Year: 2025
Type: article
Abstract: Genetic mutations cause hereditary deafness, in which mutations in the POU4 transcription factor 3 gene (POU4F3) lead to autosomal dominant non-syndromic deafness 15 (DFNA15), for which no effective clinical treatment currently exists. Gene editing holds promise for precisely repairing mutated nucleotides, thus offering a potential cure for hereditary hearing loss. Here, we establish a Pou4f3WT/Q113* mutant mouse model mimicking DFNA15. We develop and screen adenine base editors (ABEs) targeting the Pou4f3Q113* allele by fusing diverse adenine deaminases to Cas9 we discovered before. SchABE8e accomplishes highly precise and efficient editing (up to 48.5%) at sgRNA3 in vitro. Neonatal Pou4f3WT/Q113* mice are treated via synthetic AAV (Anc80L65)-delivered SchABE8e-sgRNA3, resulting in near-complete hearing recovery, with the effect persisting for at least four months. Biosafety analyses further support the feasibility of base editing, providing a therapeutic strategy for DFNA15. Genetic mutations causing hereditary deafness, including autosomal dominant non-syndromic deafness 15 (DFNA15), currently have no effective treatment. Here, authors establish a Pou4f3WT/Q113* mutant mouse model and engineer and deliver an adenine base editor for near-complete hearing recovery.
Source: Nature Communications
Institutions: Nantong University, Zhongda Hospital Southeast University, State Key Laboratory of Digital Medical Engineering, Southeast University, Wuhan University, Zhongnan Hospital of Wuhan University, Fudan University, Obstetrics and Gynecology Hospital of Fudan University, Beijing Institute of Technology, Zhuhai People's Hospital, University of Electronic Science and Technology of China
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: National Natural Science Foundation of China, China Postdoctoral Science Foundation, Government of Jiangsu Province, Natural Science Foundation of Jiangsu Province, Southeast University, Science, Technology and Innovation Commission of Shenzhen Municipality, National Key Research and Development Program of China
Awards: G1083476708, G1184380988, G2430708696, G2522891566, G2562545184, G267354232, G3584413249, G3852078645, G4210868709, G4393150170, G4855079309, G4858099901, G5417391657, G5591760066, G608665539, G6171391990, G6973767439, G6983853783, G7242850194, G7640387804, G7797219003, G7844431965, G8132676078, G8162577065, G8228227916, G8272360692, G8454626044, G8475999273, G95219777, G997334894
OpenAlex ID: W4414308407