David G. Birch, Janet K. Cheetham, Stephen P. Daiger, Carel Hoyng, Christine Kay, Ian M. MacDonald, Mark E. Pennesi, Lori S. Sullivan | Translational Vision Science and Technology | 2023 June 9 | doi: 10.1167/tvst.12.6.5
Abstract
X-linked retinitis pigmentosa (XLRP) is a rare inherited retinal disease manifesting as impaired night vision and peripheral vision loss that progresses to legal blindness. Although several trials of ocular gene therapy for XLRP have been conducted or are in progress, there is currently no approved treatment. In July 2022, the Foundation Fighting Blindness convened an expert panel to examine relevant research and make recommendations for overcoming the challenges and capitalizing on the opportunities in conducting clinical trials of RPGR-targeted therapy for XLRP. Data presented concerned RPGR structure and mutation types known to cause XLRP, RPGR mutation–associated retinal phenotype diversity, patterns in genotype/phenotype relationships, disease onset and progression from natural history studies, and the various functional and structural tests used to monitor disease progression. Panel recommendations include considerations, such as genetic screening and other factors that can impact clinical trial inclusion criteria, the influence of age on defining and stratifying participant cohorts, the importance of conducting natural history studies early in clinical development programs, and the merits and drawbacks of available tests for measuring treatment outcomes. We recognize the need to work with regulators to adopt clinically meaningful end points that would best determine the efficacy of a trial. Given the promise of RPGR-targeted gene therapy for XLRP and the difficulties encountered in phase III clinical trials to date, we hope these recommendations will help speed progress to finding a cure.
Introduction
X-linked retinitis pigmentosa (XLRP) is a severe, aggressive, inherited retinal disease characterized by progressive photoreceptor deterioration and loss eventually leading to blindness. Pathogenic variants associated with XLRP affect predominately male individuals. Female carriers of a disease-causing variant sometimes can be affected clinically, and, in these cases, typically present with a milder phenotype than male patients, potentially due in part to random or skewed X chromosome inactivation. The most common causes of XLRP are pathogenic variants in two genes, retinitis pigmentosa guanosine triphosphatase regulator (RPGR) and RP2, accounting for approximately 70% and 20% of cases, respectively. Currently, there is no treatment for XLRP. Although several investigational XLRP therapies targeting the RPGR gene have met with early successes in phase I/II clinical studies, the only phase II/III study to read out to date, the XIRIUS study of adeno-associated virus serotype 8 (AAV8) vector-based gene therapy, cotoretigene toliparvovec, failed to meet its primary end point.
On July 23, 2022, The Foundation Fighting Blindness convened a virtual meeting of experts in ophthalmology and genetics to discuss the challenges and opportunities in the clinical development of XLRP genetic therapies.
Key topics were:
Delineating the target patient population, including defining pathogenic RPGR genetic mutations and associated retinal disease clinical phenotypes
Establishing XLRP disease course and identifying factors associated with disease outcomes
Selecting the structural and functional tests best suited to measure outcomes
The Expert Panel's goal was to formulate recommendations for designing XLRP gene therapy clinical studies to provide the best chance of successful treatment development. This article summarizes the meeting's presentations and discussions and the panel's recommendations.
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