Six companies are actively developing therapies for Stargardt disease, an inherited retinal disease that affects approximately 60,000 people in the United States. Baruch D. Kupperman, MD, PhD, presented an overview of the growing pipeline of investigational Stargardt therapies during the 2025 Retina World Congress in Fort Lauderdale, Florida.

“There’s a lot going on in [the Stargardt] space,” noted Dr. Kupperman, the Steinert Endowed Professor and chairman of the department of ophthalmology at the University of California, Irvine School of Medicine and director of the Gavin Herbert Eye Institute. “The inherited retinal disease universe has gotten a lot of attention. Multiple treatments are in development. Mechanisms of action include gene therapy, visual cycle vitamin A modulation, and optogenetics. A limited number of patients have been treated to date. Results are early but promising. Further clinical trials are under way or in planning.”

Stargardt disease is usually caused by mutations in the ABCA4 gene, which impair the normal transport of vitamin A derivatives in the visual cycle. “There’s excess vitamin A dimerization, and A2E damage results in lipofuscin accumulation in the RPE and photoreceptors, leading to cell death,” Dr. Kupperman explained. This toxic buildup gradually damages retinal cells, leading to progressive vision loss, often beginning in childhood or adolescence.

Belite Bio is developing tinlarebant, a once-daily oral therapy designed to reduce the delivery of vitamin A to the eye by binding to retinol-binding protein 4 (RBP4) in the serum. This modulation slows the formation of toxic vitamin A dimers that accumulate in the retinal pigment epithelium (RPE) and lead to cell death. In early-phase studies, the drug stabilized disease progression but was associated with some visual side effects, including delayed dark adaptation and yellow vision (xanthopsia), which led to a small number of dropouts, Dr. Kupperman noted. “But they have completely enrolled the phase 3 DRAGON study, so they’re well along the way of development.”

Dr. Kupperman mentioned that he is a consultant to Alkeus Pharmaceuticals, which is advancing ALK-001 (gildeuretinol), a chemically modified form of vitamin A in which hydrogen atoms are replaced with deuterium to reduce dimerization and slow the formation of atrophic lesions while preserving visual cycle function.

“It’s a new molecular entity,” said Dr. Kupperman. “It was well tolerated with mild to moderate side effects—very minimal.” The treatment showed no clinically significant changes in liver function or signs of delayed dark adaptation, he noted. Alkeus is conducting multiple trials, including TEASE-1, TEASE-2, TEASE-3, and TEASE-4, with more than 200 patients expected to be enrolled across the program.

Ocugen is developing OCU410ST, a subretinal gene therapy that delivers the nuclear hormone receptor RORA, a modulator of lipid metabolism, with the aim of restoring retinal health in Stargardt disease. In the phase 1 GARDian study, study, the therapy demonstrated a favorable safety profile and early signals of visual improvement compared to untreated eyes. A phase 2/3 study is in planning, pending further regulatory review.

Nanoscope Therapeutics is working on MCO-010, an optogenetic therapy delivered by intravitreal injection. The therapy introduces a multicharacteristic opsin (MCO) designed to confer light sensitivity to surviving retinal cells, enabling improved visual function even in advanced retinal degeneration. In the open-label phase 2 STARLIGHT study, MCO-010 showed functional gains in vision and increased use of assistive devices among treated patients. The company plans to initiate a phase 3 registration trial later this year.

Ascidian Therapeutics has developed ACDN-01, an RNA exon-editing gene therapy aimed at restoring full-length ABCA4 mRNA in patients with Stargardt disease. Delivered subretinally via an adeno-associated virus (AAV) vector, the treatment uses RNA editing to correct the ABCA4 transcript without altering the underlying DNA. The phase 1/2 STELLAR trial is currently under way and actively enrolling patients.

AAVantgarde Bio is developing a gene therapy platform called AAVB-039, which utilizes a proprietary dual AAV vector system designed for large-gene delivery. Their Stargardt disease program focuses on delivering a functional ABCA4 gene to retinal cells using this dual AAV vector approach. First-in-human studies are planned to begin in 2025, with a proof-of-concept trial anticipated for 2027.

While each therapy varies in design and target mechanism, the rapid expansion of clinical programs reflects an increasingly competitive pipeline. “We’ll see what happens as it continues to be developed,” Dr. Kupperman said of the Alkeus program, but his statement applied more broadly to the field. With no approved therapy for Stargardt disease, these investigational agents represent early but significant steps toward filling that gap. RP