Defining therapeutic targets in hypertrophic cardiomyopathy (renewal)

A faulty gene makes heart muscle proteins stick too tightly to calcium, and this project aims to loosen that grip. Hypertrophic cardiomyopathy (HCM) is a common inherited heart condition where the heart muscle thickens and stiffens, often without symptoms for years. The underlying problem is that mutations in sarcomere proteins—the molecular motors that make heart cells contract—disrupt energy use and calcium handling. Some people’s hearts compensate for these defects, but when compensation fails, the disease progresses. Current drugs can help symptoms but do not correct the root cause. This research tests two new strategies in rodent models. First, it will redirect glucose metabolism toward aerobic glycolysis to improve the heart’s energy supply. Second, it will directly reduce the excessive calcium sensitivity of the mutant sarcomeres. The team will also explore whether gene-editing tools called TALENs can target and disable the faulty gene copy itself. If successful, this work could lead to entirely new classes of drugs that prevent or reverse HCM by restoring the heart’s compensated state—a fundamental shift from managing symptoms to repairing the molecular defect.