5931):189-193, Nature Publishing Group, United Kingdom (Sep. 1983). [cited by applicant]
Neef, A., et al., “Probing the Mechanism of Exocytosis at the Hair Cell Ribbon Synapse,” The Journal of Neuroscience 27(47):12933-12944, Society for Neuroscience, United States (Nov. 2007). [cited by applicant]
No., D., et al., “Ecdysone-inducible Gene Expression in Mammalian Cells and Transgenic Mice,” Proceedings of the National Academy of Sciences of the United States of America 93(8):3346-3351, National Academy of Sciences… [cited by applicant]
Ohlfest, J.R., et al., “Phenotypic Correction and Long-term Expression of Factor Viii in Hemophilic Mice by Immunotolerization and Nonviral Gene Transfer Using the Sleeping Beauty Transposon System,” Blood 105(7):2691-2… [cited by applicant]
Ohtsuka, E., et al., “An Alternative Approach to Deoxyoligonucleotides as Hybridization Probes by Insertion of Deoxyinosine at Ambiguous Codon Positions,” The Journal of Biological Chemistry 260(5):2605-2608, Elsevier I… [cited by applicant]
Orkin, S.H., et al., “Thalassemia Due to a Mutation in the Cleavage-polyadenylation Signal of the Human Beta-globin Gene,” The EMBO Journal 4(2):453-456, Wiley Blackwell, United Kingdom (Feb. 1985). [cited by applicant]
Padmanarayana, M., et al., “Characterization of the Lipid Binding Properties of Otoferlin Reveals Specific Interactions Between PI (4,5)P2 and the C2C and C2F Domains,” Biochemistry 53(30):5023-5033, American Chemical S… [cited by applicant]
Pangrsic, T., et al., “Hearing Requires Otoferlin-dependent Efficient Replenishment of Synaptic Vesicles in Hair Cells,” Nature Neuroscience 13(7):869-876, Nature Publishing Group, United States (Jul. 2010). [cited by applicant]
Pangrsic, T., et al., “Otoferlin: A Multi-C2 Domain Protein Essential for Hearing,” Trends in Neurosciences 35(11):671-680, Elsevier Applied Science Publishing, United Kingdom (Nov. 2012). [cited by applicant]
Pelletier, J., et al., “Cap-Independent Translation of Poliovims mRNA is Conferred by Sequence Elements within the 5′ Noncoding Region,” Molecular and Cellular Biology 8(3):1103-1112, American Society for Microbiology, … [cited by applicant]
Pezzoli, D., et al., “Lipid-Based Nanoparticles as Nonviral Gene Delivery Vectors,” Methods in Molecular Biology 1025:269-279, Humana Press, United States (2013). [cited by applicant]
Piccioli, P., et al., “Neuroantibodies: Ectopic Expression of a Recombinant Anti-substance P Antibody in the Central Nervous System of Transgenic Mice,” Neuron 15(2):373-384, Cell Press, United States (Aug. 1995). [cited by applicant]
Piccioli, P., et al., “Neuroantibodies: Molecular Cloning of a Monoclonal Antibody Against Substance P for Expression in the Central Nervous System,” Proceedings of the National Academy of Sciences of the United States … [cited by applicant]
Powell, S.K., et al., “Viral Expression Cassette Elements to Enhance Transgene Target Specificity and Expression in Gene Therapy,” Discovery Medicine 19(102):49-57, Discovery Medicine, United States (Jan. 2015). [cited by applicant]
Praetorius, M., et al., “Adenovector-Mediated Hair Cell Regeneration is Affected by Promoter Type,” Acta Oto-Laryngologica 130(2):215-222, Taylor & Francis, United States (Feb. 2010). [cited by applicant]
Proudfoot, N.J., et al., “Integrating mRNA Processing with Transcription,” Cell 108(4):501-512, Cell Press, United States (Feb. 2002). [cited by applicant]
Pryadkina, M., et al., “A comparison of AAV Strategies Distinguishes Overlapping Vectors for Efficient Systemic Delivery of the 6.2 kb Dysferlin Coding Sequence,” Molecular Therapy. Methods & Clinical Development 2:1500… [cited by applicant]
Reich, S.J., et al., “Efficient Trans-Splicing in the Retina Expands the Utility of Adeno-Associated Vims as a Vector for Gene Therapy,” Human Gene Therapy 14(1):37-44, M.A. Liebert, United States (Jan. 2003). [cited by applicant]
