Grant: Foundation Grant

Huntington disease (HD) is an inherited brain disease that affects approximately 1 in 7300 people in the Western world. HD is caused by a mutation in one copy of the HTT gene, which produces a toxic mutant huntingtin (mHTT) protein. This mutant protein disrupts many vital cellular functions and is ultimately responsible for the brain cell death associated with HD. There is no treatment for this disease. We propose targeting different steps of the disease process, including suppression of the mutant HTT gene, increasing clearance of the mutant protein, and inhibiting its toxic effects to advance complementary therapies for treating HD. One therapeutic strategy to prevent production of mHTT is to silence (or turn off) the mutant HTT gene using antisense oligonucleotides (ASOs) targeted to genetic variations found in mutant HTT. Our goal is to develop multiple ASO drugs targeting the most common genetic variations in HD patients, maximizing the number that could be treated through gene silencing of mutant HTT. ASOs are unable to enter the brain when delivered in the blood and must be injected directly into the fluid that bathes the brain. This procedure is invasive, and ASOs delivered this way do not reach all susceptible areas of the brain. Therefore, we are developing new non-invasive ways to enhance delivery of ASOs to the brain. Another strategy is to reduce levels of mHTT protein by increasing its degradation in the cell through a process called autophagy. Autophagy is abnormally reduced in HD which may be due to altered protein modifications of mHTT. We will target specific mechanisms that could increase clearance of mHTT from the cell and reduce its toxicity. Our final therapeutic strategy is to target pathways that are disrupted by the presence of toxic mHTT. We are investigating the effect of modifying molecular components of these pathways using small molecules to promote protection and survival of brain cells, and in the long run improve patient outcomes.