Role of Gene Therapy in Treating Heart Failure

Heart failure (HF) is a global public health problem that affects 1-2% of the western countries. Further, it is associated with high morbidity, mortality and health expenditures. Despite the advancements in the pharmacological treatment of HF, only 50% of patients survive at 5 years.
Recent advances in the pathophysiologic mechanisms of HF have created a new opportunity in developing non-pharmacological approaches for treatment. Physiologic studies showed that cardiac sarco-endoplasmic reticulum Ca2+ATPase (SERCA2a) plays a major role in regulating the calcium levels in cardiomyocytes. Alteration in calcium handling within the cardiomyocytes is one of the main pathognomonic processes that occurs in the failing heart caused by the reduction in SERCA2a activity, which adversely affects both systolic and diastolic functions.
Gene transfer therapy is a novel approach that is used to target the calcium dysregulation seen in the failing cardiomyocytes. New vectors, namely adeno-associated viruses (AAVs), were re-engineered to become more cardiotropic resulting in sustained transgene expression within the affected cardiac tissue. The above advancements have been coupled with the development of new delivery methods that include endovascular, surgical, and direct myocardial approaches. As a promising target for treating HF, AAV1-SERCA2a is being used in several clinical trials with promising clinical outcomes.
Despite the significant progress of the cardiac gene therapy field, several challenges remain to be overcome including host neutralizing antibodies of AAV, improving AAV vector cardiac-transduction affinity, and optimizing the dose, route and method of delivery.

Keywords: Heart failure; Gene therapy; Ca2+ATPase; Vector; Cardiomyocytes