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Gene therapy for cardiovascular disease: advances in vector development, targeting, and delivery for clinical translation

Gene therapy is a promising modality for the treatment of inherited and acquired cardiovascular diseases. The identification of the molecular pathways involved in the pathophysiology of heart failure and other associated cardiac diseases led to encouraging preclinical gene therapy studies in small a...

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Autores principales: Rincon, Melvin Y., VandenDriessche, Thierry, Chuah, Marinee K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4571836/
https://www.ncbi.nlm.nih.gov/pubmed/26239654
http://dx.doi.org/10.1093/cvr/cvv205
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author Rincon, Melvin Y.
VandenDriessche, Thierry
Chuah, Marinee K.
author_facet Rincon, Melvin Y.
VandenDriessche, Thierry
Chuah, Marinee K.
author_sort Rincon, Melvin Y.
collection PubMed
description Gene therapy is a promising modality for the treatment of inherited and acquired cardiovascular diseases. The identification of the molecular pathways involved in the pathophysiology of heart failure and other associated cardiac diseases led to encouraging preclinical gene therapy studies in small and large animal models. However, the initial clinical results yielded only modest or no improvement in clinical endpoints. The presence of neutralizing antibodies and cellular immune responses directed against the viral vector and/or the gene-modified cells, the insufficient gene expression levels, and the limited gene transduction efficiencies accounted for the overall limited clinical improvements. Nevertheless, further improvements of the gene delivery technology and a better understanding of the underlying biology fostered renewed interest in gene therapy for heart failure. In particular, improved vectors based on emerging cardiotropic serotypes of the adeno-associated viral vector (AAV) are particularly well suited to coax expression of therapeutic genes in the heart. This led to new clinical trials based on the delivery of the sarcoplasmic reticulum Ca(2+)-ATPase protein (SERCA2a). Though the first clinical results were encouraging, a recent Phase IIb trial did not confirm the beneficial clinical outcomes that were initially reported. New approaches based on S100A1 and adenylate cyclase 6 are also being considered for clinical applications. Emerging paradigms based on the use of miRNA regulation or CRISPR/Cas9-based genome engineering open new therapeutic perspectives for treating cardiovascular diseases by gene therapy. Nevertheless, the continuous improvement of cardiac gene delivery is needed to allow the use of safer and more effective vector doses, ultimately bringing gene therapy for heart failure one step closer to reality.
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spelling pubmed-45718362015-09-18 Gene therapy for cardiovascular disease: advances in vector development, targeting, and delivery for clinical translation Rincon, Melvin Y. VandenDriessche, Thierry Chuah, Marinee K. Cardiovasc Res Reviews Gene therapy is a promising modality for the treatment of inherited and acquired cardiovascular diseases. The identification of the molecular pathways involved in the pathophysiology of heart failure and other associated cardiac diseases led to encouraging preclinical gene therapy studies in small and large animal models. However, the initial clinical results yielded only modest or no improvement in clinical endpoints. The presence of neutralizing antibodies and cellular immune responses directed against the viral vector and/or the gene-modified cells, the insufficient gene expression levels, and the limited gene transduction efficiencies accounted for the overall limited clinical improvements. Nevertheless, further improvements of the gene delivery technology and a better understanding of the underlying biology fostered renewed interest in gene therapy for heart failure. In particular, improved vectors based on emerging cardiotropic serotypes of the adeno-associated viral vector (AAV) are particularly well suited to coax expression of therapeutic genes in the heart. This led to new clinical trials based on the delivery of the sarcoplasmic reticulum Ca(2+)-ATPase protein (SERCA2a). Though the first clinical results were encouraging, a recent Phase IIb trial did not confirm the beneficial clinical outcomes that were initially reported. New approaches based on S100A1 and adenylate cyclase 6 are also being considered for clinical applications. Emerging paradigms based on the use of miRNA regulation or CRISPR/Cas9-based genome engineering open new therapeutic perspectives for treating cardiovascular diseases by gene therapy. Nevertheless, the continuous improvement of cardiac gene delivery is needed to allow the use of safer and more effective vector doses, ultimately bringing gene therapy for heart failure one step closer to reality. Oxford University Press 2015-10-01 2015-08-03 /pmc/articles/PMC4571836/ /pubmed/26239654 http://dx.doi.org/10.1093/cvr/cvv205 Text en © The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Reviews
Rincon, Melvin Y.
VandenDriessche, Thierry
Chuah, Marinee K.
Gene therapy for cardiovascular disease: advances in vector development, targeting, and delivery for clinical translation
title Gene therapy for cardiovascular disease: advances in vector development, targeting, and delivery for clinical translation
title_full Gene therapy for cardiovascular disease: advances in vector development, targeting, and delivery for clinical translation
title_fullStr Gene therapy for cardiovascular disease: advances in vector development, targeting, and delivery for clinical translation
title_full_unstemmed Gene therapy for cardiovascular disease: advances in vector development, targeting, and delivery for clinical translation
title_short Gene therapy for cardiovascular disease: advances in vector development, targeting, and delivery for clinical translation
title_sort gene therapy for cardiovascular disease: advances in vector development, targeting, and delivery for clinical translation
topic Reviews
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4571836/
https://www.ncbi.nlm.nih.gov/pubmed/26239654
http://dx.doi.org/10.1093/cvr/cvv205
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