An insight into allele-selective approaches to lowering mutant huntingtin protein for Huntington's disease treatment.

Huntington's disease (HD), a monogenic neurodegenerative disorder, stems from a CAG repeat expansion within the mutant huntingtin gene (HTT). This leads to a detrimental gain-of-function of the mutated huntingtin protein (mHTT). As of now, there exist no efficacious therapies to alter the disease progression. In view of the monogenetic mutation nature and an indispensable role of wild-type HTT in healthy neurodevelopment and cellular functions, the developing strategy of allele-selectively deleting/silencing mutant HTT as well as only inactivating mHTT without altering wild-type HTT or wild-type huntingtin protein (wtHTT) comes highly recommended, and may offer a promising treatment option for HD. Here, we reviewed the therapeutic approaches that allele-selective lowering mHTT expression by targeting only mutant HTT DNA, RNA and mHTT along with recent preclinical and clinical outcomes and challenges, in anticipation of some novel ideas to be introduced into HD therapeutic research.