Adenoviral gene transfer of SERCA2a improves left-ventricular function in aortic-banded rats in transition to heart failure

Miyamoto, Michael I.; Monte, Federica del; Schmidt, Ulrich; DiSalvo, Thomas S.; Zhao, Kang; Mizutani, Takashi; Guerrero, J. Luis; Gwathmey, Judith K.; Rosenzweig, Anthony; Hajjar, Roger J.

doi:10.1073/pnas.97.2.793

Cited by 493 publications

(324 citation statements)

References 38 publications

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“…Myocardial SERCA expression has been increased using gene therapy-based approaches in a number of small animal models, with varying success. 4,8,11 In conjunction with the improvement in contractile function, some deleterious aspects of increased calcium cycling have been observed, 12 such as impaired myocyte shortening at high SERCA1a activity, indicating the potential importance of dose optimization. Our study supports the notion of a beneficial effect of augmented SERCA expression in the failing heart.…”

Section: Discussionmentioning

confidence: 99%

Recirculating cardiac delivery of AAV2/1SERCA2a improves myocardial function in an experimental model of heart failure in large animals

et al. 2008

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Abnormal excitation-contraction coupling is a key pathophysiologic component of heart failure (HF), and at a molecular level reduced expression of the sarcoplasmic reticulum (SR) Ca 2+ ATPase (SERCA2a) is a major contributor. Previous studies in small animals have suggested that restoration of SERCA function is beneficial in HF. Despite this promise, the means by which this information might be translated into potential clinical application remains uncertain. Using a recently established cardiac-directed recirculating method of gene delivery, we administered adeno-associated virus 2 (AAV2)/1SERCA2a to sheep with pacing-induced HF. We explored the effects of differing doses of AAV2/1SERCA2a (low 1 Â 10 10 d.r.p.; medium 1 Â 10 12 d.r.p. and high 1 Â 10 13 d.r.p.) in conjunction with an intra-coronary delivery group (2.5 Â 10 13 d.r.p.). At the end of the study, haemodynamic, echocardiographic, histopathologic and molecular biologic assessments were performed. Cardiac recirculation delivery of AAV2/1SERCA2a elicited a dose-dependent improvement in cardiac performance determined by left ventricular pressure analysis, (+d P/d t max ; low dose À220 ± 70, P40.05; medium dose 125 ± 53, Po0.05; high dose 287 ± 104, Po0.05) and echocardiographically (fractional shortening: low dose À3 ± 2, P40.05; medium dose 1 ± 2, P40.05; high dose 6.5 ± 3.9, Po0.05). In addition to favourable haemodynamic effects, brain natriuretic peptide expression was reduced consistent with reversal of the HF molecular phenotype. In contrast, direct intra-coronary infusion did not elicit any effect on ventricular function. As such, AAV2/1SERCA2a elicits favourable functional and molecular actions when delivered in a mechanically targeted manner in an experimental model of HF. These observations lay a platform for potential clinical translation.

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Section: Discussionmentioning

confidence: 99%

Recirculating cardiac delivery of AAV2/1SERCA2a improves myocardial function in an experimental model of heart failure in large animals

et al. 2008

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“…39,40 This was followed by evidence of improvement in contractile function in rodents with HF. 41,42 Finally, gene transfer of SERCA2a was found to be effective in large animal models of HF. 18 Most importantly in a preclinical model of HF, it was found that SERCA2a improved the contractile function in a dose-dependent manner.…”

Section: Serca2a Gene Therapymentioning

confidence: 99%

Sarcoplasmic reticulum and calcium cycling targeting by gene therapy

Hulot

Senyei

2012

Gene Ther

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Although progress in conventional treatments is making steady and incremental gains to reduce mortality associated with heart failure (HF), there remains a need to explore potentially new therapeutic approaches. HF induced by different etiologies such as coronary artery disease, hypertension, diabetes, infection or inflammation results generally in calcium cycling dysregulation at the myocyte level. Recent advances in understanding of the molecular basis of these calcium cycling abnormalities, together with the evolution of increasingly efficient gene transfer technology, has placed HF within the reach of gene-based therapy. Furthermore, the recent successful completion of a phase 2 trial targeting the sarcoplasmic reticulum calcium pump ushers in a new era for gene therapy for the treatment of HF.

