Model‐specific selection of molecular targets for heart failure gene therapy

Abstract

Heart failure (HF) is a complex multifaceted problem of abnormal ventricular function and structure. In recent years, new information has been accumulated allowing for a more detailed understanding of the cellular and molecular alterations that are the underpinnings of diverse causes of HF, including myocardial ischemia, pressure-overload, volume-overload or intrinsic cardiomyopathy. Modern pharmacological approaches to treat HF have had a significant impact on the course of the disease, although they do not reverse the underlying pathological state of the heart. Therefore gene-based therapy holds a great potential as a targeted treatment for cardiovascular diseases. Here, we survey the relative therapeutic efficacy of genetic modulation of β-adrenergic receptor signaling, Ca2+ handling proteins and angiogenesis in the most common extrinsic models of HF.

MCARD-Mediated Gene Transfer of GRK2 Inhibitor in Ovine Model of Acute Myocardial Infarction

“…First, in addition to showing improvement in regional and global contractility, we demonstrate the failure of BARKct expression to attenuate adverse ventricular remodeling in a large animal model, which contrasts with the results reported in rodents [9]. It is likely due to differences in molecular signaling responsible for pathological hypertrophy (remodeling) between large and small animals [13]. This finding is particularly important because current thinking about heart failure has a balanced view of the relative importance of systolic and diastolic dysfunction [14, 15].…”

Long-Term Robust Myocardial Transduction of the Dog Heart from a Peripheral Vein by Adeno-Associated Virus Serotype-8

“…A number of complicated techniques have been developed to transduce the myocardium by direct injection (to the myocardium or ventricular cavity), pericardial injection, coronary perfusion, and aorta injection using a variety of viral and nonviral vectors (Ishikawa et al, 2011;Katz et al, 2011;Wasala et al, 2011). Some of these invasive cardiac gene delivery methods, such as percutaneous intracoronorary delivery, have begun to show promise in treating heart failure in human patients ( Jaski et al, 2009;Jessup et al, 2011).…”

The Road Ahead: Working Towards Effective Clinical Translation of Myocardial Gene Therapies

“…The experience obtained from animal models demonstrates that distinct cardiac diseases require specific genetic treatment; namely ischemic, valvular or hypertensive pathological conditions need to employ different gene therapy strategies and targets [33]. Moreover, even the large animals used in preclinical studies differ considerably from the human patients in terms of age, physiology and concomitant diseases that are difficult to replicate in animals.…”