Abstract
Inherited retinal diseases (IRDs) are genetically and phenotypically heterogeneous disorders that cause progressive vision loss and lack broadly effective disease-modifying therapies. Increasing evidence implicates metabolic stress, oxidative injury, and photoreceptor-retinal pigment epithelium (RPE) dysfunction in IRD pathophysiology. This review evaluates the evidence and limitations surrounding nutritional and metabolic interventions for retinitis pigmentosa and Stargardt disease.A narrative review of preclinical studies, randomized controlled trials, and contemporary genetic re-analyses was performed. Nutritional interventions reviewed include vitamin A, vitamin E, N-acetylcysteine (NAC), omega-3 fatty acids (docosahexaenoic acid), carotenoids and apocarotenoids, and the deuterated vitamin A analog C20-D3-retinyl acetate (ALK-001).
Initial studies suggesting a protective effect of vitamin A in retinitis pigmentosa were not confirmed in subsequent trials or genetic re-analyses, which identified baseline differences between groups as a possible contributor to the original findings. In contrast, supplemental vitamin E may accelerate disease progression. NAC demonstrated acceptable tolerability and modest short-term improvements in visual function in early-phase trials, with a phase 3 study ongoing. Omega-3 fatty acids, carotenoids, and apocarotenoids have not shown consistent clinically meaningful benefit in retinitis pigmentosa or Stargardt disease despite strong mechanistic rationale. In Stargardt disease, ALK-001 reduces lipofuscin accumulation in animal models and clinical trials are ongoing to assess efficacy in patients.
Most nutritional supplements studied to date have not demonstrated durable or clinically meaningful benefit in IRDs. Vitamin A supplementation in retinitis pigmentosa is no longer supported by current evidence, while NAC remains a promising metabolic therapy under investigation. High-quality, genotype-informed clinical trials with clinically relevant endpoints are needed before nutritional interventions can be incorporated into IRD management guidelines.