ADENO-ASSOCIATED VIRUS-MEDIATED OTOF GENE THERAPY: ADVANCES, CHALLENGES, AND FUTURE DIRECTIONS
Abstract
Hearing loss is a prevalent sensory disorder, and gene therapy has emerged as a promising therapeutic strategy, particularly through adeno-associated virus (AAV)-mediated delivery of the OT OF gene. This systematic literature review examines the current state of AAV-based OTOF gene therapy, with a focus on recent advancements, existing challenges, and future research directions. We synthesize findings from published studies to address key questions regarding the efficacy of different AAV vector platforms, the influence of immune responses on therapeutic outcomes, and the technical considerations associated with inner ear gene delivery. In addition, the review explores broader applications of AAV-mediated gene therapy across other genetic disorders, providing valuable context for its potential use in audiological treatments. Through a comprehensive analysis of the literature, we identify critical knowledge gaps, including the relationship between gene-editing approaches and hearing restoration, as well as the neural circuit mechanisms that contribute to auditory function recovery. Current evidence demonstrates encouraging preclinical outcomes, particularly in animal models of otoferlin-related hearing loss; however, significant challenges remain. These include immune-mediated barriers, limitations in vector capacity and transduction efficiency, and the need for optimized delivery strategies. The review concludes with recommendations for future research, emphasizing the development of improved vector systems, refinement of intracochlear delivery techniques, comprehensive long-term safety evaluations, and translational studies to facilitate the progression from preclinical investigations to clinical application. Overall, this review provides a comprehensive foundation for researchers and clinicians seeking to advance effective gene therapies for hereditary hearing loss.
Keywords:
Otoferlin, Intracochlear Delivery, Auditory Synaptopathy, DFNB9, Viral Vector Optimization, Adeno-Associated Virus (AAV), Gene Therapy
References
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2. Zadro C, Ciorba A, Fabris A, Morgutti M, Trevisi P, Gasparini P, Martini A. Five new OTOF gene mutations and auditory neuropathy. International journal of pediatric otorhinolaryngology. 2010 May 1;74(5):494-8.
3. Zhang L, Tan F, Qi J, Lu Y, Wang X, Yang X, Chen X, Zhang X, Fan J, Zhou Y, Peng L. AAV‐mediated gene therapy for hereditary deafness: progress and perspectives. Advanced Science. 2024 Dec;11(47):2402166.
4. Berns KI. The unusual properties of the AAV inverted terminal repeat. Human gene therapy. 2020 May;31(9-10):518-23.
5. Qi J, Zhang L, Tan F, Zhang Y, Zhou Y, Zhang Z, Wang H, Yu C, Jiang L, Liu J, Chen T. Preclinical efficacy and safety evaluation of AAV‐OTOF in DFNB9 mouse model and nonhuman primate. Advanced Science. 2024 Jan;11(3):2306201.
6. Liu SS, Yang R. Inner ear drug delivery for sensorineural hearing loss: current challenges and opportunities. Frontiers in Neuroscience. 2022 May 24;16:867453.
7. Zincarelli C, Soltys S, Rengo G, Rabinowitz JE. Analysis of AAV serotypes 1–9 mediated gene expression and tropism in mice after systemic injection. Molecular therapy. 2008 Jun 1;16(6):1073-80.
8. Mingozzi F, A High K. Immune responses to AAV in clinical trials. Current gene therapy. 2011 Aug 1;11(4):321-30.
9. Tao Y, Chu C, Cheng Z, Sun Y, Chen Y, Zhang H, Bao S, Yang B, Feng B, Huang X, Lu Y. In vivo-directed evolution identifies AAV-WM04 as a next-generation vector for potent and durable hearing restoration in DFNB9. bioRxiv. 2026 Mar 11:2026-03.
10. Hu SW, Ye C, Geng G, Zeng Y, Bao Y, Zhang S, Cui C, Zhang Y, Mu D, Wang D, Fan X. Combination of engineered cell type-specific promoters and a high-efficiency AAV capsid restores hearing in adult DFNB1 mice model with demonstrated safety in nonhuman primate. bioRxiv. 2026 Apr 18:2026-04.
