Nutritional supplements: current evidence for retinitis pigmentosa and Stargardt disease

INTRODUCTION

Inherited retinal diseases (IRDs) comprise a complex group of heterogenous disorders that lead to progressive retinal cell death and functional vision loss. This complexity arises from pleiotropic effects, genetic heterogeneity, phenotypic variability, the influence of genetic modifiers, and various patterns of inheritance [1–4]. At the molecular level, this heterogeneity manifests from defects in transcription factors, ion channels, and structural transport proteins across multiple retinal cell types, posing substantial challenges for the development of effective therapies [5,6].

The standard of care for many IRDs has largely focused on managing associated complications and the use of optical aids to improve quality of life. However, substantial advances in translational research have expanded therapeutic strategies beyond purely symptomatic management. Contemporary approaches increasingly include gene therapy and stem cell based techniques aimed at addressing the underlying disease mechanism. Alongside these modalities, growing attention is directed toward interventions that target shared metabolic and cellular stress pathways implicated across genetically diverse IRDs, creating a rational for potential adjunctive metabolic and nutritional strategies [7–9].

Early interest in nutritional interventions for IRDs arose largely from attempts to modify disease progression in conditions such as retinitis pigmentosa, most notably through studies of vitamin A supplementation. These investigations were informed by vitamin A's established role in the visual cycle and photoreceptor function, rather than a direct targeting of disease specific mechanisms, and therefore represented some of the earliest broadly applied therapeutic strategies in this field. Although clinical outcomes were variable and important safety and genotype specific considerations emerged, these early studies provided a foundation for later efforts to address shared metabolic pathways. Subsequently phototoxic injury and metabolic stress, particularly related to oxidative imbalance, were increasingly recognized as contributors to retinal degeneration [10,11–13^▪]. More recent advances in retinal metabolism and oxidative stress biology have renewed interest in nutritional approaches as potential adjunctive strategies. This review synthesizes both historical and contemporary evidence regarding dietary and nutritional interventions for IRDs. 

RETINITIS PIGMENTOSA: HISTORY, EVIDENCE, AND CONTROVERSY

Retinitis pigmentosa is one of the most common IRDs and is characterized by progressive photoreceptor cell death. It has a broad genetic heterogeneity, which makes accurate metabolomic analysis of the implicated cell death difficult to study. However, common cellular nutrient pathways and metabolism that lead to cell death may be a common denominator across various genotypes and offer an avenue for intervention [14].

Aerobic glycolysis helps meet the high energy demands of photoreceptors and support the outer retinal metabolic ecosystem by providing glucose intermediates for the biosynthetic pathways required for continuous outer segment renewal [15]. A decrease in aerobic glycolysis leads to rod malfunction and cone vulnerability, while still maintaining their survival. To meet their high energy demand, they can reprogram to oxidative phosphorylation. In retinitis pigmentosa, diverse genetic mutations that cause rod cell death not only disrupt aerobic glycolysis but also trigger a cascade of events leading to metabolic stress. Continuous loss of rods in retinitis pigmentosa causes the collapse of the outer nuclear layer, which disrupt the nutritional flow between cones and retinal pigment epithelium (RPE). Studies on mouse models of retinitis pigmentosa have demonstrated that non-cell autonomous effects exist, where cones are impacted negatively by neighboring cell death of rods [16,17]. Therapies that focus on improving photoreceptor survival and metabolism, may provide a neuroprotective strategy that can be broadly applicable and potentially gene agnostic.

OMEGA-3 FATTY ACIDS

Therapeutic strategies beyond metabolic interventions have also explored approaches aimed at preserving photoreceptor structure through modulation of retinal lipid composition (Table 1). An in-vivo stable isotope tracer study of fatty acid metabolism in X-linked retinitis pigmentosa (XLRP) patients demonstrated reduced levels of docosahexaenoic acid (DHA), an omega-3 fatty acid, attributed to decreased activity of Δ⁵-desaturase [24]. Δ⁵-desaturase is an enzyme that catalyzes the conversion of 20:4ω3 to eicosatetraenoic acid (EPA) (20:5ω3), representing a key rate-limiting step in the metabolic pathway from α-LNA to DHA.

