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Mol. Ther., Apr 18 2025, S1525-0016(25)00295-3 | https://doi.org/10.1016/j.ymthe.2025.04.021 Intravitreal adenine base editing of RS1 improves vision in a preclinical mouse model of retinoschisis

Dong Hyun Jo ^1,2,17, Hyewon Jang^3,17, Chang Sik Cho ⁴, Seok Jae Lee ⁴, Ji Hwa Heo⁵, Jung Ah Kim ^3,6,7, Se Jin Kim ^3,6,7, WonHyoung Ryu ⁸, Chan-Wook Park ^2,9,10, Byeong-Cheol Kang ^2,11, Heon Yung Gee ^3,6,7, Young Hoon Sung ^5,*, Hyongbum Henry Kim,^{3,6,7,12,13,14,15,*} and Jeong Hun Kim ^2,4,16,*

1Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
²Global Excellence Center for Gene & Cell Therapy (GEC-GCT), Seoul National University Hospital, Seoul, 03080, Republic of Korea.
³Department of Pharmacology, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.
⁴Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, Republic of Korea.
⁵Department of Cell and Genetic Engineering and Convergence Medicine Research Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 03080, Republic of Korea.
⁶Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.
⁷Woo Choo Lee Institute for Precision Drug Development, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.
⁸School of Mechanical Engineering, Yonsei University, Seoul, 03722, Republic of Korea.
⁹Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
¹⁰Department of Obstetrics and Gynecology, Seoul National University Hospital, Seoul, 03080, Republic of Korea.
¹¹Graduate School of Translational Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
¹²Center for Nanomedicine, Institute for Basic Science (IBS), Seoul, 03722, Republic of Korea.
¹³Yonsei-IBS Institute, Yonsei University, Seoul, 03722, Republic of Korea.
¹⁴Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.
¹⁵Won-Sang Lee Institute for Hearing Loss, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.
¹⁶Department of Biomedical Sciences & Ophthalmology, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
¹⁷These authors contributed equally.

^*Corresponding authors: correspondence to Young Hoon Sung, Hyongbum Henry Kim or Jeong Hun Kim

Abstract

Base editing offers high potential for treating genetic diseases, particularly those with limited treatment options. Retinoschisis, an X-linked retinal disease causing progressive vision loss, currently lacks effective therapies. We identified the c.422G>A (p.Arg141His) variant of the RS1 gene in six male patients with retinoschisis and generated a humanized mouse model harboring this variant, which mimicked the disease phenotype. By testing adenine base editors and single guide RNAs, we identified an optimal combination of high editing efficiency and low bystander editing. Intravitreal injection of adeno-associated viral vectors encoding this adenine base editor achieved approximately 40% editing efficiency in all retinal cells, restored retinal layer integrity, and preserved visual functions in 2-week-old male hemizygous mice. These mice exhibited retinal layer splitting at baseline, further validating the model. This study demonstrates a strategy for identifying effective base editing tools for clinical use through the preclinical evaluation of humanized mouse lines with patient-derived mutations and highlights their applicability in treating genetic diseases.

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형식Research article
게재일2025년 04월 (BRIC 등록일 2025-04-23)
연구진국내 연구진
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