Perspectives on Gene Therapy: Choroideremia Represents a Challenging Model for the Treatment of Other Inherited Retinal Degenerations

PURPOSE: To report combined viewpoints on ocular gene therapy from a select group of clinician scientists and a patient advocacy group. METHODS: With the support of Randy Wheelock and Dr. Chris Moen from the Choroideremia Research Foundation (CRF), a special interest group at the 2019 Annual meeting of the Association for Research in Vision and Ophthalmology in Vancouver, Canada, shared their knowledge, experience, concepts, and ideas and provided a forum to discuss therapeutic strategies for the treatment of inherited retinal disorders, using experience in choroideremia (CHM) as a model. RESULTS: A member of the CRF presented the patient perspective and role in clinical trials. Five clinician scientists presented reasons for limited long-term visual improvement in many gene therapy trials, including challenges with dose, incomplete understanding of photoreceptor metabolism, vector delivery, inflammation, and identification of patients likely to benefit from treatment. CONCLUSIONS: The shared experience of the five clinician scientists indicates that the results of ocular gene therapy for choroideremia have been less successful than for RPE65-related Leber congenital amaurosis. Improvement in vector delivery and developing a better understanding of gene expression in target tissues, treatment dose and side effects, and inflammation, as well as identifying patients who are most likely to benefit without suffering excessive risk, are necessary to advance the development of effective therapies for inherited retinal degenerations. TRANSLATIONAL RELEVANCE: Additional long-term data are required to determine if ocular gene therapy will be sufficient to alter natural progression in choroideremia. Combination therapies may have to be considered, as well as alternative vectors that minimize risk.