Treatment of autosomal dominant hearing loss by in vivo delivery of genome editing agents.

Nature
Authors
Keywords
Abstract

Although genetic factors contribute to almost half of all cases of deafness, treatment options for genetic deafness are limited. We developed a genome-editing approach to target a dominantly inherited form of genetic deafness. Here we show that cationic lipid-mediated in vivo delivery of Cas9-guide RNA complexes can ameliorate hearing loss in a mouse model of human genetic deafness. We designed and validated, both in vitro and in primary fibroblasts, genome editing agents that preferentially disrupt the dominant deafness-associated allele in the Tmc1 (transmembrane channel-like gene family 1) Beethoven (Bth) mouse model, even though the mutant Tmc1 allele differs from the wild-type allele at only a single base pair. Injection of Cas9-guide RNA-lipid complexes targeting the Tmc1 allele into the cochlea of neonatal Tmc1 mice substantially reduced progressive hearing loss. We observed higher hair cell survival rates and lower auditory brainstem response thresholds in injected ears than in uninjected ears or ears injected with control complexes that targeted an unrelated gene. Enhanced acoustic startle responses were observed among injected compared to uninjected Tmc1 mice. These findings suggest that protein-RNA complex delivery of target gene-disrupting agents in vivo is a potential strategy for the treatment of some types of autosomal-dominant hearing loss.

Year of Publication
2018
Journal
Nature
Volume
553
Issue
7687
Pages
217-221
Date Published
2018 01 11
ISSN
1476-4687
DOI
10.1038/nature25164
PubMed ID
29258297
PubMed Central ID
PMC5784267
Links
Grant list
F32 DC000138 / DC / NIDCD NIH HHS / United States
R01 DC000188 / DC / NIDCD NIH HHS / United States
R01 DC009836 / DC / NIDCD NIH HHS / United States
R35 GM118062 / GM / NIGMS NIH HHS / United States
R01 DC013521 / DC / NIDCD NIH HHS / United States
Howard Hughes Medical Institute / United States
U54 HD090255 / HD / NICHD NIH HHS / United States
P30 DC005209 / DC / NIDCD NIH HHS / United States
R01 DC006908 / DC / NIDCD NIH HHS / United States
R01 EB022376 / EB / NIBIB NIH HHS / United States