PROJECT SUMMARY / ABSTRACT Advances in genetics and genomics have raised hopes for the development of gene-based treatments for inherited retinal diseases (IRDs) which are single-gene defects that cause vision loss. Some of the greatest successes for gene-based treatments has occurred in the most severe subset of IRDs that fall into the rubric of Leber congenital amaurosis (LCA) with vision loss often occurring congenitally. LCA success stories from human clinical trials include those caused by deleterious variants in the genes RPE65, LRAT, CEP290, GUCY2D, and AIPL1. Although these disorders present with severe vision loss in early childhood, the great majority of trials have not included young pediatric patients, where efficacy measures are very challenging. Our overarching long-term goal is to evaluate treatments for congenital blinding conditions in younger pediatric patients who stand to gain the most before the window of cortical plasticity closes. Recently we initiated gene augmentation therapy for adults with LCA5, which is a retinal ciliopathy resulting in particularly severe early onset vision loss. Improving vision for the adult population with LCA5 would immensely impact quality of life. Initial results in this adult trial using an AAV8 vector with a subretinal injection appear very promising with evidence of safety and efficacy. We propose to perform a clinical trial of LCA5 gene augmentation therapy in the older pediatric population (i.e. adolescents) and prepare for future clinical trials by developing novel outcome measures in, and for, the very young pediatric population. We will leverage the existing IND, regulatory support, and OPGx-001 clinical vector provided by our industry partner (Opus Genetics), to accomplish two Aims. Aim 1: Perform a clinical trial of OPGx-001 for LCA5 in pediatric patients aged 13 to 18 years. Re-defined outcome measures (including the addition of innovative measures tested in a `seamless' clinical trial design) will be used to determine the safety and efficacy of uniocular subretinal gene delivery of OPGx-001 in a Phase I/II dose escalation (1.0x1010, 3.0x1010 and 1.0x1011 vg/eye) clinical trial. Three eligible patients ages >13 to 18 will enter each dose group and will be followed for 3 years as an extension of the current gene therapy trial in the adult population. Aim 2: Develop novel ocular outcome measures for pediatric patients aged >1 to ≤13 years with LCA5 and other forms of LCA for future interventional trials. We will develop subjective and objective measures of vision, and validate their performance in patients ages ≥8 before deploying them in a younger (<8) group of patients with LCA that are the target population in this and future trials. At completion, the project will provide safety and efficacy data for OPGx-001 in adolescent patients, and a specific path for treating very young patients with vision loss due to LCA5 or other gene defects.