DHA constitutes approximately 50–60% of the fatty acid content of rods outer segment membranes, a proportion markedly higher than that observed in other tissues. In addition to its structural role, DHA is associated with anti-apoptotic effects, including free radical scavenging, which may support cell survival. Based on these observations, a prospective randomized, double-blind, placebo-controlled clinical trial investigated the effect of DHA [400 mg twice daily (b.i.d.)] on rate of cone ERG decline in XLRP. Although mean red blood cell DHA levels were significantly increased in the treatment group (n = 23), no significant difference in ERG decline was observed compared with placebo (n = 21) [25].

Subsequently, a randomized, double-masked, placebo-controlled phase 2 clinical trial examined a higher dosage of DHA (30 mg/kg/day) in a larger cohort of patients (n = 60). As in the prior study, red blood cell-DHA concentrations were significantly elevated in the treatment group (n = 33) relative to placebo (n = 27). However, no slowing of disease progression was observed based on cone, rod, or maximal ERG functional loss [26]. A secondary analysis of this trial (DHAX) reported a reduction in the rate of visual field sensitivity loss with DHA supplementation, though no benefit was detected for visual acuity, ellipsoid zone width, or fundus appearance [27].

CAROTENOIDS STUDIES: XANTHOPHYLLS VS. CAROTENE

Carotenoids are plant-derived provitamins synthesized from eight isoprenoid units, resulting in a 40-carbon backbone structure. They are broadly classified into two groups: carotenes (hydrocarbon carotenoids) and xanthophyll (oxygenated carotenoids). Lutein and zeaxanthin are xanthophyll present in the retina, with lutein more concentrated in the macula and zeaxanthin enriched in the fovea. These compounds filter high-energy blue wavelength light and act as antioxidants by neutralizing free radicals within the retina [28].

The effect of lutein on visual function in RP was evaluated in a double-masked, randomized, placebo-controlled crossover trial (n = 34). In this study, lutein supplementation did not result in significant improvements in visual acuity, overall disease progression, or contrast sensitivity under normal or low illumination levels. Although the mean logarithmic visual field area was greater in the lutein arm compared with placebo, lutein did not significantly alter the rate of visual field loss [29].

A larger randomized, controlled, double-masked clinical trial assessed the effect of lutein supplementation (12 mg once daily) on central visual field sensitivity, measured using a Humphrey field (HFA 30-2), as well as visual acuity. No significant differences were observed between the lutein plus vitamin A group (n = 110) and the control plus vitamin A group (n = 115) with respect to ERG amplitude, combined visual field outcomes, or visual acuity. Stratified analyses by genetic subtypes (dominant, recessive, X-linked, or isolated retinitis pigmentosa) similarly demonstrated no significant treatment effects. However, participants receiving lutein showed a slower rate of mid-peripheral visual field loss compared to the controls [30].

Other studies have examined carotenes as chromophore precursor in the retinoid cycle and as antioxidant to support residual photoreceptor function. A randomized, double-masked, placebo-controlled, crossover clinical trial (n = 29) evaluated the effect of 9-cis β-carotene (20 mg) supplementation [31]. Although a statistically significant improvement in maximal scotopic b-wave amplitude was observed on ERG, the magnitude of change was modest, with an average increase of 8 μV. The clinical relevance of this primary endpoint is difficult to interpret, particularly given that only 10 participants demonstrated measurable improvement. It is possible that the benefit could be limited to a subset of patients if they shared specific mutations. No significant differences were observed between groups for visual field or visual acuity outcomes [31].

