Double-Barrelled Gene Therapy Shows Promise for Autosomal Dominant Retinitis Pigmentosa
March 22, 2011 - Irish scientists are moving forward with a new gene therapy approach for some forms of autosomal dominant retinitis pigmentosa (adRP). The therapy, currently referred to as GT083, recently received orphan drug approval in the European Union.
Up to 40% of people with retinitis pigmentosa have an autosomal dominant form of the disease. In any autosomal dominant disease, the person inherits one healthy copy of the gene, and one gene damaged by mutation. Because the mutated gene is “dominant” its ill effects over-ride the healthy genes. So a person with autosomal dominant RP will experience vision loss even though one of the pair of genes is undamaged.
A mutation in the rhodopsin gene is the most common form of autosomal dominant RP, accounting for about 25% of all adRP cases. However, many different mutations – more than 150 – have already been identified in the rhodopsin gene; and it would be difficult and extremely expensive to create corrective gene therapies for all of the disease-causing mutations, since each individual mutation is so rare. Accordingly, a group of Irish scientists from Trinity College Dublin, led by Dr. Jane Farrar, developed a new double-barrelled approach.
The GT083 treatment simultaneously introduces two different genetic modifications, into the retinal cells, using specially adapted viruses. The first virus introduces a genetic “off switch” into the retina cells, turning off all of the natural copies of the rhodopsin gene – both the mutated copies and the healthy ones. The second virus adds a healthy version of the rhodopsin gene into the retina cells, but one that has been subtly altered so that it is not affected by the “off switch” therapy.
GT083 therapy is currently being tested ONLY in animals. However, these animal studies have produced positive results, demonstrating that it is possible to preserve the rod photoreceptors by making these two genetic modifications simultaneously. Studies of mice that were bred with damaged rhodopsin genes have shown this gene therapy slowed down the degeneration of rod photoreceptor cells and preserved a substantial level of visual function.
“This is a milestone in the treatment of RP,” says Dr. Bill Stell, Director of FFB Research Programs, “it is the first gene therapy to treat an autosomal dominant disease, and it is an approach that should be effective regardless of the specific mutations present. It should be equally effective for adRP due to any of the 150-plus adRP-causing mutations in the rhodopsin gene.”
Dr. Farrar and her team hope this approach will have benefits, not only for RP, but also for autosomal dominant conditions that affect other tissues and organs in the body. They will continue animal studies, to further validate the therapy and ultimately to prepare it for testing in human clinical trials.