Over the past several decades, researchers have identified hundreds of genes that contribute to inherited eye diseases, including Stargardt disease. This information has led to better diagnostic tests, and is providing insight into possible treatments.
Scientists are also working to find new mutations in the ABCA4 gene, and in other genes, that might contribute to Stargardt disease. NEI’s National Ophthalmic Disease Genotyping and Phenotyping Network (eyeGENE) is an important resource for these efforts. The eyeGENE network gives patients access to genetic studies and clinical trials, while giving researchers access to patient DNA samples and clinical information.
Many studies continue to explore the biology and genetics of Stargardt disease, and of macular degeneration more generally. For example, NEI is conducting a natural history study of Stargardt and other ABCA4-related diseases. The study is following 45 individuals with ABCA4 mutations for five years. The main goals are to better understand the natural course of the disease, to make contact with people who may be interested in future clinical trials, and to collect blood, skin, and DNA samples from those people. These samples can be studied in the lab to explore the mechanisms of Stargardt disease.
Such mechanistic studies can lead to new treatment strategies. One strategy currently under study is to reduce the build-up of lipofuscin and other toxic byproducts in the retina. An NEI-funded group based at Columbia University is working with a synthetic form of vitamin A, called ALK-001, that isn’t readily converted into lipofuscin. In mice and larger animal models, an oral form of ALK-001 slows the formation of lipofuscin deposits. ALK-001 is being tested for safety in healthy volunteers before testing begins on people with Stargardt disease.
A group based at Case Western Reserve University and supported by the NEI Translational Research Program on Therapy for Visual Disorders is taking another approach. The group has tested a panel of drugs already deemed safe by the Food and Drug Administration (FDA) in a mouse model of Stargardt. They found that some FDA-approved drugs can reduce retinal damage in the mice. They are now evaluating chemical compounds with a similar structure to FDA-approved drugs, and exploring different modes of drug delivery.
Gene therapy — that is, repairing or replacing the defective ABCA4 gene — also holds promise for treating Stargardt disease. Gene replacement therapy requires a method for delivering the gene of interest into cells, and for some diseases, the solution has been to package the gene inside a small, harmless virus called the adeno-associated virus (AAV). The ABCA4 gene is too large to fit within this virus. Researchers funded by NEI therefore modified a larger virus from the lentivirus family, and engineered it to carry ABCA4. Tests in the Stargardt mouse model showed that this approach can reduce lipofuscin accumulation. Oxford Biomedica has refined this technology, and licensed it under the name StarGen. Human safety trials of StarGen began in 2011.
Finally, stem cell-based therapies are showing promise for Stargardt disease in clinical trials. Stem cells are immature cells that can generate many mature cells types in the body, including the photoreceptors that die off in Stargardt disease. Human stem cells can be derived from embryonic or adult tissues. Both kinds of cells are being tested in patients with Stargardt disease and age-related macular degeneration (AMD), which is a leading cause of vision loss in the United States.
A U.S. company called Advanced Cell Technology (ACT) is conducting a trial of retinal pigment epithelium (RPE) cells for AMD and Stargardt disease. These cells provide support and nourishment to the retina. The RPE cells under study in the ACT trial are derived from human embryonic stem cells.
Other clinical and laboratory studies are making use of adult cells that have been reprogrammed into stem cells, called induced pluripotent — or iPS — cells. In 2014, Japanese scientists launched the first clinical trial of iPS cells to treat AMD, and indeed the first trial ever of iPS cells. The goal is to coax the iPS cells into making RPE cells. NEI scientists are planning a similar trial and going a step further — by seeding the RPE cells onto a scaffold so that they form a sheet, similar to how they arrange themselves in the eye. NEI scientists also plan to make iPS cells from the skin cells collected in the Stargardt natural history study. These iPS cells could be used to make photoreceptors and RPE cells — for use in potential cell therapies and as a research tool to study how potential drugs will affect these cell types.