STARGARDT DISEASE: SUPPLEMENTS, EMERGING THERAPIES, AND LIMITATIONS

Stargardt disease (STGD1), caused by autosomal recessive mutations in ABCA4, is the most common inherited macular dystrophy. Therapeutic development is challenging, as gene and cell-based approaches must contend with marked clinical heterogeneity arising from the large allelic diversity of ABCA4, with over 2300 pathogenic variants reported [32]. Aspects of STGD1 pathophysiology are relatively well characterized, including its effects on vitamin A metabolism. During the retinoid cycle in photoreceptors, 11-cis-retinal is photoisomerized to all-trans-retinal following exposure to light. During the subsequent dark phase, all-trans-retinal undergoes a series of enzymatic reactions to regenerate 11-cis-retinal. One of the key enzymatic reactions during this process is the reduction of all-trans-retinal to its less toxic form, all-trans-retinol, by retinol dehydrogenase in the outer segments. Under increased light conditions, large amounts of all-trans-retinal are generated, and retinol dehydrogenase can become saturated. Excess all-trans-retinal then reacts with the phospholipid phosphatidylethanolamine in the outer segment disc membranes, producing N-retinylidene-phosphatidylethanolamine (N-Ret-PE) [33]. This adduct is subsequently transported to the cytoplasmic side of the disc membrane by the flippase and transporter ABCA4, allowing regeneration of all-trans-retinal for further processing by retinol dehydrogenase [34].

Pathogenic variants in ABCA4 renders the protein product defective, which in turns increases the toxic substrate all-trans-retinal and decreases clearance of N-Ret-PE. The aldehyde group and lipophilic properties of all-trans-retinal confer substantial cytotoxicity. Its toxic effects include creation of reactive oxygen species that promote caspase activation and mitochondrial-associated cell death. Its lipophilicity prevents compartmentalization and allows it to diffuse across multiple cellular compartments and neighboring cells to cause more oxidative stress [35]. In addition, accumulation of N-Ret-PE leads to the bisretinoid pathway, which is initiated when readily available N-retinylidene-PE reacts with a second molecule of all-trans-retinal. Further nonenzymatic reaction leads to the formation of A2-dihydropyridine-phosphatidylethanolamine (A2-DHP-PE), A2-dihydropyridine-ethanolamine (A2-DHP-E) and N-retinylidene-N-retinyl-ethanolamine (A2E) deposits in the outer segment. As the RPE continuously turns over photoreceptor outer segments, complex bisretinoid compounds are transferred to the RPE. Because lysosomal enzymes cannot break down these molecules, they accumulate over time and form lipofuscin deposits, one of the pathological hallmarks of Stargardt disease [36].

MODIFIED VITAMIN A

Vitamin A supplementation and high vitamin A intake should be avoided in Stargardt disease given high-dose vitamin A specifically increases retinal accumulation of the toxic byproduct A2E in patients with ABCA4 mutations. Two oral pharmacologic therapies, deuterated vitamin A analog ALK-001 and the retinol-binding protein 4 antagonist Tinlarebant, are under active clinical investigation to slow disease progression by reducing toxic vitamin A byproducts and lipofuscin accumulation.

To target the RPE lipofuscin pathway, the replacement of vitamin A with orally administered C20-D3-retinyl acetate (ALK-001) has been studied in animal models and now clinical trials. ALK-001 is a deuterated analog of vitamin A, in which three hydrogen atoms are replaced with deuterium atoms (Table 2). This modification is intended to slow key hydrogen-dependent reactions involved in bisretinoid formation, thereby reducing lipofuscin accumulation.

ALK-001 (15 000 IU/kg diet) was administered to mice lacking the ABCA4 protein and wild-type mice. For the control groups, null mice and wild-type mice received vitamin A supplements (15 000 IU/kg diet). A significant attenuation of autofluorescence, A2E accumulation, and lipofuscin formation was observed in the C20-D₃-vitamin groups. However, the disease process was not halted and continuous treatment with ALK-001was required to prevent further A2E accumulations and lipofuscin [37]. A true control group without vitamin A supplementation may have provided a more appropriate comparison [38].

