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  • 1
    Keywords: RECEPTOR ; EXPRESSION ; Germany ; IN-VIVO ; THERAPY ; TOOL ; liver ; GENE ; GENE-EXPRESSION ; EFFICIENCY ; HEART ; gene therapy ; MICE ; gene transfer ; GENE-TRANSFER ; RAT ; BINDING ; virus ; MOUSE ; TRANSGENIC MICE ; gene expression ; PROMOTER ; DELIVERY ; specificity ; TYPE-2 ; HEPARAN-SULFATE PROTEOGLYCAN ; ENHANCER ; INCREASE ; in vivo ; ADULT MICE ; cytomegalovirus ; VIRUS VECTORS
    Abstract: Objective: Vectors based on recombinant adeno-associated virus 2 (AAV-2) are a promising tool for cardiac gene transfer. However, potential therapeutic applications need to consider the predominant transduction of the liver once AAV-2 vectors enter the systemic circulation. We therefore aimed to increase efficiency and specificity of cardiac vector delivery by combining transcriptional and cell surface targeting. Methods: For analysis of transcriptional targeting, recombinant AAV vectors were generated harboring a luciferase reporter gene under control of the cytomegalovirus (CMV) promoter or the 1.5-kb cardiac myosin light chain promoter fused to the CMV immediate-early enhancer (CMVenh/MLC1.5). Luciferase activities were determined in representative organs three weeks after intravenous injection of the vector into adult mice. Transductional targeting was studied using luciferase-reporter constructs crosspackaged into capsids of AAV serotypes I to 6 and modified AAV-2 capsids devoid of binding their primary receptor heparan sulfate proteoglycan. Results: Intravenous injections of AAV-2 vectors harboring the CMVenh/MLC1.5 promoter enabled a specific and 50-fold higher reporter gene expression in left ventricular myocardium, of adult mice compared to vectors containing the CMV promoter. Comparison of AAV-2 vector genomes crosspackaged into capsids of AAV-1 to -6 showed that AAV-1, -4, -5, and -6 capsids increased cardiac transduction efficiency by about 10-fold. However, transduction of other organs such as the liver was also increased after systemic administration. In contrast, AAV-2-based vectors with ablated binding to their primary receptor heparan sulfate proteoglycan enabled a significantly increased efficiency of cardiac gene transfer and reduced transduction of the liver. Conclusions: Combining transcriptional targeting by the CMVenh/MLC1.5 promoter and AAV vectors devoid of binding the AAV-2 primary receptor results in an efficient cardiac gene transfer with a significantly reduced hepatic transduction. Q 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 16448634
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  • 2
    Keywords: EXPRESSION ; TRIAL ; CALCIUM ; MYOCARDIAL-INFARCTION ; DILATED CARDIOMYOPATHY ; FEASIBILITY ; LEFT-VENTRICULAR DYSFUNCTION ; cardiomyocytes ; BASIC SCIENCE ; CA2+-BINDING PROTEIN S100A1 ; CONTRACTILE PERFORMANCE ; ENERGY-METABOLISM ; FAILING MYOCARDIUM
    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
    Type of Publication: Journal article published
    PubMed ID: 21775667
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  • 3
    Keywords: CANCER ; SURVIVAL ; Germany ; LUNG ; PROSTATE ; THERAPY ; lung cancer ; LUNG-CANCER ; DEATH ; DISEASE ; LONG-TERM ; MORTALITY ; POPULATION ; RISK ; HEART ; prognosis ; BREAST ; breast cancer ; BREAST-CANCER ; MALIGNANCIES ; AGE ; colorectal cancer ; COLORECTAL-CANCER ; COUNTRIES ; PROSTATE-CANCER ; LONG-TERM SURVIVAL ; CANCER-PATIENTS ; UNITED-STATES ; FAILURE ; TRENDS ; STROKE ; ONCOLOGY ; HEART-FAILURE ; COMPETING RISKS ; 1ST-EVER STROKE ; 5 CONTINENTS ; 5-YEAR SURVIVAL ; PERTH COMMUNITY STROKE ; PRESERVED EJECTION FRACTION
    Abstract: Background: Cancer, heart failure and stroke are among the most common causes of death worldwide. Investigation of the prognostic impact of each disease is important, especially for a better understanding of competing risks. Aim of this study is to provide an overview of long term survival of cancer, heart failure and stroke patients based on the results of large population- and hospital-based studies. Methods: Records for our study were identified by searches of Medline via Pubmed. We focused on observed and relative age- and sex-adjusted 5-year survival rates for cancer in general and for the four most common malignancies in developed countries, i.e. lung, breast, prostate and colorectal cancer, as well as for heart failure and stroke. Results: Twenty studies were identified and included for analysis. Five-year observed survival was about 43% for all cancer entities, 40-68% for stroke and 26-52% for heart failure. Five-year age and sex adjusted relative survival was 50-57% for all cancer entities, about 50% for stroke and about 62% for heart failure. In regard to the four most common malignancies in developed countries 5-year relative survival was 12-18% for lung cancer, 73-89% for breast cancer, 50-99% for prostate cancer and about 43-63% for colorectal cancer. Trend analysis revealed a survival improvement over the last decades. Conclusions: The results indicate that long term survival and prognosis of cancer is not necessarily worse than that of heart failure and stroke. However, a comparison of the prognostic impact of the different diseases is limited, corroborating the necessity for further systematic investigation of competing risks
    Type of Publication: Journal article published
    PubMed ID: 20307299
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