Toward Improved Therapy for Classic Galactosemia

University Of Miami School Of Medicine, Coral Gables FL

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Inherited deficiency of galactose-1-phosphate uridyltransferase (GALT) can result in a potentially lethal disease called Classic Galactosemia. Although the neonatal lethality associated with this disease can be prevented through early diagnosis and a galactose-restricted diet, the lack of effective therapy continues to haunt the surviving children to their adulthood. 85% of treated galactosemic females suffer premature ovarian failure, while many others are inflicted with neurological disorders and developmental delay. Several lines of evidence suggested that elevated level of galactose-1-phosphate (gal-1-p), the product of galactokinase (GALK), is a major, if not sole, pathogenic mechanism in patients with galactosemia. We therefore hypothesize that elimination of gal-1-p production by inhibiting GALK will relieve GALT-deficient cells from galactose toxicity. To identify selective GALK inhibitors, we have purified large quantity of GALK and developed a robust high throughput (HTS) GALK assay, which will be used to screen over 300,000 chemical compounds of diverse structural scaffolds (Specific Aim 1). Positive hits identified in Aim 1 will be validated and characterized in Specific Aim 2 to assess their potency, selectivity and efficacy to reduce gal-1-p accumulation in galactose-intoxicated cells. PUBLIC HEALTH RELEVANCE: Classic Galactosemia is a potentially lethal metabolic disorder that is included in the newborn screening programs of all 50 states in the U.S.. Although a galactose-restricted diet, which is the current standard of care, can prevent the neonatal lethality of this disorder, many well-treated patients continue to develop debilitating complications such as mental retardation, premature ovarian failure and other neurological deficits. The long-term goal of this project is to develop more effective therapies for this disorder. [unreadable] [unreadable] [unreadable]