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May 12, 2003
Paper published online the week of May 12, 2003 by Proceedings of the National Academy of Sciences

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UCSD Researchers Determine Cellular Defect
For Syndrome Causing Blindness

Researchers at the University of California, San Diego (UCSD) School of Medicine have isolated a defective cellular process within mouse retinas that is the cause of a severe form of blindness seen in people with a disorder called Usher syndrome 1B.

Published online the week of May 12, 2003 in the journal Proceedings of the National Academy of Sciences, the study determined that a malfunction in clearing phagosomes (internalized disk membranes from the eye’s photoreceptor cells) from the retinal pigment epithelium (RPE) within the eye, causes Usher syndrome 1B blindness.

Usher syndrome type 1 is a rare disorder that causes severe deafness and blindness in about 7,000 Americans. Children are born profoundly deaf, and then start going blind later in life. Previous studies had identified a mutant gene called myosin VIIa as playing a role in Usher syndrome 1B. The current investigation details the method the defective gene uses to undermine normal cellular function in the retina.

Senior author David Williams, Ph.D., UCSD professor of pharmacology, said the current findings “provide a necessary basis for gene therapy. Usher syndrome 1B results from the loss of function of a single gene. Our study demonstrates the precise location where that gene needs to be corrected in the retina to provide a potential cure for the blindness associated with the disorder.”

He added that “from a patient point-of-view, the possibility of gene therapy to cure blindness in Usher syndrome is especially important. These patients are born profoundly deaf and have been brought up using sign language. By losing their sight, they suffer more than others who go blind because they also lose their ability to communicate effectively.”

In both lab cell cultures and in mice bred without the myosin VIIa gene, the researchers identified an intercellular process that takes place between the photoreceptor and RPE cells, which are one of the outer layers of the retina. In contact with the tips of the photoreceptor cells, the RPE cells play a role in refreshing the photoreceptors’ disk membranes by engulfing and degrading the older disk. The myosin VIIa helps transport the engulfed disks to the lysosomes within the RPE. The process of phagocytosis and degradation of photoreceptor disk membranes could not take place properly when the myosin VIIa gene was missing in the mice. Defects in this process result in photoreceptor cell degeneration.

“Our study demonstrates that the RPE needs to be targeted for gene therapy of Usher IB,” said Williams. “Because Usher syndrome results from loss of gene function, gene therapy can be affected by simply adding the normal
gene to the cells. Fortunately, the RPE cells appear to be good candidates for viral-mediated incorporation of genes in gene therapy, even for large genes like myosin VIIa.”

The study was supported by the National Institutes of Health and a grant from the Foundation Fighting Blindness. The papers co-first authors were Daniel Gibbs, Ph.D. and Junko Kitamoto, Ph.D., UCSD Department of Pharmacology.