Stargardt disease could soon benefit from innovative treatments

Stargardt disease, the most common form of inherited macular dystrophy, is a major cause of early loss of central vision. It is caused by mutations in the ABCA4 gene, which prevent the elimination of toxic waste products from the visual cycle. These substances, called bisretinoids, accumulate in the retinal pigment epithelium, causing its dysfunction and the progressive degeneration of photoreceptors. The disease often manifests in childhood or early adulthood with a gradual decline in central vision, difficulty distinguishing colors, and slow adaptation to darkness. Its progression varies widely among individuals, depending on the age of onset, genetic variations, and environmental factors.

Currently, there is no approved treatment to stop or reverse this disease. Management relies on supportive measures such as visual rehabilitation and advice to limit exposure to aggravating factors. For example, excessive exposure to light, particularly ultraviolet and blue rays, accelerates retinal damage. Patients are therefore encouraged to wear filtering glasses and avoid overly bright environments. Smoking and a diet rich in vitamin A are also discouraged, as they promote the accumulation of lipofuscin, a substance toxic to retinal cells. A Mediterranean-style diet, low in saturated fats, is instead recommended to reduce inflammation.

Visual aids, such as electronic magnifiers, screen readers, or telescopes, play a key role in optimizing residual vision and improving quality of life. Their choice depends on the patient’s age, the stage of the disease, and specific individual needs. For younger patients, biofeedback training can help develop eccentric fixation, thereby improving gaze stability and retinal sensitivity.

However, recent advances in molecular genetics, retinal imaging, and translational research have paved the way for promising new therapeutic strategies. Several approaches are currently being studied to target different mechanisms of the disease. Some molecules act by modulating the visual cycle, thereby reducing the formation of toxic bisretinoids. This is the case with gildeuretinol, a modified form of vitamin A that slows the progression of retinal lesions by limiting the production of these harmful substances. Clinical trials have shown a significant reduction in the expansion of atrophic areas in treated patients, with good tolerance.

Another approach involves blocking the transport of vitamin A to the retina. Tinlarebant, for example, is a retinol-binding protein antagonist that reduces the supply of vitamin A to the eye, thereby decreasing the formation of bisretinoids. Trial results in adolescents show a slowing in the growth of lesions and preservation of visual acuity. This treatment has also received an innovative therapy designation from U.S. health authorities.

Gene therapies represent another major advancement. The main challenge lies in the size of the ABCA4 gene, which is too large to be carried by conventional viral vectors. Innovative solutions, such as the use of two complementary viral vectors, now make it possible to consider correcting the defective gene. These approaches have shown encouraging results in animal models, with a reduction in lipofuscin accumulation and preservation of retinal structure. Clinical trials are underway to assess their efficacy in humans.

Cellular and regenerative therapies also offer prospects for advanced stages of the disease. Transplantation of retinal pigment epithelial cells derived from stem cells has demonstrated good tolerance and prolonged graft survival in some patients. However, functional benefits remain limited and variable, highlighting the need to intervene earlier or to combine these approaches with other treatments to achieve lasting results.

Optogenetics, a technique that makes remaining retinal cells light-sensitive, is emerging as a solution to restore partial vision in patients with advanced forms of the disease. Clinical trials have shown moderate improvements in visual acuity and contrast sensitivity, particularly when this therapy is combined with visual assistance devices.

Finally, combined approaches, such as gene therapy paired with visual cycle modulation, could offer more robust results. The idea is to act simultaneously on multiple disease mechanisms to slow its progression and preserve vision as much as possible. Ongoing clinical trials increasingly incorporate patient stratification based on genotype and disease stage to optimize treatment efficacy.

These innovations, although still in development, offer a more optimistic future for people with Stargardt disease. Challenges remain, particularly due to the genetic diversity of the disease and the need to validate these approaches over the long term. However, the progress made in recent years suggests that effective therapeutic solutions could soon emerge.

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Study Citation

DOI: https://doi.org/10.1007/s40123-026-01407-z

Title: Update on the Management of ABCA4 Retinopathy (Stargardt Disease)

Journal: Ophthalmology and Therapy

Publisher: Springer Science and Business Media LLC

Authors: Deepika C. Parameswarappa; Dhanashree Ratra; Goura Chattannavar; Srikanta Kumar Padhy