11. Akil O, Dyka F, Calvet C, Emptoz A, Lahlou G, Nouaille S, Boutet de Monvel J, Hardelin JP, Hauswirth WW, Avan P, Petit C. Dual AAV-mediated gene therapy restores hearing in a DFNB9 mouse model. Proceedings of the National Academy of Sciences. 2019 Mar 5;116(10):4496-501.
12. Strenzke N. A cure for deafness?. Med. 2024 Apr 12;5(4):285-7.
13. Ivanchenko MV, Corey DP. Finding a window for gene therapy for hereditary deafness. Proceedings of the National Academy of Sciences. 2023 Sep 26;120(39):e2311864120.
14. Qi J, Xu L, Zeng FG, Chai R. OTOF-related gene therapy: a new way but a long road ahead. The Lancet. 2025 Mar 8;405(10481):777-9.
15. Tertrais M, Bouleau Y, Emptoz A, Belleudy S, Sutton RB, Petit C, Safieddine S, Dulon D. Viral transfer of mini-otoferlins partially restores the fast component of exocytosis and uncovers ultrafast endocytosis in auditory hair cells of otoferlin knock-out mice. Journal of Neuroscience. 2019 May 1;39(18):3394-411.
16. Tsai YH, Wu PY, Chuang YC, Huang CY, Takeda H, Hibino H, Wu CC, Cheng YF. Postnatal Slc26a4 gene therapy improves hearing and structural integrity in a hereditary hearing loss model. The Journal of Clinical Investigation. 2026 Apr 15;136(8).
17. Das S, Manor U. Gene therapy for hearing loss: challenges and the promise of cellular plasticity and epigenetic modulation. Frontiers in Neurology. 2024 Dec 11;15:1511938.
18. Zhang B, Hu Y, Du H, Han S, Ren L, Cheng H, Wang Y, Gao X, Zheng S, Cui Q, Tian L. Tissue engineering strategies for spiral ganglion neuron protection and regeneration. Journal of Nanobiotechnology. 2024 Jul 31;22(1):458.
19. Ronzitti G, Gross DA, Mingozzi F. Human immune responses to adeno-associated virus (AAV) vectors. Frontiers in Immunology. 2020 Apr 17;11:670.
20. Verdera HC, Kuranda K, Mingozzi F. AAV vector immunogenicity in humans: a long journey to successful gene transfer. Molecular Therapy. 2020 Mar 4;28(3):723-46.
21. Bessis N, GarciaCozar FJ, Boissier MC. Immune responses to gene therapy vectors: influence on vector function and effector mechanisms. Gene therapy. 2004 Oct;11(1):S10-7.
22. Leborgne C, Barbon E, Alexander JM, Hanby H, Delignat S, Cohen DM, Collaud F, Muraleetharan S, Lupo D, Silverberg J, Huang K. IgG-cleaving endopeptidase enables in vivo gene therapy in the presence of anti-AAV neutralizing antibodies. Nature medicine. 2020 Jul;26(7):1096-101.
23. Burger C, Gorbatyuk OS, Velardo MJ, Peden CS, Williams P, Zolotukhin S, Reier PJ, Mandel RJ, Muzyczka N. Recombinant AAV viral vectors pseudotyped with viral capsids from serotypes 1, 2, and 5 display differential efficiency and cell tropism after delivery to different regions of the central nervous system. Molecular Therapy. 2004 Aug 1;10(2):302-17.
24. Tervo DG, Hwang BY, Viswanathan S, Gaj T, Lavzin M, Ritola KD, Lindo S, Michael S, Kuleshova E, Ojala D, Huang CC. A designer AAV variant permits efficient retrograde access to projection neurons. Neuron. 2016 Oct 19;92(2):372-82.
25. Zingg B, Chou XL, Zhang ZG, Mesik L, Liang F, Tao HW, Zhang LI. AAV-mediated anterograde transsynaptic tagging: mapping corticocollicular input-defined neural pathways for defense behaviors. Neuron. 2017 Jan 4;93(1):33-47.
