A synthetic AAV vector enables safe and efficient gene transfer to the mammalian inner ear.
Efforts to develop gene therapies for hearing loss have been hampered by the lack of safe, efficient, and clinically relevant delivery modalities. Here we demonstrate the safety and efficiency of Anc80L65, a rationally designed synthetic vector, for transgene delivery to the mouse cochlea. Ex vivo transduction of mouse organotypic explants identified Anc80L65 from a set of other adeno-associated virus (AAV) vectors as a potent vector for the cochlear cell targets. Round window membrane injection resulted in highly efficient transduction of inner and outer hair cells in mice, a substantial improvement over conventional AAV vectors. Anc80L65 round window injection was well tolerated, as indicated by sensory cell function, hearing and vestibular function, and immunologic parameters. The ability of Anc80L65 to target outer hair cells at high rates, a requirement for restoration of complex auditory function, may enable future gene therapies for hearing and balance disorders.
Eaton Peabody Laboratories, Department of Otolaryngology, Massachusetts Eye and Ear, Boston, Massachusetts, USA.|Department of Otolaryngology, Harvard Medical School, Boston, Massachusetts, USA.|Department of Otolaryngology, Vienna General Hospital, Medical University of Vienna, Vienna, Austria.
Lukas D
0000-0002-9660-2625
LD
Landegger
Department of Otolaryngology, Harvard Medical School, Boston, Massachusetts, USA.|Department of Otolaryngology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts, USA.
Bifeng
0000-0001-9746-3420
B
Pan
Department of Otolaryngology, Harvard Medical School, Boston, Massachusetts, USA.|Department of Otolaryngology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts, USA.
Charles
0000-0002-6131-6602
C
Askew
Grousbeck Gene Therapy Center, Schepens Eye Research Institute and Massachusetts Eye and Ear, Boston, Massachusetts, USA.|Ocular Genomics Institute, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.
Sarah J
SJ
Wassmer
Department of Otolaryngology, Harvard Medical School, Boston, Massachusetts, USA.|Department of Otolaryngology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts, USA.|Harvard Program in Speech and Hearing Bioscience and Technology, Boston, Massachusetts, USA.
Sarah D
SD
Gluck
Department of Otolaryngology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts, USA.
Alice
A
Galvin
Center for Auditory Research, UCL Ear Institute, London, UK.
Ruth
R
Taylor
Center for Auditory Research, UCL Ear Institute, London, UK.
Andrew
A
Forge
Eaton Peabody Laboratories, Department of Otolaryngology, Massachusetts Eye and Ear, Boston, Massachusetts, USA.|Department of Otolaryngology, Harvard Medical School, Boston, Massachusetts, USA.|Harvard Program in Speech and Hearing Bioscience and Technology, Boston, Massachusetts, USA.
Konstantina M
KM
Stankovic
Department of Otolaryngology, Harvard Medical School, Boston, Massachusetts, USA.|Department of Otolaryngology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Jeffrey R
JR
Holt
Grousbeck Gene Therapy Center, Schepens Eye Research Institute and Massachusetts Eye and Ear, Boston, Massachusetts, USA.|Ocular Genomics Institute, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.|Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA.
Luk H
0000-0002-3508-4924
LH
Vandenberghe
D000818:Animals; D003051:Cochlea / Q000502:physiology* / Q000821:virology; D000229:Dependovirus / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D010957:Plasmids / Q000008:administration & dosage / Q000235:genetics*; D014161:Transduction, Genetic / Q000379:methods*