Pathogenic variants in the retinitis pigmentosa guanosine triphosphatase regulator (RPGR) gene and RP2 gene are the most common causes of X-linked retinitis pigmentosa (XLRP). In the absence of a treatment option for XLRP, researchers are working to develop genetic therapies targeting these genes; however, designing gene therapy trials for XLRP has presented many challenges. Although some of these clinical trials have been successful, others have had disappointing results.

A Better Approach to Future Research

The Foundation Fighting Blindness convened a panel of experts in July 2022, to discuss the various opportunities and challenges associated with the pursuit of advancing treatment options for XLRP. An overview of the panel’s assessment was published in Transitional Vision Science & Technology.

David G. Birch, PhD, a member of the panel and of the Retina Foundation of the Southwest, described the purpose of this think tank to Physician’s Weekly. “There are several ongoing trials exploring gene enhancement therapy of RPGR-mediated XLRP,” he says. “To date, none of these trials have reached efficacy endpoints. [The panel] felt that this would be an opportune time to review the molecular genetics of the disease and present our thoughts on what might be necessary for success in the future.”

Parameters for Clinical Trials

The panel focused on three key topics during the proceedings. The first was honing the target patient population for future study including a clear definition of RPGR pathogenic variants. The second was agreeing on a generalized course of disease progression including markers to herald disease outcomes. The third was identifying which testing would be most appropriate to gauge outcomes.

The panel noted that patient selection and stratification for clinical trials would require a determination of the specific parameters of the pathogenic variants in RPGR to be included in the study. Because there are wide variations, the panel suggests that as much information as possible about the variants should be collected and examined to determine whether marked differentiation even exists. The panel also agreed that patients should be younger than 35 to participate in these clinical trials.

Potential Genetic Therapy Is Promising

The panel agreed that the potential for genetic therapy development is promising. “We tried to make the case that [XLRP] is an excellent condition for developing successful gene therapy,” Dr. Birch says. “The disease has rapid progression, making this an urgent clinical need. The disease can be detected soon after birth, giving us a large window of opportunity for developing therapies.”

In terms of tools of detection, Dr. Birch says, “Excellent functional measures are available for following these patients. Structural measures such as ellipsoid zone area from the optical coherence tomography allow us to detect progression over as little as 2 years.”

As researchers work to incorporate the panel’s recommendations into designing future clinical trials, Dr. Birch shares his thoughts on how physicians may apply the knowledge of pathogenic variants into their practice. “Physicians need to be aware that it is imperative to diagnose XLRP at the earliest possible age,” he says. “Genetic testing is now readily available. The patients should then be offered the opportunity to contact one of the many sites conducting clinical trials for RPGR-mediated XLRP.”