26. Suarez-Amaran L, Song L, Tretiakova AP, Mikhail SA, Samulski RJ. AAV vector development, back to the future. Molecular Therapy. 2025 May 7;33(5):1903-36.
27. Witteveen I, Balmer T. Comparative analysis of six adeno-associated viral vector serotypes in mouse inferior colliculus and cerebellum. Eneuro. 2024 Nov 1;11(11).
28. Petrs-Silva H, Dinculescu A, Li Q, Deng WT, Pang JJ, Min SH, Chiodo V, Neeley AW, Govindasamy L, Bennett A, Agbandje-McKenna M. Novel properties of tyrosine-mutant AAV2 vectors in the mouse retina. Molecular therapy. 2011 Feb 1;19(2):293-301.
29. Choi VW, McCarty DM, Samulski RJ. AAV hybrid serotypes: improved vectors for gene delivery. Current gene therapy. 2005 Jun 1;5(3):299-310.
30. Nakai H, Fuess S, Storm TA, Muramatsu SI, Nara Y, Kay MA. Unrestricted hepatocyte transduction with adeno-associated virus serotype 8 vectors in mice. Journal of virology. 2005 Jan 1;79(1):214-24.
31. Zhang H, Yang B, Mu X, Ahmed SS, Su Q, He R, Wang H, Mueller C, Sena-Esteves M, Brown R, Xu Z. Several rAAV vectors efficiently cross the blood–brain barrier and transduce neurons and astrocytes in the neonatal mouse central nervous system. Molecular therapy. 2011 Aug 1;19(8):1440-8.
32. Kaneda Y, Nakajima T, Nishikawa T, Yamamoto S, Ikegami H, Suzuki N, Nakamura H, Morishita R, Kotani H. Hemagglutinating virus of Japan (HVJ) envelope vector as a versatile gene delivery system. Molecular Therapy. 2002 Aug 1;6(2):219-26.
33. Schnepp BC, Clark KR, Klemanski DL, Pacak CA, Johnson PR. Genetic fate of recombinant adeno-associated virus vector genomes in muscle. Journal of virology. 2003 Mar 15;77(6):3495-504.
34. Zhou Y, Zhang C, Xiao W, Herzog RW, Han R. Systemic delivery of full-length dystrophin in Duchenne muscular dystrophy mice. Nature Communications. 2024 Jul 21;15(1):6141.
35. Bowles DE, McPhee SW, Li C, Gray SJ, Samulski JJ, Camp AS, Li J, Wang B, Monahan PE, Rabinowitz JE, Grieger JC. Phase 1 gene therapy for Duchenne muscular dystrophy using a translational optimized AAV vector. Molecular Therapy. 2012 Feb 1;20(2):443-55.
36. Mendell JR, Sahenk Z, Malik V, Gomez AM, Flanigan KM, Lowes LP, Alfano LN, Berry K, Meadows E, Lewis S, Braun L. A phase 1/2a follistatin gene therapy trial for becker muscular dystrophy. Molecular Therapy. 2015 Jan 1;23(1):192-201.
37. Acland GM, Aguirre GD, Bennett J, Aleman TS, Cideciyan AV, Bennicelli J, Dejneka NS, Pearce-Kelling SE, Maguire AM, Palczewski K, Hauswirth WW. Long-term restoration of rod and cone vision by single dose rAAV-mediated gene transfer to the retina in a canine model of childhood blindness. Molecular Therapy. 2005 Dec 1;12(6):1072-82.
38. Mauriac SA, Lee J, Zhang J, Jin J, Nist-Lund C, Martin CT, Von Muhlenbrock CR, O’Malley S, Chaves MG, Madison MA, Foster K. AAV-mediated exon skipping therapy for Usher syndrome, type 2A. Molecular Therapy. 2026 Jan 7;34(1):179-202.
