RNA base editing therapy cures hearing loss induced by OTOF gene mutation.

Abstract

Otoferlin (OTOF) gene mutations represent the primary cause of hearing impairment and deafness in auditory neuropathy. The c.2485C>T (p. Q829X) mutation variant is responsible for approximately 3% of recessive prelingual deafness cases within the Spanish population. Previous studies have used two recombinant AAV vectors to overexpress OTOF, albeit with limited efficacy. In this study, we introduce an enhanced mini-dCas13X RNA base editor (emxABE) delivered via an AAV9 variant, achieving nearly 100% transfection efficiency in inner hair cells. This approach is aimed at treating OTOFQ829X, resulting in an approximately 80% adenosine-to-inosine conversion efficiency in humanized OtofQ829X/Q829X mice. Following a single scala media injection of emxABE targeting OTOFQ829X (emxABE-T) administered during the postnatal day 0-3 period in OtofQ829X/Q829X mice, we observed OTOF expression restoration in nearly 100% of inner hair cells. Moreover, auditory function was significantly improved, reaching similar levels as in wild-type mice. This enhancement persisted for at least 7 months. We also investigated P5-P7 and P30 OtofQ829X/Q829X mice, achieving auditory function restoration through round window injection of emxABE-T. These findings not only highlight an effective therapeutic strategy for potentially addressing OTOFQ829X-induced hearing loss but also underscore emxABE as a versatile toolkit for treating other monogenic diseases characterized by premature termination codons.

• Authors: Yuanyuan Xue, Yong Tao, Xing Wang, Xueling Wang, Yilai Shu, Yuanhua Liu, Wen Kang, Sifan Chen, Zhenzhe Cheng, Boou Yan, Yanwei Xie, Lanting Bi, Haitao Jia, Jinhui Li, Qingquan Xiao, Liying Chen, Xuan Yao, Linyu Shi, Hui Yang, Hao Wu
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 31 Issue 12 Pg. 3520-3530 (Dec 06 2023) ISSN: 1525-0024 [Electronic] United States
• PMID: 37915172 (Publication Type: Journal Article)
• Copyright: Copyright © 2023 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Topics

• Animals
• Mice
• Gene Editing
• Hearing Loss (genetics, therapy)
• Mutation
• Deafness
• Hearing Loss, Central