Dayma Kunal, Rajanala Kalpana, Upadhyay Arun
Ocugen India, 5th Floor, AYDIV IT Park, Financial District, Nanakramguda, Hyderabad 500032, Telangana, India.
Ocugen, 11 Great Valley Parkway, Malvern, PA 19355, USA.
Int J Mol Sci. 2025 Jul 21;26(14):7006. doi: 10.3390/ijms26147006.
Stargardt's disease (STGD1) is an autosomal recessive juvenile macular degeneration caused by mutations in the gene, impairing clearance of toxic retinoid byproducts in the retinal pigment epithelium (RPE). This leads to lipofuscin accumulation, oxidative stress, photoreceptor degeneration, and central vision loss. Over 1200 pathogenic/likely pathogenic variants highlight the genetic heterogeneity of STGD1, which manifests as progressive central vision loss, with phenotype influenced by deep intronic variants, modifier genes, and environmental factors like light exposure. variants also show variable penetrance and geographical prevalence. With no approved treatment, investigational therapies target different aspects of disease pathology. Small-molecule therapies target vitamin A dimerization (e.g., ALK-001), inhibit lipofuscin accumulation (e.g., soraprazan), or modulate the visual cycle (e.g., emixustat hydrochloride). Gene therapy trials explore ABCA4 supplementation including strategies like RNA exon editing (ACDN-01) and bioengineered ambient light-activated OPSIN. RORA gene therapy (Phase 2/3) addresses oxidative stress, inflammation, lipid metabolism, and complement system dysregulation. Trials like DRAGON (Phase 3, tinlarebant), STARLIGHT (phase 2, bioengineered OPSIN) show promise, but optimizing efficacy remains challenging. With the key problem of establishing genotype-phenotype correlations, the future of STGD1 therapy may rely on approaches targeting oxidative stress, lipid metabolism, inflammation, complement regulation, and genetic repair.
斯塔加特病（STGD1）是一种常染色体隐性青少年黄斑变性，由该基因突变引起，损害视网膜色素上皮（RPE）中有毒类视黄醇副产物的清除。这会导致脂褐素积累、氧化应激、光感受器变性和中心视力丧失。超过1200种致病/可能致病的变异突出了STGD1的遗传异质性，其表现为进行性中心视力丧失，表型受内含子深处变异、修饰基因和光照等环境因素影响。变异还表现出可变的外显率和地理患病率。由于没有获批的治疗方法，研究性疗法针对疾病病理的不同方面。小分子疗法靶向维生素A二聚化（如ALK - 001）、抑制脂褐素积累（如索拉普赞）或调节视觉循环（如盐酸依米司他）。基因治疗试验探索ABCA4补充，包括RNA外显子编辑（ACDN - 01）和生物工程化的环境光激活视蛋白等策略。RORA基因治疗（2/3期）解决氧化应激、炎症、脂质代谢和补体系统失调问题。像DRAGON（3期，替奈雷班）、STARLIGHT（2期，生物工程化视蛋白）这样的试验显示出前景，但优化疗效仍然具有挑战性。由于存在建立基因型 - 表型相关性的关键问题，STGD1治疗的未来可能依赖于针对氧化应激、脂质代谢、炎症、补体调节和基因修复的方法。