39. Pichavant C, Aartsma-Rus A, Clemens PR, Davies KE, Dickson G, Takeda SI, Wilton SD, Wolff JA, Wooddell CI, Xiao X, Tremblay JP. Current status of pharmaceutical and genetic therapeutic approaches to treat DMD. Molecular Therapy. 2011 May 1;19(5):830-40.
40. Majowicz A, Salas D, Zabaleta N, Rodríguez-Garcia E, González-Aseguinolaza G, Petry H, Ferreira V. Successful repeated hepatic gene delivery in mice and non-human primates achieved by sequential administration of AAV5ch and AAV1. Molecular Therapy. 2017 Aug 2;25(8):1831-42.
41. Johnson PR, Schnepp BC, Zhang J, Connell MJ, Greene SM, Yuste E, Desrosiers RC, Reed Clark K. Vector-mediated gene transfer engenders long-lived neutralizing activity and protection against SIV infection in monkeys. Nature medicine. 2009 Aug;15(8):901-6.
42. Yáñez-Muñoz RJ, Balaggan KS, MacNeil A, Howe SJ, Schmidt M, Smith AJ, Buch P, MacLaren RE, Anderson PN, Barker SE, Duran Y. Effective gene therapy with nonintegrating lentiviral vectors. Nature medicine. 2006 Mar 1;12(3):348-53.
43. Sago CD, Lokugamage MP, Paunovska K, Vanover DA, Monaco CM, Shah NN, Gamboa Castro M, Anderson SE, Rudoltz TG, Lando GN, Munnilal Tiwari P. High-throughput in vivo screen of functional mRNA delivery identifies nanoparticles for endothelial cell gene editing. Proceedings of the National Academy of Sciences. 2018 Oct 16;115(42):E9944-52.
44. Bellettato CM, Scarpa M. Possible strategies to cross the blood–brain barrier. Italian journal of pediatrics. 2018 Nov 16;44(Suppl 2):131.
45. Khateeb K, Griggs DJ, Sabes PN, Yazdan-Shahmorad A. Convection enhanced delivery of optogenetic adeno-associated viral vector to the cortex of rhesus macaque under guidance of online MRI images. JoVE (Journal of Visualized Experiments). 2019 May 23(147):e59232.
46. Iranfar S, Cornille M, Roldan MS, Plion B, Lecomte MJ, Safieddine S, Lahlou G. Cell tropism of adeno-associated viruses within the mouse inner ear in vivo: from embryonic to adult stages. Scientific Reports. 2025 Apr 18;15(1):13479.
47. Gu X, Wang D, Xu Z, Wang J, Guo L, Chai R, Li G, Shu Y, Li H. Prevention of acquired sensorineural hearing loss in mice by in vivo Htra2 gene editing. Genome biology. 2021 Mar 22;22(1):86.
48. Crispo M, Mulet AP, Tesson L, Barrera N, Cuadro F, dos Santos-Neto PC, Nguyen TH, Créneguy A, Brusselle L, Anegon I, Menchaca A. Efficient generation of myostatin knock-out sheep using CRISPR/Cas9 technology and microinjection into zygotes. PloS one. 2015 Aug 25;10(8):e0136690.
49. Znamenskiy P, Zador AM. Corticostriatal neurons in auditory cortex drive decisions during auditory discrimination. Nature. 2013 May 23;497(7450):482-5.
50. Kim EJ, Juavinett AL, Kyubwa EM, Jacobs MW, Callaway EM. Three types of cortical layer 5 neurons that differ in brain-wide connectivity and function. Neuron. 2015 Dec 16;88(6):1253-67.
51. Smith ML, Asada N, Malenka RC. Anterior cingulate inputs to nucleus accumbens control the social transfer of pain and analgesia. Science. 2021 Jan 8;371(6525):153-9.
52. Cui G, Jun SB, Jin X, Pham MD, Vogel SS, Lovinger DM, Costa RM. Concurrent activation of striatal direct and indirect pathways during action initiation. Nature. 2013 Feb 14;494(7436):238-42.
53. Leinweber M, Ward DR, Sobczak JM, Attinger A, Keller GB. A sensorimotor circuit in mouse cortex for visual flow predictions. Neuron. 2017 Sep 13;95(6):1420-32.
