Stargardt disease

Genetic form of macular degeneration

Stargardt disease is the most common inherited single gene retinal disease. In terms of the first description of the disease, it follows an autosomal recessive inheritance pattern, which has been later linked to bi allelic ABCA4 gene variants (STGD1). However, there are Stargardt like diseases with mimicking phenotypes that are referred to as STGD3 and STGD4, and have a autosomal dominant inheritance due to defects with ELOVL4 or PROM1 genes, respectively. It is characterized by macular degeneration that begins in childhood, adolescence or adulthood, resulting in progressive loss of vision.

Diagnosis is firstly clinical through history and examination usually with a Slit lamp. If characteristic features are found the investigations undertaken will depend on locally available equipment and may include Scanning laser ophthalmoscopy which highlights areas of autofluorescence which are associated with retinal pathology. Spectral domain optical coherence tomography, electroretinography and microperimetry are also useful for diagnostic and prognostic purposes. Fluorescein angiography is used less often than in the past. These investigations may be followed by genetic testing in order to avoid misdiagnosis. Other diseases may have overlapping phenotypic features with Stargardt Disease and the disease itself has multiple variants. In one study, 35% of patients diagnosed with Stargardt Disease through physical ophthalmic examination were found to be misdiagnosed when subsequent genetic testing was done. Genetic testing can be utilized to ensure a proper diagnosis for which the correct treatment can be applied.

At present there is no gene therapy for Stargardt Disease. However, ophthalmologists recommend measures that could slow the rate of progression. There are no prospective clinical trials to support these recommendations, but they are based on scientific understanding of the mechanisms underlying the disease pathology. There are three strategies doctors recommend for potential harm reduction: reducing retinal exposure to damaging ultraviolet light, avoiding excess Vitamin A with the hope of lowering lipofuscin accumulation and maintaining good general health and diet. MD Stem Cells' approach using Bone Marrow Derived Stem Cells has shown benefit in various retinal diseases. In Stargardt, 94.1% of patients had improved vision or remained stable with results showing high statistical significance (p=0.0004). Reasons for improvement may include transfer of organelles (mitochondria, lysosomes), enhanced clearing of toxic Vitamin A byproducts, and neuroprotection of photoreceptors. Ultra violet light has more energy and is a more damaging wavelength spectra than visible light. In an effort to mitigate this, some ophthalmologists may recommend that the patient wears a broad brimmed hat or sunglasses when they are outdoors. Foods with a high vitamin A content are often yellow or orange in color, such as squash, pumpkin, and sweet potato, but some, such as liver, are not. There are supplements on the market with more than a daily allowance of vitamin A that should be avoided, but each individual should discuss this with their doctor. Smoking, overweight or obesity, and poor diet quality may also contribute to more rapid degeneration. On the other hand, the consumption of oily fish, in a diet similar to that which doctors recommend for age related macular degeneration, can be used to slow the progression of the disease. Advances in technology have brought devices that help Stargardt patients who are losing their vision maintain their independence. Low vision aids can range from hand lenses to electronic devices and can allow those losing their vision to be able to carry out daily activities. Stargardt disease has no impact on general health and life expectancy is normal. Some patients, usually those with the late onset form, can maintain excellent visual acuities for extended periods and are therefore able to perform tasks such as reading or driving.

Karl Stargardt (1875–1927) was a German ophthalmologist born in Berlin. He studied medicine at the University of Kiel, qualifying in 1899. He later became head of the Bonn University's ophthalmology clinic, followed by a post as chair of ophthalmology at the University of Marburg. In 1909 he described 7 patients with a recessively inherited macular dystrophy, now known as Stargardt's disease, being described as a progressive and severe reduction of central vision, which develops in the first and second decade of life. Kubota Vision is in Phase III clinical trials of a visual cycle modulator that modulates RPE65 activity to treat Stargardt's. Kubota Vision published the results of a dose range study of a drug known as Emixustat, with findings that will effect dose selection for their phase III trial set to complete in June 2022. Stem cell therapy involves injecting cells with the potential to mature into differentiated and functioning retinal cells. This therapy has the potential stop disease progression and in the long term improve vision. To improve vision this technique will need to replicate the complex multi layered and neurally anatomy of the retina. There are a number of research groups working with stem cells one of which is Ocata Therapeutics. Alkeus Pharma is evaluating the potential of deuterated vitamin A as the drug ALK 001. The hope is that the deuterated vitamin A will reduce the build up of toxic vitamin A metabolites in the retina and therefore slow rate of visual deterioration. To create deuterated vitamin A some of the hydrogen atoms are replaced with the isotope deuterium which has an extra neutron and is therefore twice the standard atomic weight of hydrogen. A Phase II clinical trial is taking place using ALK 001 with an estimated completion date of December 2024. MD Stem Cells, a research physician clinical development company using autologous bone marrow derived stem cells (BMSC), has released results of the Stargardt Disease cohort within their ongoing Stem Cell Ophthalmology Study II (SCOTS2) clinical trial (NCT 03011541). Average visual improvement was 17.96% (95% CI, 16.39 to 19.53%) with 61.8% of eyes improving and 23.5% remaining stable with no adverse events occurring. Retinal implants are in the early stages of development and their use could be of benefit to many people with visual impairment though implanting and maintaining an electrical device within the eye that interfaces with the optic nerve presents many challenges. An example of a device is made by Argus retinal prosthesis, the camera is an external device held on spectacles, the camera signal is processed and then fed via wires into the retina to terminate in some electrodes that interface with the optic nerve.