Ricardo Mouro-Pinto, PhD

Instructor in Neurology, Vanessa Wheeler, PhD and Samuel Frank, MD, Center for Genomic Medicine, Massachusetts General Hospital and Harvard Medical School

Development of CAG Contraction-based Therapeutics for Huntington’s Disease

Huntington’s Disease (HD) is a devastating neurodegenerative disorder for which there is no cure or significant disease-modifying treatment. It is caused by a rare genetic mutation – an expanded CAG repeat – that results in the production of a toxic form of huntingtin protein. In general, the longer the CAG repeat, the earlier in life the patient will develop HD symptoms. In addition to being expanded in HD patients, this repeat has a strong tendency for further expanding, not only in transmissions from parent to child, but also throughout the life of the patient, particularly in organs primarily affected in HD. This raises the hypothesis that the CAG expansion process can accelerate the onset and progression of the disease in HD patients. To date, we have already learned that genes involved in maintaining the integrity of our genomes throughout the life of a cell (DNA repair genes) are involved in the CAG expansion mechanism. In addition, in a recent study that looked at ~9,000 HD patients, we identified various DNA repair genes as likely modifiers of HD age of onset, further echoing the potential therapeutic impact of targeting these genes. In recent studies using HD mice, we found a DNA repair complex that seems capable of contracting the HD CAG repeat. We will now carry out a set of experiments aimed at validating this ability in cells obtained from HD patients, as well as investigating the potential toxicity associated with targeting this gene. These studies will hopefully spearhead the development of therapeutics aimed at contracting the CAG repeat in HD patients.