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Stargardt Macular Dystrophy: Characteristics, Pathogenesis, and Therapeutic Approaches
abstract
This abstract is available on the publisher's site.
Access this abstract nowStargardt macular dystrophy (Stargardt disease; STGD1; OMIM 248200) is the most prevalent inherited macular dystrophy. STGD1 is an autosomal recessive disorder caused by multiple pathogenic sequence variants in the large ABCA4 gene (OMIM 601691). Major advances in understanding both the clinical and molecular features, as well as the underlying pathophysiology, have culminated in many completed, ongoing and planned human clinical trials of novel therapies.The aims of this concise review are to describe (1) the detailed phenotypic and genotypic characteristics of the disease, multimodal imaging findings, natural history of the disease, and pathogenesis, (2) the multiple avenues of research and therapeutic intervention, including pharmacological, cellular therapies and diverse types of genetic therapies that have either been investigated or are under investigation and (3) the exciting novel therapeutic approaches on the translational horizon that aim to treat STGD1 by replacing the entire 6.8 kb ABCA4 open reading frame.
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Stargardt macular dystrophy and therapeutic approaches
Br J Ophthalmol 2024 Mar 20;108(4)495-505, K Fujinami, N Waheed, Y Laich, P Yang, Y Fujinami-Yokokawa, JJ Higgins, JT Lu, D Curtiss, C Clary, M MichaelidesFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
In this study, Fujinami et al described the clinical, molecular, and pathophysiological features of Stargardt macular dystrophy (STGD1) as well as multiple therapeutic and pharmacological interventions for managing the disease. STGD1, one of the most common macular diseases, is caused by a variation in the highly polymorphic ABCA4 gene, which is involved in the transportation of retinoids in the retinoid cycle. Failure to efficiently transport N-retinylidene-PE out of the photoreceptor outer segments can result in an accumulation of the toxic metabolite A2E. Owing to the gene's vast allelic heterogeneity, characterizing genotype–phenotype correlations is often difficult and results in a wide range of clinical presentations and varying ages of onset. However, it is known that null variants tend to cause rapidly progressive, early-onset, and severe disease, whereas missense variants are commonly associated with mild, slower-progressing, and later-onset disease.
STGD1 commonly presents with bilateral loss of central vision, macular atrophy, and yellow/white flecks in the retinal pigment epithelium with or without foveal sparing. Although there are currently no proven cures for STGD1, certain pharmacological therapies have shown great potential for slowing the progression of the disease by lowering the formation of toxic metabolites, inhibiting enzymes in the retinoid cycle, or targeting toxic A2E metabolites. For advanced stages of the disease, treatment with human embryonic stem cell–derived retinal pigment epithelium cells offers promising outcomes, resulting in a slight improvement in visual acuity. Another recent intervention described is gene replacement therapy, specifically the delivery of ABCA4 using viral vectors, such as adeno-associated viruses and lentiviruses. Owing to limited carrying capacity and concerns for immune reactions to the viral vector, the authors suggest the use of nonviral vectors, such as cationic lipids and lipid nanoparticles, which have both shown success in the delivery of nucleic acids. Another potential approach to gene replacement therapy in patients with STGD1 described by the authors is CRISPR-based gene editing of the ABCA4 gene, which, however, raises concerns about double-stranded DNA breaks and the unwanted effects resulting from the associated repair mechanisms. The authors suggest a mammal-derived transposon-based system to circumvent these effects.
In conclusion, the authors of this study suggest using combinations of the therapies described for each uniquely presenting clinical case and a continuation of research into gene replacement therapy for patients with STGD1.