O35: A genotype-first approach among adults at risk for treatable monogenic disorders reveals underdiagnosis and incomplete penetrance

Introduction: Fabry disease is an X-linked disease associated with the GLA gene.The cornerstone of therapy in Fabry disease has been to improve enzyme levels by exogenous enzyme replacement therapy (ERT) or chaperone to increase endogenous enzyme activity.These medications have to be taken in repeated doses for life.The goal of lentiviral gene therapy is to provide a lifelong increase in endogenous enzyme levels by a single therapeutic application.Methods: A phase 1 clinical trial using a single dose of lentivirus-transduced CD34+ autologous hematopoietic stem cells with engineered GLA (LV-GLA) was conducted in Canada (FACTS NCT #02800070) and we report results from the 5-year end-of study analysis.All participants were males with the classical phenotype and undetectable enzyme levels at baseline.Results: At 5 years, all 5 patients had increased leukocyte and plasma enzyme levels and detectable vector copy number of the transgene.Based on the initial response, all patients were eligible to stop their standard ERT and 3 patients stopped ERT.The slope, change in eGFR, was +0.09, -0.38, -0.59, -1.80 and -5.20 ml/min/1.73m2/ year, respectively with the last 2 patients having a slope similar to pre-LV-GLA values.The slope for 24-hour protein excretion was -0.058, -0.402, -0.11, +0.003 and + 0.006 grams/24 hour, respectively.Evaluation of cardiac measures such as left ventricular mass index, and the degree of