The discovery points to a new understanding of the progression of Stargardt disease

The discovery points to a new understanding of the progression of Stargardt disease

Using a new stem cell-based model made from skin cells, scientists found the first direct evidence that Stargardt-related ABCA4 gene mutations affect a layer of cells in the eye called the retinal pigment epithelium (RPE). The discovery provides a new understanding of the progression of Stargardt disease and suggests a therapeutic strategy for the disease that currently cannot be treated. The study was conducted at the National Eye Institute (NEI), part of the National Institutes of Health. The results were published online today in Stem Cell Reports.

This new model will accelerate the development of treatments for Stargardt disease. We lack a treatment for this disease, in part because it is rare. This model theoretically creates an unlimited supply of human cells for study.”

Michael F. Chiang, MD,NEI Director

Stargardt affects about 1 in 10,000 people in the United States

Stargardt disease causes progressive loss of central and night vision. Vision loss is associated with the toxic accumulation of lipid-rich deposits in the RPE, whose primary role is to support and nourish the light-sensitive photoreceptors of the retina. Under normal conditions, the ABCA4 gene produces a protein that prevents this toxic buildup. Previous 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.

One way the RPE supports the photoreceptors is by housing their spent outer segments, keeping the cell pruned and healthy. In Stargardt's disease, many scientists believe that RPE cells die after ingesting toxic byproducts when ingesting outer segments, and that this in turn leads to photoreceptor death and loss of vision.

Much of the current understanding of Stargardt's disease has been gained through the study of mouse models, which are inherently limited due to the large genetic variability of the disease in humans. Using a human RPE model, NEI researchers were able to determine whether ABCA4 gene mutations directly affected RPE independently of photoreceptors.

To develop the model, the researchers took skin cells from Stargardt patients, converted them into stem cells, and then persuaded the stem cells to differentiate into RPE cells. When examining the patient-derived RPE, the researchers discovered the ABCA4 protein on the RPE cell membrane. They examined the role of ABCA4 in RPE development by using the CRISPR/Cas9 gene editing technology to generate patient-derived RPE without ABCA4, called an ABCA4 knockout. They found that loss of ABCA4 did not affect the maturation of the patient-derived RPE.

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

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

This is the first report linking loss of ABCA4 function in human RPE to intracellular lipid deposits in these cells without exposing the outer segments of the ABCA4 mutant photoreceptor. Over time, these lipid deposits can contribute to RPE atrophy, leading to photoreceptor degeneration.

“Our report provides guidance for a gene therapy approach to combat RPE,” said study principal investigator Kapil Bharti, Ph.D., principal investigator of NEI's Division of Ocular and Stem Cell Translation Research. “Our data suggest that in addition to correcting ABCA4 loss of function in photoreceptors, gene therapies must also target RPE cells.”

This research is part of a larger NEI effort to address the limited availability of patient-derived stem cell lines to study Stargardt disease. To overcome this barrier, the NEI initiated a STGD1 iPSC banking program from patients with various ABAC4 mutations. These cells will be made available to the general public for mechanistic and genotype-phenotype studies.

The work was funded by the NEI Intramural Research Program.

Source:

National Institutes of Health

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