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NEI Human Gene Therapy Trial for Retinoschisis Underway

April 6, 2015
Cross-sectional images of retina from retinoschisin-deficient mice, untreated and treated with XLRS gene therapy.

Cross-sectional images of retina from retinoschisin-deficient mice, untreated and treated with XLRS gene therapy.

The National Eye Institute (NEI) recently launched the first-ever human gene therapy trial for the vision disorder X-linked retinoschisis (XLRS). Researchers are conducting the trial at the National Institutes of Health Clinical Research Center in Bethesda, Maryland.

XLRS is a genetic disorder that causes splitting through the layers of the retina, the light-sensitive neural tissue in the back of the eye. XLRS gene mutations are inherited from mother to child; however, typically only males develop symptoms. Vision loss usually is evident by early grade school age and slowly worsens over the next several decades as cells in the retina lose function and die.

The causative gene was identified in 1997 and named Retinoschisin 1 (RS1). The gene codes for the retinoschisin protein, which normally works like double-sided tape, providing lateral adhesion that holds retinal cells together. RS1 gene mutations alter the protein and thereby interfere with the ability of cells to maintain proper structure of the retina.

The XLRS gene therapy technique employs an adeno-associated virus (AAV) as a carrier, or vector, to shuttle normal RS1 DNA into cells of the retina. This virus does not cause human disease. In preclinical studies, the NEI team successfully demonstrated use of the vector to deliver the RS1 gene into an XLRS mouse model. When treated, the mouse eyes showed improvements in retinal structure and visual function. A similar treatment strategy with an AAV vector, loaded with a different gene, was used in the groundbreaking gene therapy trials for Leber congenital amaurosis (LCA), another degenerative retinal disease. The XLRS gene therapy trial is one of the first ever at NIH to use the AAV vector.

While the XLRS study seeks to optimize the gene therapy dose, as a phase I/IIa clinical trial it is primarily designed to address safety. “This is the first clinical trial of gene therapy for XLRS, and our first priority is to ensure it is safe,” said Dr. Paul A. Sieving, who is leading the trial. “An important secondary goal is also to look for benefit to vision.”

The first participant has been treated and is being monitored closely. Results from the trial are expected in 2016.

Further information about this trial is available at