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Gene therapy

New approach slows retinal degeneration

Munich, 08/17/2012

Retinitis pigmentosa, a genetic disease that causes degeneration of photoreceptors in the eye, often leads to blindness. Gene therapy now offers hope for patients. In mice, a new strategy has resulted in a marked and lasting improvement in vision.

Some 20,000 people in Germany suffer from retinitis pigmentosa (RP). The disorder usually becomes manifest, as a loss of night vision, during adolescence. As the disease progresses, the visual field gradually decreases and many patients become virtually blind. The condition arises from the degeneration of photoreceptors in the retina. The first victims are the rod cells responsible for vision in dim light, but ultimately cone cells that mediate daylight and color vision are also lost.

Mutations make photoreceptors vulnerable

Mutations in any of more than 50 genes can trigger the disease. Promising gene therapies have already been developed for certain forms of RP. “However, no effective treatment exists for the most common forms, in which the mutation directly affects the photoreceptors,” says LMU pharmacologist Stylianos Michalakis. Michalakis, together with biologist Regine Mühlfriedel from the University Eye Hospital Tübingen, now report an approach for cases involving mutations that disrupt specific ion channels in rod cells.

As Mühlfriedel explains, “The so-called CNG cation channels in the plasma membrane of the rod cells play a crucial role in the perception of light.” These channels are made up of different subunits, one of which is a large transmembrane protein called CNGB1. Mice in which the gene for CNGB1 is inactive develop a condition very like that seen humans with RP, and go blind within about a year after birth.

A therapy with a lasting effect

Using what are known as AAV gene-transfer vectors, the researchers were able to introduce a functional version of the gene for CNGB1 into the retina of mutant mice that had defective copies of the gene in their DNA. They went on to show that the intervention reinstated production of CNGB1, and restored the ability of the rod cells to respond to light. As Michalakis points out, “Particularly important is the fact that the treated mice were able to process the new sensory information correctly in the brain, as demonstrated by a vision test.”

In addition to its efficiency, one other noteworthy aspect of the new approach is its long-lasting effect. In tests carried out a year later, the positive impact on the treated area of the retina was still clearly detectable. The success of this Munich-Tübingen collaboration thus represents a further milestone on the route to practical and effective gene therapies for degenerative retinal disorders in human patients. (Hum. Mol. Gen. 16. July 2012) göd

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