Progress in studies of gene therapy for Huntington's disease

Abstract

Huntington's disease (HD) is a kind of inherited neurodegenerative disorder characterized by movement problems, cognitive decline and psychiatry disturbance. HD is caused by mutation in gene IT ⁃15 involving the expansion of a trinucleotide (CAG) repeat encoding glutamine, which leads to abnormal conformation of huntingtin (Htt) protein and finally emerge cytotoxic functions. Currently, HD remains a fatal untreatable disease. Gene therapy for HD discussed in this review is under preclinical studies. Silencing of mutant IT ⁃15 via RNA interference (RNAi) or antisense oligonucleotide (ASO) has shown some effectiveness in mouse model studies. Increasing the clearance of mutant Htt protein could be achieved by viral⁃mediated delivery of anti⁃Htt intrabodies (iAbs) or induction of autophagy, and beneficial results have been observed. Ectopic expression of neurotrophic factors, such as nerve growth factor (NGF) and brain ⁃ derived neurotrophic factor (BDNF), mediated either by viral vectors or transplantation of genetically modified cells, has also been proved to be effective. Other gene⁃modifying methods aiming at correction of transcriptional dysregulation by histone modification, activation of endogenous neural stem cells, and normalization of calcium signaling and mitochondrial function, are also under intensive research. Gene therapy for Huntington's disease is promising, yet a long way remains from preclinical studies to clinical trials.

DOI：10.3969/j.issn.1672⁃6731.2012.03.003