Yusuf, Imran H; Burgoyne, Thomas; Salman, Ahmed; McClements, Michelle E; MacLaren, Robert E; Issa, Peter Charbel; (2024) Rescue of cone and rod photoreceptor function in a CDHR1-model of age-related retinal degeneration. Molecular Therapy 10.1016/j.ymthe.2024.03.026. (In press).

Text Rescue of cone and rod photoreceptor function in a CDHR1-model.pdf - Accepted Version Access restricted to UCL open access staff until 20 March 2025. Download (15MB)

Abstract

Age-related macular degeneration is the most common cause of untreatable blindness in the developed world. Recently, CDHR1 has been identified as the cause of a subset of age-related macular degeneration that has the appearance the ‘dry’ form, or geographic atrophy. Biallelic variants in CDHR1 – a specialised protocadherin highly expressed in cone and rod photoreceptors - result in blindness from shortened photoreceptor outer segments and progressive photoreceptor cell death. Here we demonstrate long-term morphological, ultrastructural, functional and behavioural rescue following CDHR1 gene therapy in a relevant murine model, sustained to 23-months post-injection. This represents the first demonstration of rescue of a monogenic cadherinopathy in vivo. Moreover, the durability of CDHR1 gene therapy appears to be near complete – with morphological findings of the rescued retina not obviously different to wildtype throughout the lifespan of the mouse model. A follow-on clinical trial in patients with CDHR1-associated retinal degeneration is warranted. Hypomorphic CDHR1 variants may mimic advanced dry age-related macular degeneration. Accurate clinical classification is now critical as their pathogenesis and treatment are distinct.

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