Galactosemia: opportunities for novel therapies

Galactosemia is an inherited metabolic disease affecting enzymes of the Leloir pathway of galactose metabolism. There are four types: type I (galactose 1-phosphate uridylyltransferase; GALT), type II (galactokinase; GALK1), type III (uridine diphosphate [UDP]-galactose 4’-epimerase; GALE), and type IV (galactose mutarotase; GALM). The range of symptoms is wide, ranging from almost asymptomatic to life-threatening damage to the liver, kidneys, and brain. Severely affected patients suffer cognitive disabilities. Current treatment relies on the restriction of galactose (and its precursors such as lactose) from the diet. This is imperfect and often slows, rather than prevents, the development of symptoms. Potential new treatment approaches include enzyme replacement therapy (ERT), inhibition of galactokinase, antioxidants, phosphate supplementation, and pharmacological chaperones. ERT has been successfully applied in other diseases, but it is likely that the proteins would need to be delivered to the brain to be fully effective. This would present problems with currently available technologies. Antioxidant therapy and phosphate supplementation would treat downstream effects of the disease and not the fundamental causes. They may be useful in conjunction with galactose restriction but are unlikely to provide a complete solution for the most severely affected patients. Galactokinase inhibition has the most underpinning research with several promising compounds identified. It has yet to be tested in clinical trials. Pharmacological chaperone therapy offers the opportunity to correct protein folding and restore activity. Challenges include development of suitable assays, potential for long-term toxicity of drugs that may be taken for a lifetime, and identifying compounds that work with different disease-associated variants.