Long-term vitamin A supplementation in a preclinical mouse model forRhoD190N-associated retinitis pigmentosa

Abstract

Retinitis pigmentosa is caused by one of many possible gene mutations. The National Institutes of Health (NIH) recommends high daily doses of vitamin A palmitate for retinitis pigmentosa (RP) patients. There is a critical knowledge gap surrounding the therapeutic applicability of vitamin A to patients with the different subtypes of the disease. Here, we present a case report of a patient with RP caused by a p.D190N mutation in Rhodopsin (RHO) associated with abnormally high quantitative autofluorescence values after long-term vitamin A supplementation. We investigated the effects of vitamin A treatment strategy on RP caused by the p.D190N mutation in RHO by exposing RhoD190N/+ and wild-type (WT) mice to experimental vitamin A-supplemented and standard control diets. The patient’s case suggests that the vitamin A treatment strategy should be further studied to determine its effect on RP caused by p.D190N mutation in RHO and other mutations. Our mouse experiments revealed that RhoD190N/+ mice on the vitamin A diet exhibited higher levels of autofluorescence and lipofuscin metabolites compared to WT mice on the same diet and isogenic controls on the standard control diet. Vitamin A supplementation diminished photoreceptor function in RhoD190N/+ mice while preserving cone response in WT mice. Our findings highlight the importance of more investigations into the efficacy of clinical treatments like vitamin A for patients with certain genetic subtypes of disease and of genotyping in the precision care of inherited retinal degenerations.

Retinitis Pigmentosa: From Pathomolecular Mechanisms to Therapeutic Strategies

“…Despite the long-established role of vitamin A palmitate and its low cost, it remains a noncurative therapy, with the only purpose of its use being to slow down the disease's progression. Furthermore, interpreting data from clinical trials on this therapy is subject to controversy, highlighting the need to genotype the patients who could be of most benefit [27]. The ethical and immunological problems related to stem cell transplantation have been bypassed by intravitreal, subretinal, and suprachoroidal MSCs implantation, which has shown a good safety profile and promising results.…”

“…They discovered that a high dose of vitamin A preserves functional rod activity, as demonstrated by ERGs tracing in RHOT17M but not in RHOP347S mice [26]. Also, a more recent study found that excess dietary vitamin A in the presence of the RHOD190N variants exacerbates photoreceptors' death, probably due to the accumulation of toxic bis retinoid lipofuscin fluorophores in the RPE cells, highlighting the need for genotype stratification as an inclusion criterion for further vitamin A studies [27]. We can surmise from this that interpreting the data on vitamin A palmitate in retinitis pigmentosa is subject to controversy, and recent studies have demonstrated that retinoic acid (RA) in degenerative retinal diseases is a trigger for retinal remodeling, reducing visual decline.…”

Rhodopsin-associated retinal dystrophy: Disease mechanisms and therapeutic strategies

“…One study showed that vitamin A supplementation helps preserve rod photoreceptors and visual function in a T17M (class II mutation) transgenic mouse ( Li et al, 1998 ) but has little beneficial effect on P347S (class I mutation) mutant mice ( Li et al, 1998 ). More importantly, a recent study showed that the D190N transgenic mice on the vitamin A diet exhibited higher levels of autofluorescence and lipofuscin metabolites, raising concerns about the potential detrimental effect of vitamin A supplementation on the retina expressing D190N ( Cui et al, 2022 ). As the vitamin A method depends on the context of mutations, when this therapeutic method is translated from the laboratory to clinical treatment, the patients should be genotyped for the mutation in rhodopsin to determine whether this treatment method should be initiated.…”

Natural history of retinitis pigmentosa based on genotype, vitamin A/E supplementation, and an electroretinogram biomarker

“…In a different study, vitamin A supplementation was found to be adverse in an RHO p.Asp190Asn mutant mouse line. In a different study, an RHO p.Asp190Asn patient was shown to have a high fundus autofluorescence level, and treatment of an RHO p.Asp190Asn mouse model cause faster progression of disease ( 24 ). A recent study showed a correlation between serum vitamin A concentrations and disease severity in RHO p.G90D patients ( 25 ).…”