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In vivo outer hair cell gene editing ameliorates progressive hearing loss in dominant-negative Kcnq4 murine model

 Byunghwa Noh  ;  John Hoon Rim  ;  Ramu Gopalappa  ;  Haiyue Lin  ;  Kyu Min Kim  ;  Min Jin Kang  ;  Heon Yung Gee  ;  Jae Young Choi  ;  Hyongbum Henry Kim  ;  Jinsei Jung 
 THERANOSTICS, Vol.12(5) : 2465-2482, 2022-02 
Journal Title
Issue Date
Animals ; Disease Models, Animal ; Gene Editing* ; Hair Cells, Auditory, Outer / metabolism ; Hearing Loss* / genetics ; Hearing Loss* / metabolism ; Hearing Loss* / therapy ; KCNQ Potassium Channels / genetics ; KCNQ Potassium Channels / metabolism ; Membrane Potentials ; Mice
Cas9 ; DFNA2 ; KCNQ4 ; gene editing ; outer hair cell
Outer hair cell (OHC) degeneration is a major cause of progressive hearing loss and presbycusis. Despite the high prevalence of these disorders, targeted therapy is currently not available. Methods: We generated a mouse model harboring Kcnq4 W276S/+ to recapitulate DFNA2, a common genetic form of progressive hearing loss accompanied by OHC degeneration. After comprehensive optimization of guide RNAs, Cas9s, vehicles, and delivery routes, we applied in vivo gene editing strategy to disrupt the dominant-negative allele in Kcnq4 and prevent progressive hearing loss. Results: In vivo gene editing using a dual adeno-associated virus package targeting OHCs significantly improved auditory thresholds in auditory brainstem response and distortion-product otoacoustic emission. In addition, we developed a new live-cell imaging technique using thallium ions to investigate the membrane potential of OHCs and successfully demonstrated that mutant allele disruption resulted in more hyperpolarized OHCs, indicating elevated KCNQ4 channel activity. Conclusion: These findings can facilitate the development of targeted therapies for DFNA2 and support the use of CRISPR-based gene therapy to rectify defects in OHCs.
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Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Laboratory Medicine (진단검사의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Otorhinolaryngology (이비인후과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Hyongbum(김형범) ORCID logo https://orcid.org/0000-0002-4693-738X
Rim, John Hoon(임정훈) ORCID logo https://orcid.org/0000-0001-6825-8479
Jung, Jinsei(정진세) ORCID logo https://orcid.org/0000-0003-1906-6969
Gee, Heon Yung(지헌영) ORCID logo https://orcid.org/0000-0002-8741-6177
Choi, Jae Young(최재영) ORCID logo https://orcid.org/0000-0001-9493-3458
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