54. Shink E, Bevan MD, Bolam JP, Smith Y. The subthalamic nucleus and the external pallidum: two tightly interconnected structures that control the output of the basal ganglia in the monkey. Neuroscience. 1996 Jul 1;73(2):335-57.
55. Threlfell S, Lalic T, Platt NJ, Jennings KA, Deisseroth K, Cragg SJ. Striatal dopamine release is triggered by synchronized activity in cholinergic interneurons. Neuron. 2012 Jul 12;75(1):58-64.
56. Xu W, Südhof TC. A neural circuit for memory specificity and generalization. Science. 2013 Mar 15;339(6125):1290-5.
2. Zadro C, Ciorba A, Fabris A, Morgutti M, Trevisi P, Gasparini P, Martini A. Five new OTOF gene mutations and auditory neuropathy. International journal of pediatric otorhinolaryngology. 2010 May 1;74(5):494-8.
3. Zhang L, Tan F, Qi J, Lu Y, Wang X, Yang X, Chen X, Zhang X, Fan J, Zhou Y, Peng L. AAV‐mediated gene therapy for hereditary deafness: progress and perspectives. Advanced Science. 2024 Dec;11(47):2402166.
4. Berns KI. The unusual properties of the AAV inverted terminal repeat. Human gene therapy. 2020 May;31(9-10):518-23.
5. Qi J, Zhang L, Tan F, Zhang Y, Zhou Y, Zhang Z, Wang H, Yu C, Jiang L, Liu J, Chen T. Preclinical efficacy and safety evaluation of AAV‐OTOF in DFNB9 mouse model and nonhuman primate. Advanced Science. 2024 Jan;11(3):2306201.
6. Liu SS, Yang R. Inner ear drug delivery for sensorineural hearing loss: current challenges and opportunities. Frontiers in Neuroscience. 2022 May 24;16:867453.
7. Zincarelli C, Soltys S, Rengo G, Rabinowitz JE. Analysis of AAV serotypes 1–9 mediated gene expression and tropism in mice after systemic injection. Molecular therapy. 2008 Jun 1;16(6):1073-80.
8. Mingozzi F, A High K. Immune responses to AAV in clinical trials. Current gene therapy. 2011 Aug 1;11(4):321-30.
9. Tao Y, Chu C, Cheng Z, Sun Y, Chen Y, Zhang H, Bao S, Yang B, Feng B, Huang X, Lu Y. In vivo-directed evolution identifies AAV-WM04 as a next-generation vector for potent and durable hearing restoration in DFNB9. bioRxiv. 2026 Mar 11:2026-03.
10. Hu SW, Ye C, Geng G, Zeng Y, Bao Y, Zhang S, Cui C, Zhang Y, Mu D, Wang D, Fan X. Combination of engineered cell type-specific promoters and a high-efficiency AAV capsid restores hearing in adult DFNB1 mice model with demonstrated safety in nonhuman primate. bioRxiv. 2026 Apr 18:2026-04.
11. Akil O, Dyka F, Calvet C, Emptoz A, Lahlou G, Nouaille S, Boutet de Monvel J, Hardelin JP, Hauswirth WW, Avan P, Petit C. Dual AAV-mediated gene therapy restores hearing in a DFNB9 mouse model. Proceedings of the National Academy of Sciences. 2019 Mar 5;116(10):4496-501.
12. Strenzke N. A cure for deafness?. Med. 2024 Apr 12;5(4):285-7.
13. Ivanchenko MV, Corey DP. Finding a window for gene therapy for hereditary deafness. Proceedings of the National Academy of Sciences. 2023 Sep 26;120(39):e2311864120.
14. Qi J, Xu L, Zeng FG, Chai R. OTOF-related gene therapy: a new way but a long road ahead. The Lancet. 2025 Mar 8;405(10481):777-9.
