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Therapeutic safety of high myocardial expression levels of the molecular inotrope S100A1 in a preclinical heart failure model

Gene Therapy volume 21, pages 131–138 (2014)Cite this article

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Abstract

Low levels of the molecular inotrope S100A1 are sufficient to rescue post-ischemic heart failure (HF). As a prerequisite to clinical application and to determine the safety of myocardial S100A1 DNA-based therapy, we investigated the effects of high myocardial S100A1 expression levels on the cardiac contractile function and occurrence of arrhythmia in a preclinical large animal HF model. At 2 weeks after myocardial infarction domestic pigs presented significant left ventricular (LV) contractile dysfunction. Retrograde application of AAV6-S100A1 (1.5 × 1013 tvp) via the anterior cardiac vein (ACV) resulted in high-level myocardial S100A1 protein peak expression of up to 95-fold above control. At 14 weeks, pigs with high-level myocardial S100A1 protein overexpression did not show abnormalities in the electrocardiogram. Electrophysiological right ventricular stimulation ruled out an increased susceptibility to monomorphic ventricular arrhythmia. High-level S100A1 protein overexpression in the LV myocardium resulted in a significant increase in LV ejection fraction (LVEF), albeit to a lesser extent than previously reported with low S100A1 protein overexpression. Cardiac remodeling was, however, equally reversed. High myocardial S100A1 protein overexpression neither increases the occurrence of cardiac arrhythmia nor causes detrimental effects on myocardial contractile function in vivo. In contrast, this study demonstrates a broad therapeutic range of S100A1 gene therapy in post-ischemic HF using a preclinical large animal model.

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Acknowledgements

We thank Barbara Leuchs and the DKFZ vector core production unit for generating high-titer AAV vector stocks. This work was supported by the following NIH grants: R01HL92130 and R01HL92130-02S1 (PM); P01HL075443, R01HL56205 and R01HL061690 (WJK); Deutsche Forschungsgemeinschaft: 1654/3-2 (OJM), 562/1-1 (PM and STP); the Bundesministerium für Bildung und Forschung: 01GU0527 (PM, OJM, HAK); Deutsche Gesellschaft für Kardiologie Otto Hess Promotionsstipendium (CW); and the German Cardiovascular Research Center (DZHK to PM, HAK).

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Authors and Affiliations

  1. Center for Molecular and Translational Cardiology, Heidelberg University Hospital, Heidelberg, Germany

    C Weber, I Neacsu, B Krautz, J Ritterhoff, P Most & S T Pleger

  2. Department of Internal Medicine III, Division of Cardiology, University of Heidelberg, Heidelberg, Germany

    C Weber, I Neacsu, B Krautz, P Schlegel, P Raake, J Ritterhoff, A Jungmann, A B Remppis, H A Katus, O J Müller, P Most & S T Pleger

  3. Department of Pediatrics, University of Heidelberg, Heidelberg, Germany

    S Sauer

  4. Institute for Animal Physiology, Ludwig-Maximilians-University Munich, Munich, Germany

    M Stangassinger

  5. Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA

    W J Koch

  6. Deutsches Zentrum für Herz-/Kreislaufforschung, University Hospital Heidelberg, Heidelberg, Germany

    H A Katus & P Most

  7. Laboratory for Cardiac Stem Cell and Gene Therapy, Temple University School of Medicine, Philadelphia, PA, USA

    P Most

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  1. C Weber
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Correspondence to S T Pleger.

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Competing interests

P Most and HA Katus report potential competing interests as they have filed US and EU patent applications on the therapeutic use of the S100A1 protein to treat heart failure. CW, IN, BK, PS, PR, JR, AJ, WJK, OJM and STP declare no conflict of interest.

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Weber, C., Neacsu, I., Krautz, B. et al. Therapeutic safety of high myocardial expression levels of the molecular inotrope S100A1 in a preclinical heart failure model. Gene Ther 21, 131–138 (2014). https://doi.org/10.1038/gt.2013.63

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