Huntington's disease: Molecular basis of pathology and status of current therapeutic approaches

Huntington's disease (HD) is a frequent and incurable hereditary neurodegenerative disorder that impairs motor and cognitive functions. Mutations in huntingtin (HTT) protein, which is essential for neuronal development, lead to the development of HD. An increase in the number of CAG repeats within the HTT gene, which lead to an expansion of polyglutamine tract in the resulting mutated HTT protein, which is toxic, is the causative factor of HD. Although the molecular basis of HD is known, there is no known cure for this disease other than symptomatic relief treatment approaches. The toxicity of mutHTT appears to be more detrimental to striatal medium spiny neurons, which degenerate in this disease. Therapeutic strategies addressing a reduction in the mutHTT content at the transcriptional level using zinc finger proteins and at the translational level with RNA interference and antisense oligonucleotides or promoting the proteosomal degradation of mutHTT are being studied extensively in preclinical models and also to a limited extent in clinical trials. The post-translational modification of mutHTT is another possibility that is currently being investigated for drug development. In addition to the pharmacological approaches, several lines of evidence suggested the potential therapeutic use of stem cell therapy, in particular using the patient-derived induced pluripotent stem cells, to replace the lost striatal neurons. The multi-pronged clinical investigations currently underway may identify therapies and potentially improve the quality of life for the HD patients in future.