Stargardt disease and progress in therapeutic strategies

Abstract

Background: Stargardt disease (STGD1) is an autosomal recessive retinal dystrophy due to mutations in ABCA4, characterized by subretinal deposition of lipofuscin-like substances and bilateral centrifugal vision loss. Despite the tremendous progress made in the understanding of STGD1, there are no approved treatments to date. This review examines the challenges in the development of an effective STGD1 therapy. Materials and Methods: A literature review was performed through to June 2021 summarizing the spectrum of retinal phenotypes in STGD1, the molecular biology of ABCA4 protein, the in vivo and in vitro models used to investigate the mechanisms of ABCA4 mutations and current clinical trials. Results: STGD1 phenotypic variability remains an challenge for clinical trial design and patient selection. Pre-clinical development of therapeutic options has been limited by the lack of animal models reflecting the diverse phenotypic spectrum of STDG1. Patient-derived cell lines have facilitated the characterization of splice mutations but the clinical presentation is not always predicted by the effect of specific mutations on retinoid metabolism in cellular models. Current therapies primarily aim to delay vision loss whilst strategies to restore vision are less well developed. Conclusions: STGD1 therapy development can be accelerated by a deeper understanding of genotypephenotype correlations.

Fenretinide in Cancer and Neurological Disease: A Two-Face Janus Molecule

“…Based on the study in geographic atrophy patients, fenretinide was also proposed as a potential treatment in the Stargardt's macular degeneration disease [103], a genetic eye disorder that causes progressive vision loss; to date, however, no clinical or preclinical data are available.…”

Characterising splicing defects of ABCA4 variants within exons 13–50 in patient-derived fibroblasts

“…Briefly, patients with subretinal hyperautofluorescent flecks, macular outer retinal atrophy and peripapillary sparing were considered for genotyping. Those with early-onset cone-rod dystrophy phenotype were genotyped if they had the typical speckled autofluorescence pattern and broadening of the external limiting membrane band on optical coherence tomography (Huang et al, 2021). Late-onset STGD1 was suspected and the patients genotyped if they had macular and peripapillary flecks with foveal sparing.…”

“…Following the discovery of the ATP-binding cassette subfamily A member 4 gene (ABCA4) as the disease-causing gene for STGD1 (Allikmets et al, 1997), over 2200 variants have been identified. Although improved clinical phenotyping with multimodal imaging (Huang et al, 2021) and the accessibility of commercial high-throughput sequencing services such as Molecular Vision (https://www.molecularvisionlab.com/), Invitae (https://www. invitae.com/en), Fulgent (https://www.fulgentgenetics.com/) and Blueprint Genetics (https://blueprintgenetics.com/) have vastly facilitated diagnostic screening of ABCA4 variants, our current understanding of these variants and their functional consequences is very limited.…”

A pathogenic in-frame deletion-insertion variant in BEST1 phenocopies Stargardt disease

“…Although the clinical presentation was consistent with Stargardt, both CLIA and extensive research genetic testing revealed no variants in ABCA4 or other known phenocopies, and EOG results revealed an abnormal light rise consistent with BVMD. Full-field ERG revealed normal scotopic rod-specific and photopic cone-specific responses, which would be expected in both Stargardt disease and BVMD (20). In contrast, P2 presented with a fundus phenocopy of more advanced Stargardt disease phenotype, likely attributable to the difference in age between the patients.…”

“…EOG, although affected by the patient's poor fixation, showed diminished light rise bilaterally and ffERG revealed preserved scotopic rod-specific responses with a low B to A ratio, suggesting inner retinal dysfunction consistent with published literature (21)(22)(23), and diminished photopic-cone single flash and 30Hz flicker responses. While ffERG findings are often normal in early BVMD and Stargardt disease, diminished scotopic and photopic responses can be expected in later stage Stargardt disease (20). Only patients diagnosed with multifocal Best disease, the autosomal recessive form of the disease (24), will show abnormal ffERG results (25,26).…”