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Nature. 2018 Jan 11;553(7687):217-221. doi: 10.1038/nature25164. Epub 2017 Dec 20.

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

Gao X1,2,3, Tao Y4,5, Lamas V4, Huang M4, Yeh WH1,2,3,6, Pan B7, Hu YJ4,5, Hu JH1,2,3, Thompson DB1,2, Shu Y4,8, Li Y9, Wang H4,10, Yang S10, Xu Q9, Polley DB4, Liberman MC4, Kong WJ5, Holt JR7, Chen ZY4, Liu DR1,2,3.

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Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Howard Hughes Medical Institute, Harvard University, Cambridge, Massachusetts 02138, USA.
Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02141, USA.
Department of Otolaryngology and Program in Neuroscience, Harvard Medical School and Eaton Peabody Laboratory, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts 02114, USA.
Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.
Program in Speech and Hearing Bioscience and Technology, Harvard University, Cambridge, Massachusetts 02138, USA.
Departments of Otolaryngology and Neurology, F.M. Kirby Neurobiology Center Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Department of Otolaryngology-Head and Neck Surgery, Eye and ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
Department of Biomedical Engineering, Tufts University, Medford, Massachusetts 02155, USA.
Department of Otolaryngology & Head Neck Surgery, Key Lab of Hearing Impairment Science of Ministry of Education, Key Lab of Hearing Impairment Prevention and Treatment of Beijing City, Chinese PLA Medical School, Beijing, China.


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 Tmc1Bth allele differs from the wild-type allele at only a single base pair. Injection of Cas9-guide RNA-lipid complexes targeting the Tmc1Bth allele into the cochlea of neonatal Tmc1Bth/+ 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 Tmc1Bth/+ 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.

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