AAV-mediated PERM1 Overexpression as a New Therapy for Heart Failure with Reduced Ejection Fraction

About This Grant

PROJECT SUMMARY Heart failure is a leading cause of death in developed countries, affecting 6 million people in the United States and approximately 64.3 million people worldwide. Mortality rates remain high, with 50% of patients dying within five years of diagnosis. About half of these patients have heart failure with reduced left ventricular ejection fraction (HFrEF), which is characterized by an ejection fraction of 40% or less and adverse cardiac remodeling. HFrEF is associated with reduced cardiac contractility and mitochondrial impairment. Currently, no therapies specifically target both muscle contractility and mitochondrial function. PERM1, a striated muscle-specific regulator of energy metabolism, is predominantly expressed in the heart and skeletal muscle. We have demonstrated that PERM1 is downregulated in both human and mouse failing hearts and that its loss in mice leads to reduced cardiac contractility and energy reserves. Our preliminary data show that gene delivery of PERM1 to the mouse heart via adeno-associated virus (AAV) fully prevents the onset of HFrEF during pressure overload in mice, preserving systolic function and promoting mitochondrial biogenesis. This study will address the hypothesis that AAV-medicated PERM1 overexpression can serve as a novel therapeutic approach to prevent and reverse contractile dysfunction under pathological stress. This translational study will initiate testing of this promising gene therapy in a well-established mouse model of HFrEF and a preclinical swine model of HFrEF induced by myocardial infarction. Additionally, it will further elucidate the novel mechanisms by which PERM1 simultaneously regulates muscle contractility and energy metabolism in the heart.