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First X-linked retinoschisis gene therapy trial launches with support of the US NEI

The US National Eye Institute (NEI) will be sponsoring the first gene therapy trials in X-linked retinoschisis, led by NEI Director Dr. Paul Sieving M.D., Ph.D. The clinical study, formally entitled, “A Phase I/IIa Study of RS1 Ocular Gene Transfer for X-linked Retinoschisis”, will evaluate the safety and tolerability of ocular RS1 AAV delivered gene transfer to the retina of patients with X-linked juvenile retinoschisis (XLRS). Commenting on the initiative, Dr. Sieving stated that, “Our trial is Phase I/IIa, so the first question we’re addressing is safety. After that step, we hope to learn whether the human biological response to the gene therapy follows the success we had in mice, and whether it can improve visual function.”


X-linked retinoschisis is an inherited genetic disorder that typically affects the macular region and accounts for a leading cause of juvenile macular degeneration in males. The disorder is caused by mutations in the retinoschisis gene (RS1) leading to splitting of the inner retinal layers resulting in visual deterioration. A number of mis-sense and protein truncating mutations have been identified in the RS1 gene which encodes a 224 amino acid secretory retinal protein (retinoschisin), implicated in cell-cell interactions and cell adhesion. Loss of retinoschisin function may occur through interference of protein secretion, by prevention of octamerisation or by reducing function in the secreted octamerised protein. Patients may experience a progressive loss of vision between the ages of 5 and 10, while other symptoms include an inability to focus both eyes, roving and involuntary eye movements. There are no current treatment options available for XLRS and 35,000 patients in the US and Europe are estimated to suffer from the disease.


According to the US clinical trials database, up to 100 male participants with the disorder may be screened for inclusion in the study. The current proptocl aims to test three (3) chohorts of three (3) dose phases with three (3) subjects in each cohort, nine (9) patients in total to begin with. However, a further six (6) patients may be recruited to the study for an identified dose that is well-tolerated and from which additional efficacy data may be assessed. One eye of each participant will receive a replacement RS1 gene delivered by AAV and administered by intravitreal injection. The three proposed doses are 1e9 vector genomes (vg)/eye, 1e10 vg/eye and 1e11 vg/eye. The study will be considered to be complete once the last particpant has received 18 months of follow-up however, all patients will continue to be followed for up to 15 years after enrollment, subject to FDA requirements. Commenting on the clinical study, Chairman and Co-Foundr of the US Foundation Fighting Blindness, stated, “we are delighted by the launch of the NEI’s landmark study, which holds great promise for reversing blindness. It’s a major step forward for the greatly expanding field of retinal-disease therapies. The Foundation began funding Dr. Sieving more than 30 years ago, when he was an up-and-coming scientist investigating retinal conditions like retinoschisis. Thanks to his innovative work and perseverance, we’re now getting an emerging therapy for a challenging disease out to the people who need it.”