Classic galactosemia (CG) is a potentially lethal genetic disease that results from profound loss of galactose-1P uridylyltransferase (GALT). While pre-symptomatic diagnosis by newborn screening and immediate dietary restriction of galactose prevent or minimize the acute and potentially lethal symptoms of disease in infants, a majority of affected children nonetheless grow to experience a constellation of debilitating cognitive, behavioral, motor, female reproductive, and other disabilities. The mechanisms that underlie these long-term complications remain unknown, hindering the development of more effective treatments. One of the major roadblocks limiting progress in the field has been the lack of a mammalian genetic model of CG that recapitulates patient outcomes. Specifically, while a GALT-null fruit fly demonstrates both acute and long-term complications reminiscent of CG, each of two mouse models created by other groups did not. Recently, we applied CRISPR-Cas9 gene editing technology to create three mutant alleles of GALT in Sprague-Dawley rats. The single male founder from whom all three distinct alleles were derived was, by definition, mosaic, at least in his germ cells, but demonstrated bilateral cataracts reminiscent of untreated patients. Here we propose to characterize both the acute and long-term outcomes of homozygous GALT deficient rats reared in the presence versus absence of dietary galactose. The results of these studies will establish the first mammalian model of GALT deficiency that recapitulates relevant phenotypes of classic galactosemia, setting the stage for future studies to define the timing and mechanisms of disease, and an amenable model for testing novel candidate interventions.
Galactosemia is one of the most common metabolic disorders identified by newborn screening in the United States. Despite neonatal diagnosis and lifelong dietary restriction of galactose, which is the standard of care, a majority of children with classic galactosemia (CG) grow to experience debilitating long-term cognitive, behavioral, motor, female reproductive, and other complications. The proposed research will establish a new and vastly superior mammalian model for CG that will provide insights into the timing and mechanism(s) of disease and provide a platform for preclinical testing of novel candidate interventions.