Stargardt's disease: new hope for patients

A drug, still in clinical trials, opens up new perspectives for people suffering from this severe progressive maculopathy.

A new molecule, currently in clinical trials, succeeds in halting the progression of this severe hereditary maculopathy when administered at an early stage of the disease.

The new molecule is gildeuretinol acetate (ALK-001), a deuterated form of vitamin A created to reduce vitamin A dimerisation without altering visual function.

Already in preclinical studies, gildeuretinol reduced vitamin A dimerisation to the normal level found in healthy individuals, and prevented retinal degeneration and blindness in animals with Stargardt's disease.

Gildeuretinol has received orphan drug and breakthrough therapy designation for the treatment of Stargardt's disease from the Food and Drug Administration (FDA).

TEASE-3 is the first open-label clinical trial of oral gildeuretinol treatment in patients who present with initial signs of the disease on retinal imaging, but not yet with symptoms of vision loss.

Background autofluorescence and other tests were used to verify the extent to which gildeuretinol is able to counteract disease progression.

This was checked year by year and the data of each participant were compared with those of siblings with Stargardt disease and identical genetic mutations. At the primary endpoint of 2 years of treatment, the first 5 patients enrolled were asymptomatic and free of disease progression for between 2 and 6 years. In the absence of treatment, patients would have experienced visual loss within 2 years and the disease would have followed the same course observed in older siblings not treated with gildeuretinol.

The data collected so far show that gildeuretinol therapy is only able to halt the progression of Stargardt's disease if the treatment is administered at an early stage. However, the primary goal of preserving visual function in patients makes it necessary to consider the impact of the new therapy in all the different stages of the disease. It should be noted that asymptomatic or paucisymptomatic patients have so far been excluded from clinical trials.

Preliminary results of TEASE-3 and definitive results of TEASE-1 on more advanced forms of the disease were presented at the 2023 American Academy of Ophthalmology (AAO) congress.

Stargardt's disease

It is a rare ocular disease, characterised by progressive loss of central vision associated with irregular yellow-white macular and perimacular patches at the back of the eye, and a central macular atrophic lesion with a 'bronze beaten' appearance.

Stargardt disease is the most common of the hereditary juvenile macular degenerations and its prevalence is estimated at 1 case per 8,000/10,000 individuals and is similar in both sexes. The disease begins in the first two decades of life, but symptoms can also occur in adulthood, up to the seventh decade.

Progression and severity are highly variable, but generally Stargardt's disease is characterised by progressive loss of central vision, associated with blurred vision and, occasionally, progressive difficulty adapting to darkness. Peripheral vision is usually normal. In most patients, colour vision is impaired. The disease may be associated with photophobia.

Aetiology

The disease is caused by mutations in the ABCA4 gene, which encodes an adenosine triphosphate (ATP)-binding cassette transporter (ABCR) and is expressed in the cones and rods of the retina. Defects in ABCR function cause the accumulation of all-tranny-retinal and its cytotoxic derivatives, in particular lipofuscin pigments (e.g. diretinoid-pyridinium-ethanolamine) in photoreceptors and retinal pigment epithelium (RPE) cells, causing RPE cell death and subsequent loss of photoreceptors.

Transmission is either autosomal recessive or autosomal dominant, with a 25 or 50% chance of transmitting the disease to offspring, respectively.

Diagnosis

The diagnosis is based on the results of a series of examinations: visual acuity assessment, visual field, ophthalmoscopy, electroretinogram (ERG), fluorescein angiography (FA), fundus autofluorescence (FAF) and optical coherence tomography (OCT), which highlight abnormalities of the macula (progressive atrophy, often with a 'beaten bronze' appearance) and pisciform yellow-white patches that may be located only in the central portion of the macula, or extend beyond the vascular arcades. These patches are hyper-autofluorescent in images obtained with FAF. Fluorescein angiography shows the characteristic dark choroid ("choroidal silence") in approximately 85% of patients.

Prenatal diagnosis would be technically possible by screening the gene ABCA4but is not used in clinical practice.

Therapy

At present, therapy is based, first and foremost, on preventive measures aimed at slowing down the progression of the disease, e.g. wearing sunglasses to avoid excessive exposure to light, and on avoiding the use of vitamin A supplements. Regular ophthalmological check-ups are also recommended. Several treatment options are currently in development. These are generally oral therapies aimed at preventing lipofuscin accumulation. These treatments either inhibit the visual cycle by blocking the action of certain enzymes in the retina (RPE65/RBP4/LRAT/RDH5), replace vitamin A with its deuterated form (ALK001), or help remove lipofuscin by degrading it.

Prognosis

The course of the disease, given the marked clinical variability, depends on a number of parameters, including age at onset and electroretinogram results. In some cases, Stardgardt's disease can progress rapidly over a few months or gradually over several years, leading to a severe reduction in visual acuity. Peripheral vision is usually spared, but some patients may develop the cone-rod phenotype, which is associated with impaired peripheral retinal function.

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Kohli P, Tripathy K, Kaur K. Stargardt Disease. 2024 Jan 8. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. PMID: 36508525. Stargardt Disease - StatPearls - NCBI Bookshelf (nih.gov)