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Abstract
Inner ear gene therapy using adeno-associated viral vectors (AAV) promises to alleviate hearing and balance disorders. We previously established the benefits of Anc80L65 in targeting inner and outer hair cells in newborn mice. To accelerate translation to humans, we now report the feasibility and efficiency of the surgical approach and vector delivery in a nonhuman primate model. Five rhesus macaques were injected with AAV1 or Anc80L65 expressing eGFP using a transmastoid posterior tympanotomy approach to access the round window membrane after making a small fenestra in the oval window. The procedure was well tolerated. All but one animal showed cochlear eGFP expression 7–14 days following injection. Anc80L65 in 2 animals transduced up to 90% of apical inner hair cells; AAV1 was markedly less efficient at equal dose. Transduction for both vectors declined from apex to base. These data motivate future translational studies to evaluate gene therapy for human hearing disorders.
Gene therapy using Adeno-associated viral vectors (AAV) rescues hearing and balance deficits in mouse models of human disorders. Here, the authors show that AAVAnc80L65 allows efficient cochlear gene transfer in nonhuman primates, and motivate future studies to evaluate gene therapy for hearing and balance disorders.
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1 Schepens Eye Research Institute and Massachusetts Eye and Ear, Grousbeck Gene Therapy Center, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Harvard Medical School, Ocular Genomics Institute, Department of Ophthalmology, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Akouos Inc., Boston, USA (GRID:grid.38142.3c)
2 Eaton Peabody Laboratories, Massachusetts Eye and Ear, Boston, USA (GRID:grid.39479.30) (ISNI:0000 0000 8800 3003); Massachusetts Eye and Ear and Harvard Medical School, Department of Otolaryngology – Head and Neck Surgery, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Vienna General Hospital and Medical University of Vienna, Department of Otolaryngology, Vienna, Austria (GRID:grid.22937.3d) (ISNI:0000 0000 9259 8492)
3 Schepens Eye Research Institute and Massachusetts Eye and Ear, Grousbeck Gene Therapy Center, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Harvard Medical School, Ocular Genomics Institute, Department of Ophthalmology, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X)
4 Massachusetts Eye and Ear and Harvard Medical School, Department of Otolaryngology – Head and Neck Surgery, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X)
5 Eaton Peabody Laboratories, Massachusetts Eye and Ear, Boston, USA (GRID:grid.39479.30) (ISNI:0000 0000 8800 3003); Massachusetts Eye and Ear and Harvard Medical School, Department of Otolaryngology – Head and Neck Surgery, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X)
6 Massachusetts Eye and Ear, Harvard Medical School, Department of Anesthesiology, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X)
7 Boston University, Animal Science Center, Boston, USA (GRID:grid.189504.1) (ISNI:0000 0004 1936 7558)
8 Eaton Peabody Laboratories, Massachusetts Eye and Ear, Boston, USA (GRID:grid.39479.30) (ISNI:0000 0000 8800 3003); Massachusetts Eye and Ear and Harvard Medical School, Department of Otolaryngology – Head and Neck Surgery, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Otopathology Laboratory, Massachusetts Eye and Ear, Boston, USA (GRID:grid.39479.30) (ISNI:0000 0000 8800 3003); Harvard University, Speech and Hearing Bioscience and Technology Program, Cambridge, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Akouos Inc., Boston, USA (GRID:grid.38142.3c)
9 Eaton Peabody Laboratories, Massachusetts Eye and Ear, Boston, USA (GRID:grid.39479.30) (ISNI:0000 0000 8800 3003); Massachusetts Eye and Ear and Harvard Medical School, Department of Otolaryngology – Head and Neck Surgery, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Harvard University, Speech and Hearing Bioscience and Technology Program, Cambridge, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Harvard University, Harvard Stem Cell Institute, Cambridge, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Stanford University School of Medicine, Department of Otolaryngology – Head and Neck Surgery, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956)
10 Schepens Eye Research Institute and Massachusetts Eye and Ear, Grousbeck Gene Therapy Center, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Harvard Medical School, Ocular Genomics Institute, Department of Ophthalmology, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Harvard University, Harvard Stem Cell Institute, Cambridge, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); The Broad Institute of Harvard and MIT, Cambridge, USA (GRID:grid.66859.34) (ISNI:0000 0004 0546 1623)