Overloaded Adeno-Associated Virus as a Novel Gene Therapeutic Tool for Otoferlin-Related Deafness
Hearing impairment is the most common sensory disorder in humans. So far, rehabilitation of profoundly deaf subjects relies on direct stimulation of the auditory nerve through cochlear implants. However, in some forms of genetic hearing impairment, the organ of Corti is structurally intact and thera...
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Published in: | Frontiers in molecular neuroscience Vol. 13; p. 600051 |
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Main Authors: | , , , , , , , , , |
Format: | Journal Article |
Language: | English |
Published: |
Switzerland
Frontiers Research Foundation
07-01-2021
Frontiers Media S.A |
Subjects: | |
Online Access: | Get full text |
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Summary: | Hearing impairment is the most common sensory disorder in humans. So far, rehabilitation of profoundly deaf subjects relies on direct stimulation of the auditory nerve through cochlear implants. However, in some forms of genetic hearing impairment, the organ of Corti is structurally intact and therapeutic replacement of the mutated gene could potentially restore near natural hearing. In the case of defects of the otoferlin gene (
), such gene therapy is hindered by the size of the coding sequence (~6 kb) exceeding the cargo capacity (<5 kb) of the preferred viral vector, adeno-associated virus (AAV). Recently, a dual-AAV approach was used to partially restore hearing in deaf otoferlin knock-out (
KO) mice. Here, we employed
and
approaches to assess the gene-therapeutic potential of naturally-occurring and newly-developed synthetic AAVs overloaded with the full-length
coding sequence. Upon early postnatal injection into the cochlea of
KO mice, overloaded AAVs drove specific expression of otoferlin in ~30% of all IHCs, as demonstrated by immunofluorescence labeling and polymerase chain reaction. Recordings of auditory brainstem responses and a behavioral assay demonstrated partial restoration of hearing. Together, our results suggest that viral gene therapy of DFNB9-using a single overloaded AAV vector-is indeed feasible, reducing the complexity of gene transfer compared to dual-AAV approaches. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Edited by: Steven Haym Green, The University of Iowa, United States These authors have contributed equally to this work Reviewed by: Sangyong Jung, Singapore Bioimaging Consortium (A*STAR), Singapore; Agnieszka J. Szczepek, Charité – Universitätsmedizin Berlin, Germany |
ISSN: | 1662-5099 1662-5099 |
DOI: | 10.3389/fnmol.2020.600051 |