Frontiers Journal of Neurology & Neuroscience

Silencing The Huntington Disease Gene: Promises, Obstacles And Solutions


The genetic mutation that caused HD was discovered in 1993 after a sustained international effort that focused on the large Venezuelan pedigree. Among the  St. Viteros (the Venezuelan HD people), there was an expectation, if not a promise, that the same international efforts would lead to a definitive cure. Among the scientists, the HD gene discovery fueled new research to understand how the mutated huntingtin protein (htt) causes cellular dysfunction and death. New insights into how the abnormal (htt)  protein caused disturbances of many cellular functions (mitochondrial energy production, gene transcription, neurotansmission) led to promises of novel disease- modifying medications. The therapeutic promise of silencing mutant htt expression was demonstrated in a tetracycline-regulated conditional mouse model of HD in 2010. In these mice the HD gene could be turned on and off. When the gene was “on” cellular inclusions of htt protein and motor dysfunction developed.  When  the gene was “turned off” inclusions disappeared and behavioral changes improved. Most recently, clinical trials in patients with HD have shown that intrathecal injection of anit-htt ASO decreases the levels of mutant htt in cerebrospinal (CSF).