15. Tertrais M, Bouleau Y, Emptoz A, Belleudy S, Sutton RB, Petit C, Safieddine S, Dulon D. Viral transfer of mini-otoferlins partially restores the fast component of exocytosis and uncovers ultrafast endocytosis in auditory hair cells of otoferlin knock-out mice. Journal of Neuroscience. 2019 May 1;39(18):3394-411.
16. Tsai YH, Wu PY, Chuang YC, Huang CY, Takeda H, Hibino H, Wu CC, Cheng YF. Postnatal Slc26a4 gene therapy improves hearing and structural integrity in a hereditary hearing loss model. The Journal of Clinical Investigation. 2026 Apr 15;136(8).
17. Das S, Manor U. Gene therapy for hearing loss: challenges and the promise of cellular plasticity and epigenetic modulation. Frontiers in Neurology. 2024 Dec 11;15:1511938.
18. Zhang B, Hu Y, Du H, Han S, Ren L, Cheng H, Wang Y, Gao X, Zheng S, Cui Q, Tian L. Tissue engineering strategies for spiral ganglion neuron protection and regeneration. Journal of Nanobiotechnology. 2024 Jul 31;22(1):458.
19. Ronzitti G, Gross DA, Mingozzi F. Human immune responses to adeno-associated virus (AAV) vectors. Frontiers in Immunology. 2020 Apr 17;11:670.
20. Verdera HC, Kuranda K, Mingozzi F. AAV vector immunogenicity in humans: a long journey to successful gene transfer. Molecular Therapy. 2020 Mar 4;28(3):723-46.
21. Bessis N, GarciaCozar FJ, Boissier MC. Immune responses to gene therapy vectors: influence on vector function and effector mechanisms. Gene therapy. 2004 Oct;11(1):S10-7.
22. Leborgne C, Barbon E, Alexander JM, Hanby H, Delignat S, Cohen DM, Collaud F, Muraleetharan S, Lupo D, Silverberg J, Huang K. IgG-cleaving endopeptidase enables in vivo gene therapy in the presence of anti-AAV neutralizing antibodies. Nature medicine. 2020 Jul;26(7):1096-101.
23. Burger C, Gorbatyuk OS, Velardo MJ, Peden CS, Williams P, Zolotukhin S, Reier PJ, Mandel RJ, Muzyczka N. Recombinant AAV viral vectors pseudotyped with viral capsids from serotypes 1, 2, and 5 display differential efficiency and cell tropism after delivery to different regions of the central nervous system. Molecular Therapy. 2004 Aug 1;10(2):302-17.
24. Tervo DG, Hwang BY, Viswanathan S, Gaj T, Lavzin M, Ritola KD, Lindo S, Michael S, Kuleshova E, Ojala D, Huang CC. A designer AAV variant permits efficient retrograde access to projection neurons. Neuron. 2016 Oct 19;92(2):372-82.
25. Zingg B, Chou XL, Zhang ZG, Mesik L, Liang F, Tao HW, Zhang LI. AAV-mediated anterograde transsynaptic tagging: mapping corticocollicular input-defined neural pathways for defense behaviors. Neuron. 2017 Jan 4;93(1):33-47.
26. Suarez-Amaran L, Song L, Tretiakova AP, Mikhail SA, Samulski RJ. AAV vector development, back to the future. Molecular Therapy. 2025 May 7;33(5):1903-36.
27. Witteveen I, Balmer T. Comparative analysis of six adeno-associated viral vector serotypes in mouse inferior colliculus and cerebellum. Eneuro. 2024 Nov 1;11(11).
28. Petrs-Silva H, Dinculescu A, Li Q, Deng WT, Pang JJ, Min SH, Chiodo V, Neeley AW, Govindasamy L, Bennett A, Agbandje-McKenna M. Novel properties of tyrosine-mutant AAV2 vectors in the mouse retina. Molecular therapy. 2011 Feb 1;19(2):293-301.
29. Choi VW, McCarty DM, Samulski RJ. AAV hybrid serotypes: improved vectors for gene delivery. Current gene therapy. 2005 Jun 1;5(3):299-310.
