CDHR1-associated retinal degeneration: Clinical phenotypes and therapeutic approaches

CDHR1 is a recently identified cause of autosomal recessive retinal degeneration manifesting as three distinct clinical phenotypes: macular dystrophy, cone-rod dystrophy or retinitis pigmentosa. In this review, we summarise the discovery and characterisation of CDHR1, clinical phenotypes, natural history and therapeutic approaches including gene supplementation and CRISPR gene editing. CDHR1 is a non-classical cadherin that is highly expressed in cone and rod photoreceptors and is essential for the higher-order organisation of the functionally critical outer segments. Promising pre-clinical data show that AAV gene supplementation therapy delivered by subretinal injection can lead to long-term morphological, structural, functional and behavioural improvements in the Cdhr1 knockout mouse model. Notably, CDHR1 supplementation restored full-length photoreceptor outer segments that are usually shortened and disorganised in disease models and prolonged photoreceptor survival - key mechanisms for the functional and behavioural rescue effects that were observed. The disease is likely to be underdiagnosed because CDHR1-associated macular dystrophy - likely to be the most common disease phenotype - is most often caused by a 'silent' nucleotide substitution that has previously been overlooked by genetic testing. Since the macular dystrophy phenotype has phenotypic similarities to advanced dry age-related macular degeneration (AMD), misdiagnoses are common. CDHR1-associated macular dystrophy also shares phenotypic features with a variety of monogenic masquerades such as ABCA4, PRPH2 and GUCY2D-associated macular dystrophies; we present a flowchart to guide the clinical distinction of these disorders which is now critical for patients as their treatments diverge. AAV gene therapy may be beneficial across the CDHR1 disease spectrum - including those with hypomorphic variants associated with macular dystrophy or retinitis pigmentosa. The coding sequence fits into AAV and with the macular dystrophy phenotype, there is a large time window for potential intervention and a large treatable population. Hence clinical trials are anticipated. It is therefore important that patients with CDHR1-associated retinal degeneration are accurately phenotyped and genetically confirmed to support the application of CDHR1 gene therapy.