Stargardt’s syndrome, also known as juvenile macular degeneration, is a rare genetic disorder that usually develops in young adults and causes a progressive degeneration of the macula, the central region of the retina responsible for vsharp, central and color vision. Consequently, the main symptom of Stargardt’s disease is the loss of central vision and color blindness.
The main gene causing Stargardt’s macular dystrophy (STGD1) is ABCA4. The protein encoded by this gene removes some of the products that accumulate in the retina during the visual cycle, specially A2E. Mutations in both copies of the gene (ABCA4) result in failure of the detoxification process, and lead to the accumulation of fatty material that can be observed as yellowish clumps in the eye fundus. This pile up is toxic for the cells of the retina and destroys the central vision. Besides ABCA4, two other genes have been described to be the cause of the dominant forms of Stargardt: ELOVL4 (STGD3) and PROM1 (STGD4). Although these forms of the disease also result from a defective detoxifying process of the subproducts of the visual process or the cellular regeneration, the trigger is a mutation of only one of the alelles. Due to the number of similarities and differences among the different classes of Stargardt disease, some of the therapies currently assayed are specific for each type, whereas others aim to be valid for all Stargardt forms.
Nowadays, there is a variety of strategies proposed for the treatment of this disorder. Dietary supplements (DHA, Omega-3, Safron) and drugs (Emuxistat, Zimura,…) are designed primarily to reduce the accumulation of cytotoxic products and thus stop the progression of the visual decay. In the case of gene therapy, a phase 1/2 clinical trial was proposed to transfer the correct coding region of ABCA4 with a lentiviral vector. Although this trial has been discontinued, there is an ongoing follow-up of the treated patients. The results published so far are not enough to evaluate the safety and efficacy of this treatment.
Another approach, cellular therapy, has been adopted by several pharmaceutical companies (Astellas Pharma Inc., MD Stem Cells). This treatment is based in the substitution of the damaged cells of the macula by healthy pigmented epithelium cells. (More information about recent therapies in Piotter et al. 2021). In this case, it is not the origin of the problem that is corrected, but one of the effects, that is, cell death.
With the same goal in mind, the recently FDA-approved therapy developed by Nanoscope Therapeutics Inc. aims to the restore cell function by transferring bacterial genes encoding light-sensitive proteins (opsins) that can capture different light wavelengths (colors) and directly activate the neural circuit (ganglion cells). Another essential component of the optogenetic therapy are the special glasses (that have to be adapted to the patient) to translate the environmental light into light stimuli that can be absorbed by opsins. This direct communication between opsins and neurons does not require the function of photoreceptors neither retinal pigment epithelium cells. For this reason, this approach could be extended to treat other similar dystrophies.