Grant: CIHR Fellowship

Huntington disease (HD) is a fatal, genetic neurodegenerative disorder caused by a mutation in the huntingtin gene, which codes for a protein called huntingtin (Htt). The pathogenesis of HD is complicated and multiple cellular mechanisms and functions are compromised leading to loss of motor control, dementia and psychiatric disturbance. Death usually occurs 15-20 years after onset of symptoms, and there is currently no effective therapy. Therefore attacking the problem at its root by reducing mutant huntingtin (mHtt) expression is a promising therapeutic strategy to prevent pathology and delay or prevent the onset of disease. Most HD patients have one normal copy and one mutant copy of the Htt gene (one copy from their mother and one copy from their father). Normal Htt is essential for brain function and therefore selectively and specifically reducing mutant and sparing normal Htt is ideal, especially when considering the fact that treatment will mostly begin early and continue throughout life. To achieve this goal we target DNA sequence variations, which are associated with the mutant gene and are not present in the normal gene. HD can be found everywhere in the world, but the genetic background of HD patients differs between ethnic populations and therefore a personalized approach is required for a successful therapy. We have previously found reagents targeting one of these DNA sequence variations in half of the Caucasian HD population. However, we need to identify DNA sequence variants present in the remaining population including other ethnicities across the world with HD and design new reagents targeting these sites. The main goal of this project is to design and evaluate new reagents for the ability to selectively reduce mHtt expression in the remaining Caucasian HD population as well as in HD patient populations of other ethnic origins allowing a treatment option for every HD patient.