Project 461749

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a form of electrical heart disease that is associated with a risk of sudden death. The majority of CPVT patients have an abnormality in the RYR2 gene, whose protein product plays an important role in directing the flow of calcium in heart cells. Treatment of CPVT primarily involves medications called betablockers, however many patients continue to have life-threatening heart arrhythmias despite taking their medication. The development of new genetic techniques carry the promise of more effective therapies for CPVT and potentially even a cure for this life-threatening condition. Individuals have 2 copies of every gene, however we have accumulated evidence that only 1 copy of the RyR2 gene may be necessary for health. We propose to evaluate large databases of both CPVT patients and healthy individuals in order to better clarify if 1 normal RYR2 copy is sufficient for normal heart function. In parallel, we are going to study the impact of deleting the abnormal functioning copy of the RYR2 gene in mice with CPVT using a genetic engineering technique called CRISPR. Our preliminary data involving modification of the abnormal copy of the RYR2 gene in embryos suggested that this approach is safe and also appeared to have effectively treated the condition when these mice grew into adulthood. Subsequent experiments involving injection of adult CPVT mice with CRISPR tools directed to enter heart cells using a virus also appear promising. In addition to this approach, we are also working with a biotechnology company that makes molecules (called ASOs) that reduce the amount of protein generated from the RYR2 gene. We anticipate that injection of RYR2 ASOs into adult CPVT mice will fix their electrical abnormalities. Should these goals be met, we believe our findings will provide the framework to work towards human clinical trials that may revolutionize treatment for CPVT.