Gene Therapy in a GALT-null Rat Model of Classic Galactosemia

Classic galactosemia (CG) is a potentially lethal genetic disease that is one of the most common metabolic disorders identified by newborn screening in the United States. Despite neonatal detection and lifelong dietary restriction of galactose, which is the current standard of care, most babies born with CG grow to experience a constellation of lifelong speech, cognitive, motor, growth, female reproductive, and/or other deficits thought to result from chronic exposure to endogenously produced galactose. The mechanisms that underlie these many long-term complications remain unknown, including which of the galactose metabolites that accumulate in the blood and tissues of patients – galactose, galactose-1P, and galactitol – may be causal of each outcome. This makes candidate interventions designed to lower one metabolite, e.g., galactose-1P or galactitol, without addressing the others, uncertain to provide broad rescue. Further, the possibility of enzyme replacement therapy is complicated by the location of the missing enzyme: galactose-1-P uridylyltransferase (GALT) is cytoplasmic but not lysosomal. Combined, these factors point to GALT gene therapy using an established viral vector as perhaps the best near-horizon approach to improved intervention. The goal of this 2-year study is to test whether AAV9-based GALT gene therapy is sufficient to prevent representative long-term complications in an existing GALT-null rat model of CG. In short, we propose preclinical studies testing the long-term biochemical and phenotypic efficacy of a single dose of scAAV9-hGALT administered intravenously to neonatal GALT-null rat pups. The results of this work will set the stage for more extensive pre-clinical studies and will help to inform future clinical trials in patients with CG.