Updates on Emerging Interventions for Autosomal Recessive ABCA4-Associated Stargardt Disease

Abstract

Autosomal recessive Stargardt disease (STGD1) is an inherited retinal degenerative disease associated with a mutated ATP-binding cassette, subfamily A, member 4 (ABCA4) gene. STGD1 is the most common form of juvenile macular degeneration with onset in late childhood to early or middle adulthood and causes progressive, irreversible visual impairment and blindness. No effective treatment is currently available. In the present article, we review the most recent updates in clinical trials targeting the management of STGD1, including gene therapy, small molecule therapy, and stem cell therapy. In gene therapy, dual adeno-associated virus and non-viral vectors have been successful in delivering the human ABCA4 gene in preclinical studies. For pharmaceutical therapies ALK-001, deuterated vitamin A shows promise with preliminary data for phase 2 trial, demonstrating a decreased atrophy growth rate after two years. Stem cell therapy using human pluripotent stem cell-derived retinal pigment epithelium cells demonstrated long-term safety three years after implantation and visual acuity improvements in the first two years after initiation of therapy. Many other treatment options have ongoing investigations and clinical trials. While multiple potential interventions have shown promise in attenuating disease progression, further exploration is necessary to demonstrate treatment safety and efficacy.

Keywords: ABCA4; Stargardt disease; adeno-associated viral vectors; deuterated vitamin A; emixustat; gene therapy; human embryonic stem cells; stem cell therapy; visual cycle modulators.

Figure 1

Typical presentation of Stargardt Type 1 at diagnosis (A₁–A₃) and 3-year follow-up (B₁–B₃). Color fundus (A₁,B₁) shows macular atrophy with yellow-white retinal flecks. Fundus autofluorescence (A₂,B₂) shows patches of hypoautofluorescence surrounded by an increased signal with flecks of both increased and decreased autofluorescence. Optical coherence tomography B-scans (A₃,B₃) show outer retinal and retinal pigment epithelium loss with hypertransmission defects corresponding to atrophy. Atrophy growth is significant at 3-year follow-up (B₁–B₃) compared to presentation at diagnosis (A₁–A₃). Best corrected visual acuity (BCVA) remains stable at 0.9 Snellen decimals (20/160). Reprinted from [1], used under an open-access license agreement distributed under the terms of the Creative Commons CC-BY license.

Figure 2

Potential pharmaceutical interventions for Stargardt disease (STGD1). Treatment options (blue “x”) are shown in a summarized representation of the visual cycle with mutated ATP-binding cassette, subfamily A, member 4 (ABCA4) gene resulting in the accumulation of lipofuscin in the retinal pigment epithelium (RPE). Treatment for STGD1 includes several strategies. Gene therapy includes vector delivery of human ABCA4 gene. Pharmaceutical therapies include visual cycle modulators (VCM), metformin, avacincaptad pegol, and docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). VCM represented are retinol binding protein 4 (RBP4) antagonists, deuterated vitamin A, and retinal pigment epithelium-specific 65 kDa protein (RPE65) inhibitor (emixustat). Stem cell therapy includes human pluripotent stem cell-derived retinal pigment epithelium (hESC-RPE) transplantation for regenerating RPE layer. Created with BioRender.com.