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Status: Bibliographieeintrag

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Verfasst von:Pleger, Sven Torsten [VerfasserIn]   i
 Shan, Changguang [VerfasserIn]   i
 Ksienzyk, Jan [VerfasserIn]   i
 Bekeredjian, Raffi [VerfasserIn]   i
 Boekstegers, Peter [VerfasserIn]   i
 Hinkel, Rabea [VerfasserIn]   i
 Schinkel, Stefanie [VerfasserIn]   i
 Leuchs, Barbara [VerfasserIn]   i
 Ludwig, Jochen [VerfasserIn]   i
 Qiu, Gang [VerfasserIn]   i
 Weber, Christophe [VerfasserIn]   i
 Raake, Philip [VerfasserIn]   i
 Koch, Walter J. [VerfasserIn]   i
 Katus, Hugo [VerfasserIn]   i
 Müller, Oliver J. [VerfasserIn]   i
 Most, Patrick [VerfasserIn]   i
Titel:Cardiac AAV9-S100A1 gene therapy rescues post-ischemic heart failure in a preclinical large animal model
Verf.angabe:Sven T. Pleger, Changguang Shan, Jan Ksienzyk, Raffi Bekeredjian, Peter Boekstegers, Rabea Hinkel, Stefanie Schinkel, Barbara Leuchs, Jochen Ludwig, Gang Qiu, Christophe Weber, Philip Raake, Walter J. Koch, Hugo A. Katus, Oliver J. Müller, and Patrick Most
E-Jahr:2011
Jahr:20 July 2011
Umfang:10 S.
Fussnoten:Gesehen am 21.12.2022
Titel Quelle:Enthalten in: Science translational medicine
Ort Quelle:Washington, DC : AAAS, 2009
Jahr Quelle:2011
Band/Heft Quelle:3(2011), 92 vom: Juli, Artikel-ID 92ra64, Seite 1-10
ISSN Quelle:1946-6242
Abstract:As a prerequisite for clinical application, we determined the long-term therapeutic effectiveness and safety of adeno-associated virus (AAV)-S100A1 gene therapy in a preclinical large animal model of heart failure. S100A1, a positive inotropic regulator of myocardial contractility, becomes depleted in failing cardiomyocytes in humans and animals, and myocardial-targeted S100A1 gene transfer rescues cardiac contractile function by restoring sarcoplasmic reticulum calcium (Ca(2+)) handling in acutely and chronically failing hearts in small animal models. We induced heart failure in domestic pigs by balloon occlusion of the left circumflex coronary artery, resulting in myocardial infarction. After 2 weeks, when the pigs displayed significant left ventricular contractile dysfunction, we administered, by retrograde coronary venous delivery, AAV serotype 9 (AAV9)-S100A1 to the left ventricular, non-infarcted myocardium. AAV9-luciferase and saline treatment served as control. At 14 weeks, both control groups showed significantly decreased myocardial S100A1 protein expression along with progressive deterioration of cardiac performance and left ventricular remodeling. AAV9-S100A1 treatment prevented and reversed these functional and structural changes by restoring cardiac S100A1 protein levels. S100A1 treatment normalized cardiomyocyte Ca(2+) cycling, sarcoplasmic reticulum calcium handling, and energy homeostasis. Transgene expression was restricted to cardiac tissue, and extracardiac organ function was uncompromised. This translational study shows the preclinical feasibility of long-term therapeutic effectiveness of and a favorable safety profile for cardiac AAV9-S100A1 gene therapy in a preclinical model of heart failure. Our results present a strong rationale for a clinical trial of S100A1 gene therapy for human heart failure that could potentially complement current strategies to treat end-stage heart failure.
DOI:doi:10.1126/scitranslmed.3002097
URL:Bitte beachten Sie: Dies ist ein Bibliographieeintrag. Ein Volltextzugriff für Mitglieder der Universität besteht hier nur, falls für die entsprechende Zeitschrift/den entsprechenden Sammelband ein Abonnement besteht oder es sich um einen OpenAccess-Titel handelt.

Volltext: https://doi.org/10.1126/scitranslmed.3002097
 DOI: https://doi.org/10.1126/scitranslmed.3002097
Datenträger:Online-Ressource
Sprache:eng
Sach-SW:Animals
 Biomarkers
 Calcium
 Dependovirus
 Disease Models, Animal
 Energy Metabolism
 Gene Transfer Techniques
 Genetic Therapy
 Heart Failure
 Heart Function Tests
 Homeostasis
 Humans
 Myocardial Infarction
 Myocardial Ischemia
 Myocardium
 Myocytes, Cardiac
 Organ Specificity
 S100 Proteins
 Sarcoplasmic Reticulum
 Sus scrofa
K10plus-PPN:1828231312
Verknüpfungen:→ Zeitschrift

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