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2025

bioRxiv 2025 Dec 11. doi: 10.64898/2025.12.09.692426

Pre-clinical validation of a novel AAV-mediated gene therapy for KCNV2 retinopathy improves visual function in a mouse model and expression in patient organoids

Rabab Rashwan1, Paula I Fuller-Carter, Xin Ru Lim, Alicia A Brunet, Annie L Miller, Yashvi Bhatt, Rebekah James, Denise Anderson, Valentina Voigt, Joao A Paulo, Mehdi Mirzaei, Melissa M Mangala, Emilie O Wong, Robyn V Jamieson, Anai Gonzalez-Cordero, David M Hunt, Livia S Carvalho

Retinal Genomics and Therapy Group, Lions Eye Institute, Perth, Australia. Department of Microbiology and Immunology, Faculty of Medicine, Minia University, Minia, Egypt. Centre for Ophthalmology and Visual Science, The University of Western Australia, Perth, Australia. INSiGENe Pty Ltd, Perth, Australia. Department of Cell Biology, Harvard Medical School, Boston, MA, USA. Department of Clinical Medicine, Health and Human Sciences, Macquarie Medical School, Macquarie University, Sydney, NSW, Australia. Stem Cell Medicine Unit Group, Children's Medical Research Institute, Faculty of Medicine and Health, Children's Medical Research Institute, The University of Sydney, Westmead, Australia. Save Sight Institute, University of Sydney, Sydney, New South Wales, Australia. Eye Genetics Research Unit, Children's Medical Research Institute, The Children's Hospital at Westmead, Westmead, New South Wales, Australia. Western Sydney Genetics Program, Sydney Children's Hospitals Network, Sydney, NSW, Australia Department of Optometry and Vision Sciences, The University of Melbourne, Melbourne, Australia

Service type: Stock strains

Abstract

Voltage-gated (Kv) potassium channels are critical for neuronal physiology, and their dysfunction can lead to serious consequences. For example, mutations in the silent modulatory Kv8.2 subunit are known to cause irreversible inherited blindness (KCNV2 retinopathy). This is a currently incurable condition that causes lifelong visual loss, reduced visual acuity, photoaversion, night blindness and abnormal colour vision, alongside a distinctive supernormal electrophysiological (ERG) retinal response to light. In this study, we demonstrate that AAV-mediated gene replacement therapy delivering a codon-optimised human KCNV2 gene subretinally into Kv8.2 knock-out mice significantly restores retinal function. Treated mice exhibited improved ERG responses and correct expression of KCNV2 and its encoded Kv8.2 protein in photoreceptors. Recovery of visually guided scotopic and photopic optomotor responses to wildtype levels was achieved at lower vector doses, highlighting dose-dependent efficacy. Furthermore, treatment of human retinal organoids derived from a KCNV2 patient iPSC line resulted in substantial Kv8.2 protein rescue. This work provides the first preclinical proof-of-concept for the safety and therapeutic potential of gene therapy for KCNV2 retinopathy, laying a strong foundation for future clinical trials.