Translation of Cardiac Myosin Activation With 2-Deoxy-ATP to Treat Heart Failure Via an Experimental Ribonucleotide Reductase-Based Gene Therapy

Despite recent advances, chronic heart failure remains a significant and growing unmet medical need, reaching epidemic proportions carrying substantial morbidity, mortality, and costs. A safe and convenient therapeutic agent that produces sustained inotropic effects could ameliorate symptoms and imp...

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Autores principales: Thomson, Kassandra S., Odom, Guy L., Murry, Charles E., Mahairas, Gregory G., Moussavi-Harami, Farid, Teichman, Sam L., Chen, Xiaolan, Hauschka, Stephen D., Chamberlain, Jeffrey S., Regnier, Michael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444879/
https://www.ncbi.nlm.nih.gov/pubmed/28553667
http://dx.doi.org/10.1016/j.jacbts.2016.07.006
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author Thomson, Kassandra S.
Odom, Guy L.
Murry, Charles E.
Mahairas, Gregory G.
Moussavi-Harami, Farid
Teichman, Sam L.
Chen, Xiaolan
Hauschka, Stephen D.
Chamberlain, Jeffrey S.
Regnier, Michael
author_facet Thomson, Kassandra S.
Odom, Guy L.
Murry, Charles E.
Mahairas, Gregory G.
Moussavi-Harami, Farid
Teichman, Sam L.
Chen, Xiaolan
Hauschka, Stephen D.
Chamberlain, Jeffrey S.
Regnier, Michael
author_sort Thomson, Kassandra S.
collection PubMed
description Despite recent advances, chronic heart failure remains a significant and growing unmet medical need, reaching epidemic proportions carrying substantial morbidity, mortality, and costs. A safe and convenient therapeutic agent that produces sustained inotropic effects could ameliorate symptoms and improve functional capacity and quality of life. The authors discovered that small amounts of 2-deoxy-ATP (dATP) activate cardiac myosin leading to enhanced contractility in normal and failing heart muscle. Cardiac myosin activation triggers faster myosin cross-bridge cycling with greater force generation during each contraction. They describe the rationale and results of a translational medicine effort to increase dATP levels using a gene therapy strategy that up-regulates ribonucleotide reductase, the rate-limiting enzyme for dATP synthesis, selectively in cardiomyocytes. In small and large animal models of heart failure, a single dose of this gene therapy has led to sustained inotropic effects with no toxicity or safety concerns identified to date. Further animal studies are being conducted with the goal of testing this agent in patients with heart failure.
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spelling pubmed-54448792017-05-25 Translation of Cardiac Myosin Activation With 2-Deoxy-ATP to Treat Heart Failure Via an Experimental Ribonucleotide Reductase-Based Gene Therapy Thomson, Kassandra S. Odom, Guy L. Murry, Charles E. Mahairas, Gregory G. Moussavi-Harami, Farid Teichman, Sam L. Chen, Xiaolan Hauschka, Stephen D. Chamberlain, Jeffrey S. Regnier, Michael JACC Basic Transl Sci TRANSLATIONAL PERSPECTIVE Despite recent advances, chronic heart failure remains a significant and growing unmet medical need, reaching epidemic proportions carrying substantial morbidity, mortality, and costs. A safe and convenient therapeutic agent that produces sustained inotropic effects could ameliorate symptoms and improve functional capacity and quality of life. The authors discovered that small amounts of 2-deoxy-ATP (dATP) activate cardiac myosin leading to enhanced contractility in normal and failing heart muscle. Cardiac myosin activation triggers faster myosin cross-bridge cycling with greater force generation during each contraction. They describe the rationale and results of a translational medicine effort to increase dATP levels using a gene therapy strategy that up-regulates ribonucleotide reductase, the rate-limiting enzyme for dATP synthesis, selectively in cardiomyocytes. In small and large animal models of heart failure, a single dose of this gene therapy has led to sustained inotropic effects with no toxicity or safety concerns identified to date. Further animal studies are being conducted with the goal of testing this agent in patients with heart failure. Elsevier 2016-12-26 /pmc/articles/PMC5444879/ /pubmed/28553667 http://dx.doi.org/10.1016/j.jacbts.2016.07.006 Text en © 2016 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle TRANSLATIONAL PERSPECTIVE
Thomson, Kassandra S.
Odom, Guy L.
Murry, Charles E.
Mahairas, Gregory G.
Moussavi-Harami, Farid
Teichman, Sam L.
Chen, Xiaolan
Hauschka, Stephen D.
Chamberlain, Jeffrey S.
Regnier, Michael
Translation of Cardiac Myosin Activation With 2-Deoxy-ATP to Treat Heart Failure Via an Experimental Ribonucleotide Reductase-Based Gene Therapy
title Translation of Cardiac Myosin Activation With 2-Deoxy-ATP to Treat Heart Failure Via an Experimental Ribonucleotide Reductase-Based Gene Therapy
title_full Translation of Cardiac Myosin Activation With 2-Deoxy-ATP to Treat Heart Failure Via an Experimental Ribonucleotide Reductase-Based Gene Therapy
title_fullStr Translation of Cardiac Myosin Activation With 2-Deoxy-ATP to Treat Heart Failure Via an Experimental Ribonucleotide Reductase-Based Gene Therapy
title_full_unstemmed Translation of Cardiac Myosin Activation With 2-Deoxy-ATP to Treat Heart Failure Via an Experimental Ribonucleotide Reductase-Based Gene Therapy
title_short Translation of Cardiac Myosin Activation With 2-Deoxy-ATP to Treat Heart Failure Via an Experimental Ribonucleotide Reductase-Based Gene Therapy
title_sort translation of cardiac myosin activation with 2-deoxy-atp to treat heart failure via an experimental ribonucleotide reductase-based gene therapy
topic TRANSLATIONAL PERSPECTIVE
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444879/
https://www.ncbi.nlm.nih.gov/pubmed/28553667
http://dx.doi.org/10.1016/j.jacbts.2016.07.006
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