Base editing correction of OCRL in Lowe syndrome: ABE-mediated functional rescue in patient-derived fibroblasts.

Autor:	Chen S; Department of Ophthalmology, Stanford University School of Medicine, 1651 Page Mill Road, Rm 2220, Palo Alto, CA 94304, United States., Lo CH; Department of Ophthalmology, Stanford University School of Medicine, 1651 Page Mill Road, Rm 2220, Palo Alto, CA 94304, United States., Liu Z; Department of Ophthalmology, Stanford University School of Medicine, 1651 Page Mill Road, Rm 2220, Palo Alto, CA 94304, United States., Wang Q; Department of Ophthalmology, Stanford University School of Medicine, 1651 Page Mill Road, Rm 2220, Palo Alto, CA 94304, United States., Ning K; Department of Ophthalmology, Stanford University School of Medicine, 1651 Page Mill Road, Rm 2220, Palo Alto, CA 94304, United States., Li T; Department of Ophthalmology, Stanford University School of Medicine, 1651 Page Mill Road, Rm 2220, Palo Alto, CA 94304, United States.; Department of Ophthalmology, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Road, Pudong district, Shanghai 200120, China., Sun Y; Department of Ophthalmology, Stanford University School of Medicine, 1651 Page Mill Road, Rm 2220, Palo Alto, CA 94304, United States.; Palo Alto Veterans Administration, 3801 Miranda Avenue, Palo Alto, CA 94304, United States.
Jazyk:	angličtina
Zdroj:	Human molecular genetics [Hum Mol Genet] 2024 Jun 21; Vol. 33 (13), pp. 1142-1151.
DOI:	10.1093/hmg/ddae045
Abstrakt:	Lowe syndrome, a rare X-linked multisystem disorder presenting with major abnormalities in the eyes, kidneys, and central nervous system, is caused by mutations in OCRL gene (NG_008638.1). Encoding an inositol polyphosphate 5-phosphatase, OCRL catalyzes the hydrolysis of PI(4,5)P2 into PI4P. There are no effective targeted treatments for Lowe syndrome. Here, we demonstrate a novel gene therapy for Lowe syndrome in patient fibroblasts using an adenine base editor (ABE) that can efficiently correct pathogenic point mutations. We show that ABE8e-NG-based correction of a disease-causing mutation in a Lowe patient-derived fibroblast line containing R844X mutation in OCRL gene, restores OCRL expression at mRNA and protein levels. It also restores cellular abnormalities that are hallmarks of OCRL dysfunction, including defects in ciliogenesis, microtubule anchoring, α-actinin distribution, and F-actin network. The study indicates that ABE-mediated gene therapy is a feasible treatment for Lowe syndrome, laying the foundation for therapeutic application of ABE in the currently incurable disease. (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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