ALK-100 is currently ongoing a multicenter, randomized, double-masked, placebo-controlled phase 2 clinical trial (NCT02402660), but there are currently no peer review publications on the result of the phase 1 trial (NCT02230228).

RETINOL-BINDING PROTEIN 4 (RBP4) ANTAGONIST (TINLAREBANT)

Tinlarebant (LBS-008) is an orally administered, small-molecule retinol-binding protein 4 (RBP4) antagonist under clinical development for ABCA4-associated Stargardt disease. By inhibiting RBP4, Tinlarebant reduces systemic transport of vitamin A to the retina, thereby decreasing formation of toxic bisretinoids and lipofuscin accumulation in the RPE. Preclinical studies demonstrated reduced retinal lipofuscin deposition, and clinical evaluation is ongoing in multiple trials, including a phase 3 randomized, placebo-controlled study (DRAGON; NCT05244304) designed to assess slowing of progression macular retinal degeneration.

OMEGA-3 FATTY ACIDS

The properties of DHA have also been explored in Stargardt disease. It was hypothesized that preservation of outer segment membrane integrity through omega-3 fatty acid supplementation might support the activity of the ABCA4 protein activity and mitigate secondary photoreceptor dysfunction. This structural rationale motivated omega-3 supplementation for STGD1, although it is important to note that such approaches do not address the underlying ABCA4 defect nor directly prevent toxic bisretinoid formation. A double-masked, randomized placebo-controlled crossover clinical trial (n = 11) evaluated the effect of DHA (2000 mg daily) on multifocal ERG and visual field. None of the participants experienced a significant change from baseline for these variables [39]. Similarly, the NAT-3 open-label pilot study evaluated lower-dose DHA supplementation (840 mg/day) over 6  months in 20 patients and found no significant overall functional improvement [40].

APOCAROTENOIDS

Apocarotenoids are metabolites formed by cleavage of carotenoids. Unlike carotenoids, they are more hydrophilic and function primarily as signaling molecules. Crocins and crocetin are apocarotenoids derived from saffron plant and various crocus species. At low dose, they upregulate adaptive stress responses by increasing expression of antioxidant enzymes and inhibiting cell death pathways. These properties have been assessed in Stargardt disease. A randomized, placebo-controlled, crossover clinical trial (n = 31 patients with ABCA4 genotype) evaluated the effect of saffron extract (20 mg) with an unknown mass percentage of crocins/crocetin, on visual acuity and central focal ERG. No significant changes in these variables were observed when compared with the placebo [41].

CONSENSUS, GUIDELINES, AND KEY OPINIONS

Despite substantial advances in genomic strategies and therapeutic development, the underlying disease mechanisms of IRDs remain complex to address. This complexity has limited the broad applicability of gene-specific therapy and highlights the need for complementary, gene-agnostic approaches.

Within this context, strategies aimed at preserving photoreceptor survival and supporting retinal metabolism have emerged as a rational adjunct to disease specific interventions. Nutritional and metabolic therapies have therefore been explored as potential means of maintaining cellular homeostasis and mitigating secondary injury pathways, including oxidative stress and metabolic imbalance. However, current evidence indicates that most dietary supplements studied to date have not demonstrated consistent or durable clinical benefit, underscoring the need for cautious interpretation and evidence-based guidance.

At present, consensus recommendations do not support routine use of nutritional supplementation for IRDs outside of clinical trials, although the risks are likely low for most supplements. Patients with Stargardt disease should not take vitamin A supplementation and avoid high vitamin A intake, as excess vitamin A has been shown to increase lipofuscin accumulation and retinal toxicity in ABCA4-associated disease. In addition, it may be advisable for patients with IRD to avoid supplemental vitamin E given limited data that suggests it accelerates the progression of retinitis pigmentosa. Future progress will require rigorously designed, genotype-informed studies with clinically meaningful endpoints to clarify whether metabolic or nutritional strategies can play a defined role alongside emerging genetic and cellular therapies.

Acknowledgements

None.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

• ▪ of special interest

• ▪▪ of outstanding interest