Targeting mutant huntingtin for the development of disease-modifying therapy

Huntington's disease(HD) is a progressive and fatal neurodegenerative disease, and the most common inherited CAG repeat disorder. A polyglutamine expansion in the N-terminusof the huntingtinprotein (HTT) leads to protein misfolding and downstream pathogenic processes culminatingin widespread functional impairment and neurodegenerationin the striatum, cortex and other brain areas. To date, only symptomatic treatments are available that address motor, psychiatric and cognitive deficits. Here we review recent strategies for developing disease-modifying therapies designed to limit or abolish the pathogenic activities of the primary molecular target in HD, the mutant HTT protein itself.