Abstract Background Cardiac fibrosis (CF) is associated with increased ventricular stiffness and diastolic dysfunction and is an independent predictor of long-term clinical outcomes of patients with ...heart failure (HF). We previously showed that the matricellular CCN5 protein is cardioprotective via its ability to inhibit CF and preserve cardiac contractility. Objectives This study examined the role of CCN5 in human heart failure and tested whether CCN5 can reverse established CF in an experimental model of HF induced by pressure overload. Methods Human hearts were obtained from patients with end-stage heart failure. Extensive CF was induced by applying transverse aortic constriction for 8 weeks, which was followed by adeno-associated virus-mediated transfer of CCN5 to the heart. Eight weeks following gene transfer, cellular and molecular effects were examined. Results Expression of CCN5 was significantly decreased in failing hearts from patients with end-stage heart failure compared to nonfailing hearts. Trichrome staining and myofibroblast content measurements revealed that the established CF had been reversed by CCN5 gene transfer. Anti-CF effects of CCN5 were associated with inhibition of the transforming growth factor beta signaling pathway. CCN5 significantly inhibited endothelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation, which are 2 critical processes for CF progression, both in vivo and in vitro. In addition, CCN5 induced apoptosis in myofibroblasts, but not in cardiomyocytes or fibroblasts, both in vivo and in vitro. CCN5 provoked the intrinsic apoptotic pathway specifically in myofibroblasts, which may have been due the ability of CCN5 to inhibit the activity of NFκB, an antiapoptotic molecule. Conclusions CCN5 can reverse established CF by inhibiting the generation of and enhancing apoptosis of myofibroblasts in the myocardium. CCN5 may provide a novel platform for the development of targeted anti-CF therapies.
Reversal of Cardiac Dysfunction After Long-Term Expression of SERCA2a by Gene Transfer in a Pre-Clinical Model of Heart Failure Yoshiaki Kawase, Hung Q. Ly, Fabrice Prunier, Djamel Lebeche, Yanfen ...Shi, Hongwei Jin, Lahouaria Hadri, Ryuichi Yoneyama, Kozo Hoshino, Yoshiaki Takewa, Susumu Sakata, Richard Peluso, Krisztina Zsebo, Judith K. Gwathmey, Jean-Claude Tardif, Jean-François Tanguay, Roger J. Hajjar Studies in heart failure (HF) have reported a reduction in sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) levels and activity as key abnormalities in this disease. The subsequent impairment of Ca2+ handling leads to contractile dysfunction. Prior studies have reported improvement in cardiac dysfunction after short-term overexpression of SERCA2a, in pre-clinical models of HF. However, there is a lack of long-term data regarding the effects of SERCA2a overexpression. In this study, we show that overexpression of SERCA2a over a period of 2 months by adeno-associated virus type 1 vector restores and prevents ventricular dysfunction in a swine volume-overload model.
Abstract Background SERCA2a deficiency is commonly seen in advanced heart failure (HF). This study is designed to investigate safety and biological effects of enzyme replacement using gene transfer ...in patients with advanced HF. Methods and Results A total of 9 patients with advanced HF (New York Heart Association NYHA Class III/IV, ejection fraction EF ≤30%, maximal oxygen uptake VO2 max <16 mL·kg·min, with maximal pharmacological and device therapy) received a single intracoronary infusion of AAV1/SERCA2a in the open-label portion of this ongoing study. Doses administered ranged from 1.4 × 1011 to 3 × 1012 DNase resistant particles per patient. We present 6- to 12-month follow-up data for these patients. AAV1/SERCA2a demonstrated an acceptable safety profile in this advanced HF population. Of the 9 patients treated, several demonstrated improvements from baseline to month 6 across a number of parameters important in HF, including symptomatic (NYHA and Minnesota Living with Heart Failure Questionnaire, 5 patients), functional (6-minute walk test and VO2 max, 4 patients), biomarker (NT-ProBNP, 2 patients), and LV function/remodeling (EF and end-systolic volume, 5 patients). Of note, 2 patients who failed to improve had preexisting anti-AAV1 neutralizing antibodies. Conclusions Quantitative evidence of biological activity across a number of parameters important for assessing HF status could be detected in several patients without preexisting neutralizing antibodies in this open-label study, although the number of patients in each cohort is too small to conduct statistical analyses. These findings support the initiation of the Phase 2 double-blind, placebo-controlled portion of this study.
Mitral Regurgitation Augments Post-Myocardial Infarction Remodeling: Failure of Hypertrophic Compensation Ronen Beeri, Chaim Yosefy, J. Luis Guerrero, Francesca Nesta, Suzan Abedat, Miguel Chaput, ...Federica del Monte, Mark D. Handschumacher, Robert Stroud, Suzanne Sullivan, Thea Pugatsch, Dan Gilon, Gus J. Vlahakes, Francis G. Spinale, Roger J. Hajjar, Robert A. Levine Mitral regurgitation (MR) doubles mortality after myocardial infarction (MI), but its additive contribution to left ventricular remodeling is debated and has not been addressed in a controlled fashion. In a sheep model with apical MI and a standard moderate MR, we observed excess remodeling as compared with MI without MR, as manifested by increased gross remodeling morphology by 3-dimensional echocardiography, reduced intrinsic contractility at the global and cellular levels, exhaustion of pro-hypertrophic signaling in the cardiomyocytes, and increased extracellular matrix turnover. Hence, MR worsens post-MI remodeling.