30. Nakai H, Fuess S, Storm TA, Muramatsu SI, Nara Y, Kay MA. Unrestricted hepatocyte transduction with adeno-associated virus serotype 8 vectors in mice. Journal of virology. 2005 Jan 1;79(1):214-24.
31. Zhang H, Yang B, Mu X, Ahmed SS, Su Q, He R, Wang H, Mueller C, Sena-Esteves M, Brown R, Xu Z. Several rAAV vectors efficiently cross the blood–brain barrier and transduce neurons and astrocytes in the neonatal mouse central nervous system. Molecular therapy. 2011 Aug 1;19(8):1440-8.
32. Kaneda Y, Nakajima T, Nishikawa T, Yamamoto S, Ikegami H, Suzuki N, Nakamura H, Morishita R, Kotani H. Hemagglutinating virus of Japan (HVJ) envelope vector as a versatile gene delivery system. Molecular Therapy. 2002 Aug 1;6(2):219-26.
33. Schnepp BC, Clark KR, Klemanski DL, Pacak CA, Johnson PR. Genetic fate of recombinant adeno-associated virus vector genomes in muscle. Journal of virology. 2003 Mar 15;77(6):3495-504.
34. Zhou Y, Zhang C, Xiao W, Herzog RW, Han R. Systemic delivery of full-length dystrophin in Duchenne muscular dystrophy mice. Nature Communications. 2024 Jul 21;15(1):6141.
35. Bowles DE, McPhee SW, Li C, Gray SJ, Samulski JJ, Camp AS, Li J, Wang B, Monahan PE, Rabinowitz JE, Grieger JC. Phase 1 gene therapy for Duchenne muscular dystrophy using a translational optimized AAV vector. Molecular Therapy. 2012 Feb 1;20(2):443-55.
36. Mendell JR, Sahenk Z, Malik V, Gomez AM, Flanigan KM, Lowes LP, Alfano LN, Berry K, Meadows E, Lewis S, Braun L. A phase 1/2a follistatin gene therapy trial for becker muscular dystrophy. Molecular Therapy. 2015 Jan 1;23(1):192-201.
37. Acland GM, Aguirre GD, Bennett J, Aleman TS, Cideciyan AV, Bennicelli J, Dejneka NS, Pearce-Kelling SE, Maguire AM, Palczewski K, Hauswirth WW. Long-term restoration of rod and cone vision by single dose rAAV-mediated gene transfer to the retina in a canine model of childhood blindness. Molecular Therapy. 2005 Dec 1;12(6):1072-82.
38. Mauriac SA, Lee J, Zhang J, Jin J, Nist-Lund C, Martin CT, Von Muhlenbrock CR, O’Malley S, Chaves MG, Madison MA, Foster K. AAV-mediated exon skipping therapy for Usher syndrome, type 2A. Molecular Therapy. 2026 Jan 7;34(1):179-202.
39. Pichavant C, Aartsma-Rus A, Clemens PR, Davies KE, Dickson G, Takeda SI, Wilton SD, Wolff JA, Wooddell CI, Xiao X, Tremblay JP. Current status of pharmaceutical and genetic therapeutic approaches to treat DMD. Molecular Therapy. 2011 May 1;19(5):830-40.
40. Majowicz A, Salas D, Zabaleta N, Rodríguez-Garcia E, González-Aseguinolaza G, Petry H, Ferreira V. Successful repeated hepatic gene delivery in mice and non-human primates achieved by sequential administration of AAV5ch and AAV1. Molecular Therapy. 2017 Aug 2;25(8):1831-42.
41. Johnson PR, Schnepp BC, Zhang J, Connell MJ, Greene SM, Yuste E, Desrosiers RC, Reed Clark K. Vector-mediated gene transfer engenders long-lived neutralizing activity and protection against SIV infection in monkeys. Nature medicine. 2009 Aug;15(8):901-6.
42. Yáñez-Muñoz RJ, Balaggan KS, MacNeil A, Howe SJ, Schmidt M, Smith AJ, Buch P, MacLaren RE, Anderson PN, Barker SE, Duran Y. Effective gene therapy with nonintegrating lentiviral vectors. Nature medicine. 2006 Mar 1;12(3):348-53.
