Gene therapy restores auditory and vestibular function in a mouse model of Usher syndrome type 1c.
Because there are currently no biological treatments for hearing loss, we sought to advance gene therapy approaches to treat genetic deafness. We focused on Usher syndrome, a devastating genetic disorder that causes blindness, balance disorders and profound deafness, and studied a knock-in mouse model, Ush1c c.216G>A, for Usher syndrome type IC (USH1C). As restoration of complex auditory and balance function is likely to require gene delivery systems that target auditory and vestibular sensory cells with high efficiency, we delivered wild-type Ush1c into the inner ear of Ush1c c.216G>A mice using a synthetic adeno-associated viral vector, Anc80L65, shown to transduce 80-90% of sensory hair cells. We demonstrate recovery of gene and protein expression, restoration of sensory cell function, rescue of complex auditory function and recovery of hearing and balance behavior to near wild-type levels. The data represent unprecedented recovery of inner ear function and suggest that biological therapies to treat deafness may be suitable for translation to humans with genetic inner ear disorders.
Department of Otolaryngology, F.M. Kirby Center for Neurobiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Bifeng
0000-0001-9746-3420
B
Pan
Department of Otolaryngology, F.M. Kirby Center for Neurobiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Charles
0000-0002-6131-6602
C
Askew
Department of Otolaryngology, F.M. Kirby Center for Neurobiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Alice
A
Galvin
Department of Otolaryngology, F.M. Kirby Center for Neurobiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Selena
S
Heman-Ackah
Department of Otolaryngology, F.M. Kirby Center for Neurobiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Yukako
Y
Asai
Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.
Artur A
AA
Indzhykulian
Department of Cell Biology &Anatomy, Chicago Medical School, Rosalind Franklin University of Medicine and Science, Chicago, Illinois, USA.
Francine M
FM
Jodelka
Department of Cell Biology &Anatomy, Chicago Medical School, Rosalind Franklin University of Medicine and Science, Chicago, Illinois, USA.
Michelle L
ML
Hastings
Department of Otorhinolaryngology &Bio-communications and Neuroscience Center, LSU Health Sciences Center, New Orleans, Louisiana, USA.
Jennifer J
JJ
Lentz
Department of Ophthalmology, Grousbeck Gene Therapy Center, Schepens Eye Research Institute and Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts, USA.
Luk H
0000-0002-3508-4924
LH
Vandenberghe
Department of Otolaryngology, F.M. Kirby Center for Neurobiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Department of Neurology, F.M. Kirby Center for Neurobiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Jeffrey R
JR
Holt
Department of Otolaryngology, F.M. Kirby Center for Neurobiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Gwenaëlle S
GS
Géléoc
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D005260:Female; D055879:Gene Knock-In Techniques; D015316:Genetic Therapy / Q000379:methods*; D006319:Hearing Loss, Sensorineural / Q000175:diagnosis / Q000235:genetics / Q000628:therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010957:Plasmids / Q000008:administration & dosage / Q000235:genetics; D020127:Recovery of Function / Q000235:genetics; D016896:Treatment Outcome; D052245:Usher Syndromes / Q000235:genetics* / Q000628:therapy*; D015837:Vestibular Diseases / Q000175:diagnosis / Q000235:genetics / Q000628:therapy*
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; C492262:Ush1c protein, mouse