Unravelling CYP4V2: Clinical features, genetic insights, pathogenic mechanisms and therapeutic strategies in Bietti crystalline corneoretinal dystrophy.

Inherited retinal dystrophies (IRDs) comprise a spectrum of disease phenotypes with genetic heterogeneity and clinical phenotypic diversity. Bietti crystalline corneoretinal dystrophy (BCD) represents a distinct IRD subtype characterized by crystalline deposits in the retina. Although rare in Western populations, BCD ranks among the most prevalent IRDs in East Asia, affecting an estimated 124,000 to 377,000 individuals worldwide. As a severe type of IRD, BCD demonstrates accelerated progression and currently lacks effective treatment. The BCD disease is caused by a biallelic mutation in the CYP4V2 gene. With a coding sequence (CDS) of 1,578 bp, CYP4V2 can be effectively encapsulated into adeno-associated virus (AAV) vectors. As a hydroxylase, CYP4V2 is mainly expressed in retinal pigment epithelial (RPE) cells, which can be transduced by AAVs and are suitable for gene augmentation therapy that replaces the function of mutant proteins. Given the large patient population, severe visual impairment, and feasibility of gene therapy, several research groups are interested in developing gene therapy products for BCD, and two products entering Phase III clinical trials have made significant progress. This review outlines the clinical features, genetic insights and pathogenic mechanisms of BCD and discusses the ongoing gene therapy clinical trials, including efficacy and concerns. This knowledge will help us bridge the gap between molecular studies and clinical treatments, facilitating translation from bench to bedside. We believe that advancements in BCD gene therapy will inform the treatment of other IRDs.