DeCure for RPE65-related dominant retinopathy

The only known dominant mutation in RPE65 is the c.1430G>A (D477G) substitution, which causes a delayed-onset retinitis pigmentosa with choroidal and macular involvement. A 2018 study using a D477G knock-in mouse model found mild age-dependent changes in retinal structure and function. The mice showed ubiquitinated RPE65, reduced RPE65 expression, accumulation of retinyl esters, delayed rhodopsin regeneration, and diminished electroretinography responses. However, a cell line expressing the mutant protein had normal expression, localisation, and isomerase activity. Structural analysis suggested the mutation does not perturb protein folding but creates an aggregation-prone surface that may cause toxicity through abnormal complex formation. The authors concluded a toxic gain-of-function mechanism may be involved.

Voretigene neparvovec (Luxturna) is the only approved subretinal gene therapy for biallelic RPE65-related Leber congenital amaurosis. A 2025 multicentre retrospective case series of nine patients who met World Health Organization blindness criteria (best-corrected visual acuity below 20/400 or visual field III4e isopter less than 10 degrees) reported outcomes after a mean follow-up of 11.1 months. Mean baseline visual acuity was 1.89 LogMAR (range 1.4 to 2.7). Visual field area did not improve overall, but full-field stimulus testing improved in patients with better baseline full-field stimulus testing (−8.83 dB vs −0.56 dB; p = 0.010). Visual acuity improved in younger patients (20 vs 32 years; p = 0.011) and those with thinner central retinal thickness at 1 mm (155 vs 193 µm; p = 0.038). Visual field V4e loss occurred in older patients (38 vs 19 years; p = 0.001) with worse baseline V4e area. Subjective improvement in dim light navigation was reported in younger patients (20.3 vs 45.3 years; p < 0.001). The authors concluded that blindness is not a contraindication, and superior results correlated with greater baseline full-field stimulus testing but not with central retinal thickness, provided measurable outer retinal structures persist.

A 2024 review noted that RPE65-associated retinal dystrophies are mostly fast-progressing, with childhood onset of night blindness and progressive visual loss into middle adulthood. Rare phenotypes include congenital stationary night blindness, slowly progressing retinitis pigmentosa, and the autosomal dominant D477G variant. The review summarised current knowledge of clinical phenotypes and experience with voretigene neparvovec.

What is still missing is a specific gene therapy or pharmacological strategy for the dominant D477G form, which may require a different approach than the recessive loss-of-function disease. No clinical trial has yet tested any intervention in patients with the dominant mutation. Patient stratification by age, baseline function, and retinal structure appears critical for interpreting outcomes, but prospective data with longer follow-up are lacking. Funding for mechanistic studies of the proposed toxic gain-of-function and for development of therapies targeting aggregation or abnormal complex formation remains limited.