Reisinger, E., et al., “Probing the Functional Equivalence of Otoferlin and Synaptotagmin 1 in Exocytosis,” The Journal of Neuroscience 31(13):4886-4895, Society for Neuroscience, United States (Mar. 2011). [cited by applicant]
Remington's Pharmaceutical Sciences, 15th Edition, pp. 1035-1038 and 1570-1580, Osol, A., and Hoover, J.E., eds., Mack Publishing Co., United States (1975). [cited by applicant]
Ren, X., et al., “Human Artificial Chromosome Vectors Meet Stem Cells: New Prospects for Gene Delivery,” Stem Cell Reviews 2(1):43-50, Humana Press, United States (2006). [cited by applicant]
Rodriguez-Ballesteros, M., et al., “A Multicenter Study on the Prevalence and Spectrum of Mutations in the Otoferlin Gene (OTOF) in Subjects with Nonsyndromic Hearing Impairment and Auditory Neuropathy,” Human Mutation … [cited by applicant]
Rodriguez-Ballesteros, M., et al., “Auditory Neuropathy in Patients Carrying Mutations in the Otoferlin Gene (OTOF),” Human Mutation 22(6):451-456, Wiley-Liss, United States (Dec. 2003). [cited by applicant]
Rossolini, G.M., et al., “Use of Deoxyinosine-Containing Primers vs Degenerate Primers for Polymerase Chain Reaction Based on Ambiguous Sequence Information,” Molecular and Cellular Probes 8(2):91-98, Academic Press, Un… [cited by applicant]
Roux, I., et al., “Otoferlin, Defective in a Human Deafness Form, Is Essential for Exocytosis at the Auditory Ribbon Synapse,” Cell 127(2):277-289, Cell Press, United States (Oct. 2006). [cited by applicant]
Rozema, D.B., et al., “Dynamic Polyconjugates for Targeted in Vivo Delivery of siRNA to Hepatocytes,” Proceedings of the National Academy of Sciences USA 104(32):12982-12987, National Academy of Sciences, United States … [cited by applicant]
Ryan, M.D., et al., “Foot-and-Mouth Disease Vims 2A Oligopeptide Mediated Cleavage of an Artificial Polyprotein,” The EMBO Journal 13(4):928-933, Wiley Blackwell, United Kingdom (Feb. 1994). [cited by applicant]
Schek, N., et al., “Definition of the Upstream Efficiency Element of the Simian Vims 40 Late Polyadenylation Signal by Using in Vitro Analyses,” Molecular and Cellular Biology 12(12):5386-5393, American Society for Micr… [cited by applicant]
Shu, Y., et al., “Identification of Adeno-Associated Viral Vectors That Target Neonatal and Adult Mammalian Inner Ear Cell Subtypes,” Human Gene Therapy 27(9):687-699, Mary Ann Liebert, Inc., United States (Sep. 2016). [cited by applicant]
Smith, R.J.H., et al., “Sensorineural Hearing Loss in Children,” Lancet 365(9462):879-890, Elsevier, United Kingdom (Mar. 2005). [cited by applicant]
Staecker, H., et al., “Vestibular Hair Cell Regeneration and Restoration of Balance Function Induced by Math 1 Gene Transfer,” Otology & Neurotology 28(2):223-231, Lippincott Williams & Wilkins, United States (Feb. 2007… [cited by applicant]
Stein, G.S., et al., “The Osteocalcin Gene: A Model for Multiple Parameters of Skeletal-Specific Transcriptional Control,” Molecular Biology Reports 24(3):185-196, Dordrecht, Netherlands (Aug. 1997). [cited by applicant]
Stiller, M., et al., “Direct Multiplex Sequencing (DMPS)—A Novel Method for Targeted High-Throughput Sequencing of Ancient and Highly Degraded DNA,” Genome Research 19(10):1843-1848, Cold Spring Harbor Laboratory Press,… [cited by applicant]
Stone, I.M., et al. “Adeno-Associated Vims-Mediated Gene Transfer to Hair Cells and Support Cells of The Murine Cochlea,” Molecular therapy: The Journal of the American Society of Gene Therapy (6):843-848, American Soci… [cited by applicant]
Strenzke, N., et al., “Hair Cell Synaptic Dysfunction, Auditory Fatigue and Thermal Sensitivity in Otoferlin Ile515Thr Mutants,” The EMBO Journal 35(23):2519-2535, Wiley Blackwell, United Kingdom (Dec. 2016). [cited by applicant]
