Discovery of New Therapeutic Target for Stargardt Disease

Stargardt disease is the most common form of inherited juvenile macular degeneration. It is caused by a deterioration of the eye’s macula. The condition typically develops during childhood or adolescence, but sometimes does not cause vision problems until later in life. The macula is part of the retina that is responsible for color perception and central vision, which is needed for detailed tasks such as reading, writing, driving and seeing other fine details clearly.

The rate at which vision is lost varies for each person. However, eventually most people with Stargardt disease have 20/200 to 20/400 vision, which cannot be corrected with prescription eyeglasses, contact lenses or refractive surgery.

In most cases, Stargardt disease is inherited as an autosomal recessive disorder. People who have one gene for the disease paired with one normal gene are unaffected. These people are called carriers. When two carriers have children, each child has a 25 percent chance of inheriting two copies of the Stargardt gene (one from each parent). Children who inherit two copies of the Stargardt gene will have the disease.

The vision loss is associated with the toxic build-up of lipid-rich deposits in the RPE, whose main job is to support and nourish the retina’s light sensing photoreceptors. Under normal conditions, the ABCA4 gene makes a protein that prevents this toxic build-up. Prior research showed that Stargardt disease is caused by a variety of mutations in the ABCA4 gene. More than 800 ABCA4 mutations are known to be associated with a broad spectrum of Stargardt disease phenotypes.

Signs and Symptoms

Clinical features of this disease include slower dark adaptation and loss of central and color vision, suggesting that the disease affects both rod and cone photoreceptors (PRs).

Other symptoms may include:

  • Gray, black, or hazy spots in the center of your vision
  • Sensitivity to light
  • Needing more time for your eyes to adjust between light and dark places
  • Color blindness

Unfortunately, there is no available treatment for Stargardt disease. But there are several gene therapy and drug therapy trials going on.There are currently no proven treatments, there are three main avenues of intervention being explored, with human clinical trials of stem cell therapy, gene replacement therapy and pharmacological approaches.

New cause of Stargardt Disease

One way the Retinal pigment epithelium (RPE) supports photoreceptors is by ingesting their spent outer segments, which keeps the cell pruned and healthy. In Stargardt disease, many scientists believe that RPE cells die after they acquire toxic byproducts when they ingest outer segments, and that this in turn leads to photoreceptor death and vision loss.

Much of the current understanding of Stargardt disease was gained by studying mouse models, which are inherently limited owing to the wide genetic variability of the disease in humans. With a human model of RPE, the National Eye Institute investigators were able to determine if ABCA4 gene mutations directly affected the RPE independent of photoreceptors.

To develop the model, the researchers took skin cells from Stargardt patients, converted them to stem cells, and then coaxed the stem cells to differentiate into RPE cells. Examining the patient-derived RPE, researchers detected ABCA4 protein on the RPE cell membrane. They explored the function of ABCA4 in RPE development by using the gene editing technology CRISPR/Cas9 to generate patient-derived RPE lacking ABCA4, called an ABCA4 knockout. They found that loss of ABCA4 did not affect maturation of the patient-derived RPE.

However, when the RPE lacking ABCA4 were exposed to normal (wild type) photoreceptor outer segments, the RPE cells accumulated intracellular lipids deposits.

Further tests of the ABCA4 knockouts showed evidence of defective RPE lipid metabolism and an impaired ability to digest photoreceptor outer segments, leading to lipid deposits in RPE cells.

This is the first report where loss of ABCA4 function in human RPE has been associated with intracellular lipid deposits in those cells, without exposure to ABCA4 mutant photoreceptor outer segments. Over time, these lipid deposits may contribute to RPE atrophy, leading to photoreceptor degeneration.

This data suggests that in addition to correcting ABCA4 loss of function in photoreceptors, gene therapies need to also target RPE cells.


Mitra Farnoodian, Devika Bose, Vladimir Khristov, Praveen Joseph Susaimanickam, Savitri Maddileti, Indumathi Mariappan, Mones Abu-Asab, Maria Campos, Rafael Villasmil, Qin Wan, Arvydas Maminishkis, David McGaughey, Francesca Barone, Rebekah L. Gundry, Daniel R. Riordon, Kenneth R. Boheler, Ruchi Sharma, Kapil Bharti, (October 27 2022). Cell-autonomous lipid-handling defects in Stargardt iPSC-derived retinal pigment epithelium cells. Stem Cell Reports. Retrieved from: