Intracoronary Cytoprotective Gene Therapy: A Study of VEGF-B
                        167
                         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 Giacca; Fabio A. Recchia

doi:10.1016/j.jacc.2015.04.071

Intracoronary Cytoprotective Gene Therapy: A Study of VEGF-B ₁₆₇ 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^*

^*Corresponding author for this work

Cardiovascular Medicine & Sciences

Research output: Contribution to journal › Article › peer-review

60 Citations (Scopus)

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-B ₁₆₇ genes were infused intracoronarily at the beginning of the pacing protocol or during compensated heart failure. Moreover, we tested a novel VEGF-B ₁₆₇ transgene controlled by the atrial natriuretic factor promoter. Results Compared with control subjects, VEGF-B ₁₆₇ markedly preserved diastolic and contractile function and attenuated ventricular chamber remodeling, halting the progression from compensated to decompensated heart failure. Atrial natriuretic factor-VEGF-B ₁₆₇ 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-B ₁₆₇ gene transfer as an affordable and effective new therapy for nonischemic heart failure.

Original language	English
Article number	21362
Pages (from-to)	139-153
Number of pages	15
Journal	Journal of the American College of Cardiology
Volume	66
Issue number	2
DOIs	https://doi.org/10.1016/j.jacc.2015.04.071
Publication status	Published - 1 Jan 2015

Keywords

gene therapy
heart failure
translational approach

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jacc.2015.04.071

Cite this

Woitek, F., Zentilin, L., Hoffman, N. E., Powers, J. C., Ottiger, I., Parikh, S., Kulczycki, A. M., Hurst, M., Ring, N., Wang, T., Shaikh, F., Gross, P., Singh, H., Kolpakov, M. A., Linke, A., Houser, S. R., Rizzo, V., Sabri, A., Madesh, M., ... Recchia, F. A. (2015). Intracoronary Cytoprotective Gene Therapy: A Study of VEGF-B ₁₆₇ in a Pre-Clinical Animal Model of Dilated Cardiomyopathy. Journal of the American College of Cardiology, 66(2), 139-153. Article 21362. https://doi.org/10.1016/j.jacc.2015.04.071

@article{248238c9386f480c957de3282a645555,

title = "Intracoronary Cytoprotective Gene Therapy: A Study of VEGF-B 167 in a Pre-Clinical Animal Model of Dilated Cardiomyopathy",

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-B 167 genes were infused intracoronarily at the beginning of the pacing protocol or during compensated heart failure. Moreover, we tested a novel VEGF-B 167 transgene controlled by the atrial natriuretic factor promoter. Results Compared with control subjects, VEGF-B 167 markedly preserved diastolic and contractile function and attenuated ventricular chamber remodeling, halting the progression from compensated to decompensated heart failure. Atrial natriuretic factor-VEGF-B 167 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-B 167 gene transfer as an affordable and effective new therapy for nonischemic heart failure. ",

keywords = "gene therapy, heart failure, translational approach",

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

year = "2015",

month = jan,

day = "1",

doi = "10.1016/j.jacc.2015.04.071",

language = "English",

volume = "66",

pages = "139--153",

journal = "Journal of the American College of Cardiology",

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Woitek, F, Zentilin, L, Hoffman, NE, Powers, JC, Ottiger, I, Parikh, S, Kulczycki, AM, Hurst, M, Ring, N, Wang, T, Shaikh, F, Gross, P, Singh, H, Kolpakov, MA, Linke, A, Houser, SR, Rizzo, V, Sabri, A, Madesh, M, Giacca, M & Recchia, FA 2015, 'Intracoronary Cytoprotective Gene Therapy: A Study of VEGF-B ₁₆₇ in a Pre-Clinical Animal Model of Dilated Cardiomyopathy', Journal of the American College of Cardiology, vol. 66, no. 2, 21362, pp. 139-153. https://doi.org/10.1016/j.jacc.2015.04.071

Intracoronary Cytoprotective Gene Therapy: A Study of VEGF-B ₁₆₇ in a Pre-Clinical Animal Model of Dilated Cardiomyopathy. / Woitek, Felix; Zentilin, Lorena; Hoffman, Nicholas E. et al.
In: Journal of the American College of Cardiology, Vol. 66, No. 2, 21362, 01.01.2015, p. 139-153.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Intracoronary Cytoprotective Gene Therapy

T2 - A Study of VEGF-B 167 in a Pre-Clinical Animal Model of Dilated Cardiomyopathy

AU - Woitek, Felix

AU - Zentilin, Lorena

AU - Hoffman, Nicholas E.

AU - Powers, Jeffery C.

AU - Ottiger, Isabel

AU - Parikh, Suraj

AU - Kulczycki, Anna M.

AU - Hurst, Marykathryn

AU - Ring, Nadja

AU - Wang, Tao

AU - Shaikh, Farah

AU - Gross, Polina

AU - Singh, Harinder

AU - Kolpakov, Mikhail A.

AU - Linke, Axel

AU - Houser, Steven R.

AU - Rizzo, Victor

AU - Sabri, Abdelkarim

AU - Madesh, Muniswamy

AU - Giacca, Mauro

AU - Recchia, Fabio A.

PY - 2015/1/1

Y1 - 2015/1/1

N2 - 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-B 167 genes were infused intracoronarily at the beginning of the pacing protocol or during compensated heart failure. Moreover, we tested a novel VEGF-B 167 transgene controlled by the atrial natriuretic factor promoter. Results Compared with control subjects, VEGF-B 167 markedly preserved diastolic and contractile function and attenuated ventricular chamber remodeling, halting the progression from compensated to decompensated heart failure. Atrial natriuretic factor-VEGF-B 167 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-B 167 gene transfer as an affordable and effective new therapy for nonischemic heart failure.

AB - 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-B 167 genes were infused intracoronarily at the beginning of the pacing protocol or during compensated heart failure. Moreover, we tested a novel VEGF-B 167 transgene controlled by the atrial natriuretic factor promoter. Results Compared with control subjects, VEGF-B 167 markedly preserved diastolic and contractile function and attenuated ventricular chamber remodeling, halting the progression from compensated to decompensated heart failure. Atrial natriuretic factor-VEGF-B 167 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-B 167 gene transfer as an affordable and effective new therapy for nonischemic heart failure.

KW - gene therapy

KW - heart failure

KW - translational approach

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U2 - 10.1016/j.jacc.2015.04.071

DO - 10.1016/j.jacc.2015.04.071

M3 - Article

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AN - SCOPUS:84943571489

SN - 0735-1097

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JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

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