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“…Furthermore, success in extremities does not necessarily correspond to success in the myocardium, which is a significantly more complex system. Viral clinical trials have examined a host of other genes, including a variety of fibroblast growth factors (FGF-2 and FGF-4), and sarcoplasmic reticulum Ca 2+ ATPase (SERCA2a) [130]. While little attention has been given to these genes in non-viral trials, either clinical or pre-clinical, they have significant therapeutic potential.…”

Section: Figurementioning

confidence: 99%

Non‐viral gene therapy for myocardial engineering

Holladay

O’Brien

Pandit

2010

WIREs Nanomed Nanobiotechnol

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Despite significant advances in surgical and pharmacological techniques, myocardial infarction remains the main cause of morbidity in the developed world because no remedy has been found for the regeneration of infarcted myocardium. Once the blood supply to the area in question is interrupted, the inflammatory cascade, among other mechanisms, results in the damaged tissue becoming a scar. The goals of cardiac gene therapy are essentially to minimize damage, to promote regeneration or some combination thereof. While the vector is, in theory, less important than the gene being delivered, the choice of vector can have a significant impact. Viral therapies can have very high transfection efficiencies, but disadvantages include immunogenicity, retroviralmediated insertional mutagenesis and the expense and difficulty of manufacture. For these reasons, researchers have focused on non-viral gene therapy as an alternative. In this review, naked plasmid delivery, or the delivery of complexed plasmids, and cellmediated gene delivery to the myocardium will be reviewed. Pre-clinical and clinical trials in the cardiac tissue will form the core of the discussion. While unmodified stem cells are sometimes considered therapeutic vectors based on paracrine mechanisms of action basic understanding is limited. Thus, only genetically modified cells will be discussed as cell-mediated gene therapy.Ischemic heart disease, which includes acute damage due to myocardial infarction (MI) and chronic damage due to atherosclerotic narrowing of vessels, accounts for 35% of deaths reported in the United States every year [1]. MI, which is literally the death of cardiac tissue due to lack of 2 oxygen supply, is the result of the occlusion of a coronary artery. Within a few hours of interrupted blood supply, affected cardiomyocytes die. While the body has adaptive mechanisms, such as hypertrophy of the undamaged cardiac muscle and the development of collateral blood supply to minimize the damage, ischemic heart disease remains the most common cause of death in developed countries [2].The delivery of plasmid DNA to the myocardium is a complicated problem as the transfection efficiency of unmodified DNA is quite low, but complexation with agents designed to improve transfection can increase the cytotoxicity of the treatment [3]. Delivery of uncomplexed plasmid DNA is conceptually the simplest gene delivery technique, but these plasmids have extremely low transfection efficiencies in vitro and are not particularly effective in vivo. Compared to viral vectors, transgene expression is almost negligible and the expression time is also very limited [4]. However, there are significant advantages in using plasmids instead of viruses, such as ease of preparation (large and small scale), very low immunogenicity (as there are essentially no protein or membrane components in the plasmid), capacity for long term storage, ease of recombinant manipulation and much larger expression cassettes [4]. A variety of non-viral techniques are available to improve...

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Adenoviral gene transfer of SERCA2a improves left-ventricular function in aortic-banded rats in transition to heart failure

Cited by 493 publications

References 38 publications

Recirculating cardiac delivery of AAV2/1SERCA2a improves myocardial function in an experimental model of heart failure in large animals

Recirculating cardiac delivery of AAV2/1SERCA2a improves myocardial function in an experimental model of heart failure in large animals

Sarcoplasmic reticulum and calcium cycling targeting by gene therapy

Non‐viral gene therapy for myocardial engineering

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