43. Sago CD, Lokugamage MP, Paunovska K, Vanover DA, Monaco CM, Shah NN, Gamboa Castro M, Anderson SE, Rudoltz TG, Lando GN, Munnilal Tiwari P. High-throughput in vivo screen of functional mRNA delivery identifies nanoparticles for endothelial cell gene editing. Proceedings of the National Academy of Sciences. 2018 Oct 16;115(42):E9944-52.
44. Bellettato CM, Scarpa M. Possible strategies to cross the blood–brain barrier. Italian journal of pediatrics. 2018 Nov 16;44(Suppl 2):131.
45. Khateeb K, Griggs DJ, Sabes PN, Yazdan-Shahmorad A. Convection enhanced delivery of optogenetic adeno-associated viral vector to the cortex of rhesus macaque under guidance of online MRI images. JoVE (Journal of Visualized Experiments). 2019 May 23(147):e59232.
46. Iranfar S, Cornille M, Roldan MS, Plion B, Lecomte MJ, Safieddine S, Lahlou G. Cell tropism of adeno-associated viruses within the mouse inner ear in vivo: from embryonic to adult stages. Scientific Reports. 2025 Apr 18;15(1):13479.
47. Gu X, Wang D, Xu Z, Wang J, Guo L, Chai R, Li G, Shu Y, Li H. Prevention of acquired sensorineural hearing loss in mice by in vivo Htra2 gene editing. Genome biology. 2021 Mar 22;22(1):86.
48. Crispo M, Mulet AP, Tesson L, Barrera N, Cuadro F, dos Santos-Neto PC, Nguyen TH, Créneguy A, Brusselle L, Anegon I, Menchaca A. Efficient generation of myostatin knock-out sheep using CRISPR/Cas9 technology and microinjection into zygotes. PloS one. 2015 Aug 25;10(8):e0136690.
49. Znamenskiy P, Zador AM. Corticostriatal neurons in auditory cortex drive decisions during auditory discrimination. Nature. 2013 May 23;497(7450):482-5.
50. Kim EJ, Juavinett AL, Kyubwa EM, Jacobs MW, Callaway EM. Three types of cortical layer 5 neurons that differ in brain-wide connectivity and function. Neuron. 2015 Dec 16;88(6):1253-67.
51. Smith ML, Asada N, Malenka RC. Anterior cingulate inputs to nucleus accumbens control the social transfer of pain and analgesia. Science. 2021 Jan 8;371(6525):153-9.
52. Cui G, Jun SB, Jin X, Pham MD, Vogel SS, Lovinger DM, Costa RM. Concurrent activation of striatal direct and indirect pathways during action initiation. Nature. 2013 Feb 14;494(7436):238-42.
53. Leinweber M, Ward DR, Sobczak JM, Attinger A, Keller GB. A sensorimotor circuit in mouse cortex for visual flow predictions. Neuron. 2017 Sep 13;95(6):1420-32.
54. Shink E, Bevan MD, Bolam JP, Smith Y. The subthalamic nucleus and the external pallidum: two tightly interconnected structures that control the output of the basal ganglia in the monkey. Neuroscience. 1996 Jul 1;73(2):335-57.
55. Threlfell S, Lalic T, Platt NJ, Jennings KA, Deisseroth K, Cragg SJ. Striatal dopamine release is triggered by synchronized activity in cholinergic interneurons. Neuron. 2012 Jul 12;75(1):58-64.
56. Xu W, Südhof TC. A neural circuit for memory specificity and generalization. Science. 2013 Mar 15;339(6125):1290-5.
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M, R. (2026). ADENO-ASSOCIATED VIRUS-MEDIATED OTOF GENE THERAPY: ADVANCES, CHALLENGES, AND FUTURE DIRECTIONS . Bulletin of Advanced Drug Delivery and Therapeutics, 1(1), 39-50. Retrieved from https://saapjournals.org/index.php/baddt/article/view/918
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