Cell-autonomous restoration of splicing homeostasis and RP11 phenotype in patient-derived RPE and retinal organoids by PRPF31.AAV gene therapy

Abstract

Mutations in the PRPF31 gene cause retinitis pigmentosa type 11 (RP11), a progressive blinding disease triggered by defects in the spliceosome, the cellular machinery responsible for RNA processing. Although gene replacement holds therapeutic promise, it remains unclear whether it can effectively rescue both primary target cell types across different disease stages. Here we show that viral-mediated delivery of PRPF31 to patient-derived retinal pigment epithelium (RPE) cells and 3D retinal organoids restores RNA splicing activity and reverses core cellular pathology. Gene delivery cleared toxic protein aggregates, restored essential RPE functions, including structural polarity, cilia integrity, and cellular waste clearance, and boosted light-evoked activity in photoreceptors. Notably, robust rescue was achievable even in mature cells, whereas combining gene therapy with autophagy-activating drugs offered no added benefit. These findings demonstrate that restoring splicing homeostasis alone drives functional recovery, supporting a broad clinical window for PRPF31 gene therapy in RP11.

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Item Type:	Article
Authors/Creators:	Elia, M. Pauzuolyte, V. Georgiou, M. Basche, M. Hansohn, C. Vasconcelos, E.J.R. https://orcid.org/0000-0001-5130-6622 Atkinson, R. Grellscheid, S. Johnson, C.A. https://orcid.org/0000-0002-2979-8234 Hilgen, G. Urlaub, H. Smith, A.J. Mozaffari-Jovin, S. Ali, R.R. Lako, M.
Copyright, Publisher and Additional Information:	© The Author(s) 2026. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Dates:	Accepted: 14 September 2026 Published (online): 30 September 2026 Published: 30 September 2026
Institution:	The University of Leeds
Academic Units:	The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Medical Research (LIMR) > Division of Molecular Medicine The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds)
Date Deposited:	05 Nov 2026 12:50
Last Modified:	05 Nov 2026 12:50
Status:	Published
Publisher:	Springer Nature
Identification Number:	10.1038/s41467-026-78065-z
Related URLs:	PubMed URL
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:247494

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Cell-autonomous restoration of splicing homeostasis and RP11 phenotype in patient-derived RPE and retinal organoids by PRPF31.AAV gene therapy

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