Stargardt macular dystrophy and evolving therapies

Abstract

Stargardt macular dystrophy (STGD1) is a hereditary retinal degeneration that lacks effective treatment options. Gene therapy, stem cell therapy, and pharmacotherapy with visual cycle modulators (VCMs) and complement inhibitors are discussed as potential treatments. Areas covered: Investigational therapies for STGD1 aim to reduce toxic bisretinoids and lipofuscin in the retina and retinal pigment epithelium (RPE). These agents include C20-D3-vitamin A (ALK-001), isotretinoin, VM200, emixustat, and A1120. Avacincaptad pegol is a C5 complement inhibitor that may reduce inflammation-related RPE damage. Animal models of STGD1 show promising data for these treatments, though proof of efficacy in humans is lacking. Fenretinide and emixustat are VCMs for dry AMD and STGD1 that failed to halt geographic atrophy progression or improve vision in trials for AMD. A1120 prevents retinol transport into RPE and may spare side effects typically seen with VCMs (nyctalopia and chromatopsia). Stem cell transplantation suggests potential biologic plausibility in a phase I/II trial. Gene therapy aims to augment the mutated ABCA4 gene, though results of a phase I/II trial are pending. Expert opinion: Stem cell transplantation, ABCA4 gene therapy, VCMs, and complement inhibitors offer biologically plausible treatment mechanisms for treatment of STGD1. Further trials are warranted to assess efficacy and safety in humans.

Non-photopic and photopic visual cycles differentially regulate immediate, early, and late phases of cone photoreceptor-mediated vision

“…Our data demonstrates that fenretinide also impairs photopic vision, thus, concerns arise over potential adverse drug reactions in the clinic with fenretinide use to treat diseases such as geographic atrophy, cancer, acne, cystic fibrosis and psoriasis. Likewise, emixustat is now in Phase III clinical trial for the inherited retinal degeneration Stargardt disease with the intention of suppressing retinoid cycling (37). We show that the photopic visual cycle overcomes emixustat which may have significant impact on clinical outcomes.…”

“…To investigate the effects of visual cycle inhibitors on cone vision, we assayed the effects of pharmacological agents, previously used in human clinical trials (36,37), on the vision of 5 dpf zebrafish larvae. Previous studies demonstrate 5 dpf zebrafish rely exclusively on cones for vision (38).…”

Cost‐effective molecular inversion probe‐based ABCA4 sequencing reveals deep‐intronic variants in Stargardt disease

“…STGD1 (MIM# 248200) is an autosomal recessive disease caused by mutations in the gene encoding the ATP binding cassette type A4 ( ABCA4 ; MIM# 601691; Allikmets et al, ). With an estimated prevalence of 1 in 10,000 individuals (Blacharski et al, 1988), STGD1 is the most frequent juvenile inherited macular dystrophy and ABCA4 is the most frequently mutated IRD‐associated gene (Hussain et al, ; Tanna, Strauss, Fujinami, & Michaelides, ). In an inventory of all reported variants and cases, 5,962 (allelic) variants identified in 3,928 cases were listed (Cornelis et al, ).…”

Non-photopic and photopic visual cycles differentially regulate immediate, early and late-phases of cone photoreceptor-mediated vision

“…Our data demonstrates that fenretinide also impairs photopic vision, thus, concerns arise over potential adverse drug reactions in the clinic with fenretinide use to treat diseases such as geographic atrophy, cancer, acne, cystic fibrosis and psoriasis. Likewise, emixustat is now in Phase III clinical trial for the inherited retinal degeneration Stargardt disease with the intention of suppressing retinoid cycling (37). We have shown that the photopic visual cycle overcomes emixustat which may have significant impact on clinical outcomes.…”