Aperçu du projet
Huntington disease (HD) is an inherited neurodegenerative disease that affects approximately 1 in 7500 individuals in the Western world. The cause of HD is a mutation in one copy of the HTT gene, which produces the toxic mutant huntingtin protein responsible for the brain cell loss associated with the disease. Targeting the root cause of HD by reducing mutant huntingtin in the brain should prevent or delay disease onset. One approach to reducing mutant huntingtin is to use specialized pieces of DNA, called antisense oligonucleotides (ASOs), to prevent production of the toxic mutant protein. Unfortunately, ASOs are unable to enter the brain when delivered in the blood and must be delivered directly into the fluid that bathes the brain, the cerebrospinal fluid or CSF. This procedure is invasive, and ASOs delivered this way do not reach all areas of the brain, including the area most affected by HD, the striatum. Therefore, we are developing new non-invasive strategies to enhance delivery of ASOs to the brain and body that we will test in HD mice and monkeys. We are also developing new ways to measure huntingtin in the brain so that we can evaluate changes in brain huntingtin in response to experimental therapies, like ASOs. We have previously shown that by quantifying mutant huntingtin in CSF, we are able to approximate levels of brain mutant huntingtin. We will continue development of methods to quantify CSF mutant huntingtin and develop complementary methods to measure the normal, non-mutant, huntingtin protein and other disease associated proteins. Finally, we will apply these methods to CSF collected from HD monkeys and patients over time, which will identify optimal methods for clinical assessment of changes in brain huntingtin. Together these studies will significantly advance huntingtin lowering therapies toward use in patients.