Su, Z.Z., et al., “Insights Into Glutamate Transport Regulation in Human Astrocytes: Cloning of the Promoter for Excitatory Amino Acid Transporter 2 (EAAT2),” Proceedings of the National Academy of Sciences of the Unite… [cited by applicant]
Suzuki, J., et al., “Cochlear Gene Therapy with Ancestral AAVin Adult Mice: Complete Transduction of Inner Hair Cells Without Cochlear Dysfunction,” Scientific Reports 7:45524, Nature Publishing Group, United Kingdom (A… [cited by applicant]
Szymanski, P., et al., “Development and Validation of a Robust and Versatile One-Plasmid Regulated Gene Expression System,” Molecular therapy: The Journal of the American Society of Gene Therapy 15(7):1340-1347, Cambrid… [cited by applicant]
Talbot, G.E., “Desmin-Regulated Lentiviral Vectors for Skeletal Muscle Gene Transfer,” Molecular therapy: The Journal of the American Society of Gene Therapy 18(3):601-608, Cell Press, United States (Mar. 2010). [cited by applicant]
Tandon, V., et al., “Microfabricated Infuse-Withdraw Micropump Component for an Integrated Inner-Ear Drug-Delivery Platform,” Biomedical Microdevices 17(2):37 Springer, United States (Apr. 2015). [cited by applicant]
Tandon, V., et al., “Microfabricated Reciprocating Micropump for Intracochlear Drug Delivery with Integrated Drug/Fluid Storage and Electronically Controlled Dosing,” Lab Chip 16(5):829-846, Royal Society of Chemistry, … [cited by applicant]
Tereshchenko, J., et al., “Pharmacologically Controlled, Discontinuous GDNF Gene Therapy Restores Motor Function in a Rat Model of Parkinson's Disease,” Neurobiol Dis 65:35-42, Elsevier, Netherlands (May 2014). [cited by applicant]
Thein, S.L., et al., “The Polyadenylation Site Mutation in the Alpha-Globin Gene Cluster,” Blood 71(2):313-319, Elsevier, United States (Feb. 1988). [cited by applicant]
Trapani, I., et al., “Effective Delivery of Large Genes to the Retina by Dual AAV Vectors,” EMBO Molecular Medicine 6(2):194-211, West Sussex: Wiley-Blackwell, United Kingdom (Feb. 2014). [cited by applicant]
Varga, R., et al., “OTOF Mutations Revealed by Genetic Analysis of Hearing Loss Families Including A Potential Temperature Sensitive Auditory Neuropathy Allele,” Journal of Medical Genetics 43(7):576-581, British Medica… [cited by applicant]
Wahl, G.M., et al., “Cosmid Vectors for Rapid Genomic Walking, Restriction Mapping, and Gene Transfer,” Proceedings of the National Academy of Sciences of the United States of America 84(8):2160-2164, National Academy o… [cited by applicant]
Wang, D.Y., et al., “Screening Mutations of OTOF Gene in Chinese Patients with Auditory Neuropathy, Including A Familial Case of Temperature-Sensitive Auditory Neuropathy,” BMC Medical Genetics 11:79, BioMed Central, Un… [cited by applicant]
Wang, J., et al., “Inhibition of the C-jun N-terminal Kinase-mediated Mitochondrial Cell Death Pathway Restores Auditory Function in Sound-exposed Animals,” Molecular Pharmacology 71(3):654-666, American Society for Pha… [cited by applicant]
Wang, Y., et al., “Ligand-Inducible and Liver-Specific Target Gene Expression in Transgenic Mice,” Nature Biotechnology 15(3):239-243, Nature America Publishing, United States (Mar. 1997). [cited by applicant]
Wang, Y., et al., “Positive and Negative Regulation of Gene Expression in Eukaryotic Cells with An Inducible Transcriptional Regulator,” Gene Therapy 4(5):432-441, Nature Publishing Group, United Kingdom (May 1997). [cited by applicant]
Wanisch, K., et al., “Integration-Deficient Lentiviral Vectors: A Slow Coming of Age,” Molecular therapy: the journal of the American Society of Gene Therapy 17(8):1316-1332, Cell Press, United States (Aug. 2009). [cited by applicant]
