Intracoronary Cytoprotective Gene Therapy: A Study of VEGF-B167 in a Pre-Clinical Animal Model of Dilated Cardiomyopathy

Felix Woitek, Lorena Zentilin, Nicholas E. Hoffman, Jeffery C. Powers, Isabel Ottiger, Suraj Parikh, Anna M. Kulczycki, Marykathryn Hurst, Nadja Ring, Tao Wang, Farah Shaikh, Polina Gross, Harinder Singh, Mikhail A. Kolpakov, Axel Linke, Steven R. Houser, Victor Rizzo, Abdelkarim Sabri, Muniswamy Madesh, Mauro GiaccaFabio A. Recchia

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

Background Vascular endothelial growth factor (VEGF)-B activates cytoprotective/antiapoptotic and minimally angiogenic mechanisms via VEGF receptors. Therefore, VEGF-B might be an ideal candidate for the treatment of dilated cardiomyopathy, which displays modest microvascular rarefaction and increased rate of apoptosis. Objectives This study evaluated VEGF-B gene therapy in a canine model of tachypacing-induced dilated cardiomyopathy. Methods Chronically instrumented dogs underwent cardiac tachypacing for 28 days. Adeno-associated virus serotype 9 viral vectors carrying VEGF-B167 genes were infused intracoronarily at the beginning of the pacing protocol or during compensated heart failure. Moreover, we tested a novel VEGF-B167 transgene controlled by the atrial natriuretic factor promoter. Results Compared with control subjects, VEGF-B167 markedly preserved diastolic and contractile function and attenuated ventricular chamber remodeling, halting the progression from compensated to decompensated heart failure. Atrial natriuretic factor-VEGF-B167 expression was low in normally functioning hearts and stimulated by cardiac pacing; it thus functioned as an ideal therapeutic transgene, active only under pathological conditions. Conclusions Our results, obtained with a standard technique of interventional cardiology in a clinically relevant animal model, support VEGF-B167 gene transfer as an affordable and effective new therapy for nonischemic heart failure.

Original languageEnglish (US)
Article number21362
Pages (from-to)139-153
Number of pages15
JournalJournal of the American College of Cardiology
Volume66
Issue number2
DOIs
StatePublished - Jul 14 2015

Keywords

  • gene therapy
  • heart failure
  • translational approach

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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