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Volume 52 Issue 7
Jul.  2025
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Article Navigation >  Journal of Genetics and Genomics  > 2025  >  52(7): 887-900

In vivo adenine base editing ameliorates Rho-associated autosomal dominant retinitis pigmentosa

doi: 10.1016/j.jgg.2024.12.012
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    a. MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510275, China;

  •  

    b. Key Laboratory of Reproductive Medicine of Guangdong Province, The First Affiliated Hospital and School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510275, China;

  •  

    c. The State Key Laboratory of Ophthalmology Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong 510060, China

Funds:

This study was funded by the National Key Research and Development Program of China (2023YFC2506100), the National Natural Science Foundation of China (31971365, 32371509, 32001063, and 82271688), the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (2019BT02Y276), the Guangdong Basic and Applied Basic Research Foundation (2023A1515010176), the grant from MOE Key Laboratory of Gene Function and Regulation, the Guangzhou Science and Technology Planning Project (2023A04J1952), and the Fundamental Research Funds for the Central Universities, Sun Yat-sen University (23ptpy59).

  • Received Date: 2024-12-03
  • Accepted Date: 2024-12-16
  • Rev Recd Date: 2024-12-15
    • Available Online: 2025-07-11
  • Publish Date: 2024-12-24
    Abstract
  • Mutations in the Rhodopsin (RHO) gene are the main cause of autosomal dominant retinitis pigmentosa (adRP), 84% of which are pathogenic gain-of-function point mutations. Treatment strategies for adRP typically involve silencing or ablating the pathogenic allele, while normal RHO protein replacement has no meaningful therapeutic benefit. Here, we present an adenine base editor (ABE)-mediated therapeutic approach for adRP caused by RHO point mutations in vivo. The correctable pathogenic mutations are screened and verified, including T17M, Q344ter, and P347L. Two adRP animal models are created carrying the class 1 (Q344ter) and class 2 (T17M) mutations, and dual AAV-delivered ABE can effectively repair both mutations in vivo. The early intervention of ABE8e efficiently corrects the Q344ter mutation that causes a severe form of adRP, delays photoreceptor death, and restores retinal function and visual behavior. These results suggest that ABE is a promising alternative to treat RHO mutation-associated adRP. Our work provides an effective spacer-mediated point mutation correction therapy for dominantly inherited ocular disorders.
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