Woychik, RP., et al., “Requirement for the 3′ Flanking Region of the Bovine Growth Hormone Gene for Accurate Polyadenylylation,” Proceedings of the National Academy of Sciences of the United States of America 81(13):394… [cited by applicant]
Xiao, W., et al., “Gene Therapy Vectors Based on Adeno-Associated Vims Type 1,” Journal of Virology 73(5):3994-4003, American Society for Microbiology, United States (1999). [cited by applicant]
Xu, L., et al., “Cmv-Beta-Actin Promoter Directs Higher Expression From an Adeno-Associated Viral Vector in the Liver Than the Cytomegalovims or Elongation Factor 1 Alpha Promoter and Results in Therapeutic Levels of Hu… [cited by applicant]
Yan, Z., et al., “Trans-Splicing Vectors Expand the Utility of Adeno-Associated Vims for Gene Therapy,” Proceedings of the National Academy of Sciences of the United States of America 97(12):6716-6721, National Academy … [cited by applicant]
Yasunaga, S., et al., “A Mutation in OTOF, Encoding Otoferlin, aFER-1-like Protein, Causes DFNB9, a Nonsyndromic Form of Deafness,” Nature Genetics 21(4):363-369, Nature Pub. Co., United States (Apr. 1999). [cited by applicant]
Yasunaga, S., et al., “OTOF Encodes Multiple Long and Short Isoforms: Genetic Evidence That the Long Ones Underlie Recessive Deafness DFNB9,” American Journal of Human Genetics 67(3):591-600, Cell Press, United States (… [cited by applicant]
Yildirim-Baylan, M., et al., “Evidence for Genotype-Phenotype Correlation for OTOF Mutations,” International Journal of Pediatric Otorhinolaryngology 78(6):950-953, Elsevier, Netherlands (Jun. 2014). [cited by applicant]
Zhang, Q.J, et al., “High Frequency ofOTOF Mutations in Chinese Infants With Congenital Auditory Neuropathy Spectrum Disorder,” Clinical Genetics 90(3): 238-246, Wiley Online Library, Demnark (2016). [cited by applicant]
Wu, Chen-Chi, et al. “Identifying children with poor cochlear implantation outcomes using massively parallel sequencing,” Medicine 94(27): e1073. Wolter Kluwer Health, United States (2015). [cited by applicant]
Zhang, Wenjuan, et al. “Cochlear gene therapy for sensorineural hearing loss: current status and major remaining hurdles for translational success.” Frontiers in molecular neuroscience 11: 221, Frontiers Media, United S… [cited by applicant]
Lee, Min Yong, and Yong-Ho Park. “Potential of gene and cell therapy for inner ear hair cells.” BioMed Research International 2018: 8137614, 11 pages, Hindawi, United Kingdom (2018). [cited by applicant]
Herdewijn, P., ed., “Oligonucleotide synthesis: methods and applications,” [cited by applicant]
O'Donnell, P. B., and Mcginity, J. W., “Preparation of microspheres by the solvent evaporation technique,” Adv Drug Delivery Rev 28(1):25-42, Elsevier, Netherlands (1997). [cited by applicant]
Poulin, K. L., et al., “Use of Cre/loxP recombination to swap cell binding motifs on the adenoviral capsid protein IX,” [cited by applicant]
Vilette, D., et al., “Establishment of astrocyte cell lines from sheep genetically susceptible to scrapie,” [cited by applicant]
GenBank, “Mus musculus otoferlin (Otof), transcript variant 1, mRNA,” Accession No. NM_001100395.1, accessed at https://www.ncbi.nlm.nih.gov/nuccore/154240701?sat=46&satkey=70798641, accessed on Sep. 16, 2021, 4 pages. [cited by applicant]
Ahmad, S. et al., Restoration of connexin26 protein level in the cochlea completely rescues hearing in a mouse model of human connexin30-linked deafness, Proc. Natl. Acad. Sci., 104(4):1337-1341 (2007). [cited by applicant]
International Search Report for PCT/US17/048257 (Compositions and Methods for Treating Non-Age-Associated Hearing Impairment in a Human Subject, filed Aug. 23, 2017), received by ISA/KR, 4 pages (Dec. 27, 2017). [cited by applicant]
