Gene Therapy in the Treatment of Heart Failure

Abstract

Heart failure is a major cause of morbidity and mortality in contemporary societies. Although progress in conventional treatment modalities is making steady and incremental gains to reduce this disease burden, there remains a need to explore new and potentially therapeutic approaches. Gene therapy, for example, was initially envisioned as a treatment strategy for inherited monogenic disorders. It is now apparent that gene therapy has broader potential that also includes acquired polygenic diseases, such as heart failure. Advances in the understanding of the molecular basis of conditions such as these, together with the evolution of increasingly efficient gene transfer technology, has placed congestive heart failure within reach of gene-based therapy.

Lentiviral vectors and cardiovascular diseases: a genetic tool for manipulating cardiomyocyte differentiation and function

“…However, safety issue concerns are still restraining their use in the clinical setting: indeed, LVVs do have the potential drawback of causing insertional mutagenesis through the random integration of DNA into the host genome, leading to the aberrant expression of important genes and to tumorigenesis. 67,68 Preclinical in vivo studies have highlighted several limitations of gene therapy applications for human cardiovascular diseases: the most relevant of these regard the route of administration (LVV delivery is reviewed by Ly et al 69 ), transduction efficiency and specificity, and, most importantly, the obtainment of a functional and synchronous engraftment. In fact, arrhythmic events are often associated with cell replacement therapy of injured myocardium because homogeneous transduction of the entire myocardium is not possible and transduced cells are not uniformly distributed; engrafted cells can also fail to synchronize with the rhythm of the recipient heart.…”

SERCA 2a Gene Therapy, Game-Changer for Heart Failure

“…There has been particular emphasis on calcium-transport genes as candidates for gene therapy, including SERCA2a and PLB, as well as the ryanodine receptor (RyR2), and the sodiumcalcium exchanger (NCX) (Figure 1). SERCA has proven the most promising because its expression and activity are decreased in a wide variety of pathologic conditions in heart failure [12, [16][17][18].…”

“…SERCA2a gene therapy has been tested in a wide variety of preclinical models, including acute ischaemia/reperfusion, chronic pressure overload and chronic myocardial infarction, has resulted in a reduction in ventricular arrhythmias experimental studies have demonstrated that gene therapy could be an effective option to treat the failing myocardium [18][19][20][21][22].…”

“…These studies led to the development of in vivo gene transfer using catheter-based techniques to introduce SERCA2a into the myocardium [18][19][20][21][22][23]. Adenoviral mediated SERCA2a gene transfer in a rat model of pressure-overload hypertrophy (in which SERCA2a levels were decreased and severe contractile dysfunction was evident) restored both systolic and diastolic dysfunction to normal levels.…”

“…At least two clinical trials using SERCA2 gene transfer are underway: a phase I, randomized double-blinded, placebo-controlled study using AAV1-SERCA2a (Mydicar; Celladon Corporation, La Jolla, CA) in patients with congestive heart failure, and a phase I study using AAV6-SERCA2a to evaluate efficacy and safety in ischaemic cardiomyopathy patients with severe heart failure undergoing left ventricular assist device placement [18]. With further development of improved delivery methods and advanced viral vectors, SERCA gene therapy may not be far from reality and could be a game changer for the management of heart failure.…”