Mechanism, modification, and intervention in a pre-clinical model of galactosemia



 DESCRIPTION (provided by applicant) Classic galactosemia (CG) is a potentially lethal genetic disease that results from profound loss of galactose-1P uridylyltransferase (GALT); CG is the second most common metabolic disorder identified by newborn screening in the US. Despite neonatal diagnosis and lifelong dietary restriction of galactose, which is the current standard of care, a majority of affected children grow to experience a constellation of debilitating cognitive, behavioral, movement, female reproductive, and other disabilities. The mechanisms that underlie these long-term complications remain unknown, hindering prognosis and the development of more effective treatments. The goals of this project are to define the mechanism(s) of acute and long-term outcomes associated with GALT deficiency and leverage that knowledge in a preclinical setting to identify and test candidate pharmacological interventions for CG. To achieve these goals we will apply a combined model system plus human subjects approach. Specifically, we will conduct systems-level biochemical and genetic studies in a Drosophila melanogaster model of GALT deficiency that demonstrates both acute galactose sensitivity in development and also galactose-independent adult movement, female fertility, and learning- related behavioral phenotypes, with targeted follow-up studies using patient samples to ensure relevance. This strategy circumvents the otherwise crippling effect of limited patient numbers to enable the open-minded studies of mechanism needed to understand the bases of acute and long-term outcomes in CG. Our Specific Aims include: (1) define the metabolomic consequences of GALT deficiency in both Drosophila and humans, (2) identify genetic modifiers of acute and long-term outcomes in GALT deficient Drosophila and patients, and (3) test candidate pharmacological modifiers of outcome using a GALT-null Drosophila model of CG. The results of these studies will reveal what causes the acute and long-term sequelae of CG and will provide a first evidence-based step toward improved intervention.