International Search Report for PCT/US2019/019268 (Compositions and Methods for Treating Non-Age-Associated Hearing Impairment in a Human Subject, filed Feb. 22, 2019), received from ISA/KR, 6 pages (Jun. 13, 2019). [cited by applicant]
Allocca, M., et al., “Serotype-dependent packaging of large genes in adeno-associated viral vectors results in effective gene delivery in mice,” The Journal of Clinical Investigation 118(50):1955-1964, 2008. [cited by applicant]
Liu, M., et al., “Adeno-Associated Vims-Mediated Microdystrophin Expression Protects Young mdx Muscle from Contraction-Induced Injury,” Molecular Therapy 11(2):245-256, The American Society of Gene Therapy, United State… [cited by applicant]
Mcclements, M.E. and Maclaren, R.E., “Adeno-associated Vims (AAV) Dual Vector Strategies for Gene Therapy Encoding Large Transgenes,” Yale Journal of Biology And Medicine 09:611-623, (2017). [cited by applicant]
Chamberlain, K., et al., “Expressing Transgenes That Exceed the Packaging Capacity of Adeno-Associated Vims Capsids,” Human Gene Therapy Methods 27(1):1-12, Mary Ann Liebert, Inc., United States (2016). [cited by applicant]
Holt, J., et al., “Split Otoferlins Reunited,” EMBO Mol Med 11:1-3 (2018). [cited by applicant]
Non-Final Office Action, mailed Dec. 14, 2021, in U.S. Appl. No. 17/378,606, filed Jul. 16, 2021. [cited by applicant]
Non-Final Office Action, mailed Jun. 14, 2022, in U.S. Appl. No. 17/378,606, filed Jul. 16, 2021. [cited by applicant]
Notice of Allowance, mailed Aug. 3, 2022, in U.S. Appl. No. 17/378,606, filed Jul. 16, 2021. [cited by applicant]
Rankovic, V., et al., “Overloaded Adeno-Associated Vims as a Novel Gene Therapeutic Tool for Otoferlin-Related Deafness”, Frontiers in Molecular Neuroscience 13:600051, Frontiers Media, United States (2021). [cited by applicant]
Qiu, Y., et al., “Auditory Neuropathy Spectrum Disorder due to Two Novel Compound Heterozygous OTOF Mutations in Two Chinese Families”, Neural Plasticity, 2019:9765276, Hindawi, United Kingdom (2019). [cited by applicant]
Iyama, T., et al., “DNA repair mechanisms in dividing and non-dividing cells”, DNA Repair (Arnst), 12(8): 620-636, Elsevier, Netherlands (2013). [cited by applicant]
Xia, L., et al., “Local gene transfection in the cochlea (Review)”, Molecular Medicine Reports, 8(1):3-10, Spandidos Publications, Greece (2013). [cited by applicant]
Sacheli, R., et al.,“Gene Transfer in Inner Ear Cells: A Challenging Race,” Gene Ther. 20:237-247, Nature Publishing Group, United Kingdom (2013). [cited by applicant]
Chen. S.J., et al., “Enhancing the Utility of Adeno-Associated Virus Gene Expression through Inducible Tissue-specific Expression”, Human Gene Therapy Methods, 24:170-78, Mary Ann Liebert, Inc, United States (Aug. 2013). [cited by applicant]
Devarajan, et al., “A Review of Gene Delivery and Stem Cell Based Therapies for Regenerating Inner Ear Hair Cells,” Journal of Functional Biomaterials 2:249-270, Multidisciplinary Publishing Group, Switzerland (2011). [cited by applicant]
Nakagawa, et al., “Diversity of Preferred Nucleotide Sequences around the Translation Initiation Codon in Eukaryote Genomes,” Nucleic Acids Research 36(3):861-871, Oxford University Press (2007). [cited by applicant]
Tiffany and Kay, “Expanded Packing Capacity of AAV by Lumen Charge Alteration,” Molecular Therapy 24 (Suppl. 1): S99-100, Cell Press, United States (May 2016). [cited by applicant]
Mcalister and Owens, “Substitution of Adeno-Associated Virus Rep Protein Binding and Nicking Sites with Human Chromosome 19 Sequence,” Virol. J. 7 (Article 218): 1-11, BioMed Central, United Kingdom (2010). [cited by applicant]
Qin, et al., “Systematic Comparison of Constitutive Promoters and the Doxycycline-Inducible Promoter,” PLoS One 5(5): e10611, PLOS, United States (2010). [cited by applicant]