Rescuing the Failing Heart by Targeted Gene Transfer Kawase, Yoshiaki, MD; Ladage, Dennis, MD; Hajjar, Roger J., MD
Journal of the American College of Cardiology,
03/2011, Letnik:
57, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Congestive heart failure is a major cause of morbidity and mortality in the United States. Although progress in conventional treatments is making steady and incremental gains to decrease heart ...failure mortality, there is a critical need to explore new therapeutic approaches. Gene therapy was initially applied in the clinical setting for inherited monogenic disorders. It is now apparent that gene therapy has broader potential that also includes acquired polygenic diseases, such as congestive heart failure. Recent advances in understanding of the molecular basis of myocardial dysfunction, together with the evolution of increasingly efficient gene transfer technology, have placed heart failure within the reach of gene-based therapy. Furthermore, the recent successful and safe completion of a phase 2 trial targeting the sarcoplasmic reticulum Ca2+ ATPase pump along with the start of more recent phase 1 trials are ushering in a new era of gene therapy for the treatment of heart failure.
Abstract Background Heart failure (HF) remains a major cause of morbidity and mortality in North America. With an aging population and an unmet clinical need by current pharmacologic and ...device-related therapeutic strategies, novel treatment options for HF are being explored. One such promising strategy is gene therapy to target underlying molecular anomalies in the dysfunctional cardiomyocyte. Prior animal and human studies have documented decreased expression of SERCA2a, a major cardiac calcium cycling protein, as a major defect found in HF. Methods and Results We hypothesize that increasing the activity of SERCA2a in patients with moderate to severe HF will improve their cardiac function, disease status, and quality of life. Gene transfer of SERCA2a will be performed via an adeno-associated viral (AAV) vector, derived from a nonpathogenic virus with long-term transgene expression as well as a clinically established favorable safety profile. Conclusions We describe the design of a phase 1 clinical trial of antegrade epicardial coronary artery infusion (AECAI) administration of AAVI/SERCA2a (MYDICAR) to subjects with HF divided into 2 stages: in Stage 1, subjects will be assigned open-label MYDICAR in one of up to 4 sequential dose escalation cohorts; in Stage 2, subjects will be randomized in parallel to 2 or 3 doses of MYDICAR or placebo in a double-blinded manner.
Abstract Objective Heart failure is accompanied by up-regulation of transforming growth factor beta signaling, accumulation of collagen and dysregulation of sarcoplasmic reticulum calcium adenosine ...triphosphatase cardiac isoform 2a (SERCA2a). We examined the fibrotic response in small and large myocardial infarct, and the effect of overexpression of the SERCA2a gene. Methods Ischemic cardiomyopathy was induced via creation of large or small infarct in 26 sheep. Animals were divided into 4 groups: small infarct; large infarct with heart failure; gene-treated (large infarct with heart failure followed by adeno-associated viral vector, serotype 1.SERCA2a gene construct transfer by molecular cardiac surgery with recirculating delivery); and control. Results Heart failure was significantly less pronounced in the gene-treated and small-infarct groups than in the large-infarct group. Expression of transforming growth factor beta signaling components was significantly higher in the large-infarct group, compared with the small-infarct and gene-treated groups. Both the angiotensin II type 1 receptor and angiotensin II were significantly elevated in the small- and large-infarct groups, whereas gene treatment diminished this effect. Active fibrosis with de novo collagen synthesis was evident in the large-infarct group; the small-infarct and gene-treated groups showed less fibrosis, with a lower ratio of de novo to mature collagen. Conclusions The data presented provide evidence that progression of fibrosis is mediated through increased transforming growth factor beta and angiotensin II signaling, which is mitigated by increased SERCA2a gene expression.
The concept of gene therapy was introduced in the 1970s after the development of recombinant DNA technology. Despite the initial great expectations, this field experienced early setbacks. Recent ...years have seen a revival of clinical programs of gene therapy in different fields of medicine. There are many promising targets for genetic therapy as an adjunct to cardiac surgery. The first positive long-term results were published for adenoviral administration of vascular endothelial growth factor with coronary artery bypass grafting. In this review we analyze the past, present, and future of gene therapy in cardiac surgery. The articles discussed were collected through PubMed and from author experience. The clinical trials referenced were found through the Wiley clinical trial database ( http://www.wiley.com/legacy/wileychi/genmed/clinical/ ) as well as the National Institutes of Health clinical trial database ( Clinicaltrials.gov ).
Since its inception (1), clinical gene therapy has progressed substantially albeit slowly. ...a longer-term follow-up may have shown further benefit in the setting of AAV's long-term gene ...transduction.
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