Stable myocardial-specific AAV6-S100A1 gene therapy results in chronic functional heart failure rescue

Sven T. Pleger, Patrick Most, Matthieu Boucher, Stephen Soltys, J. Kurt Chuprun, Wiebke Pleger, Erhe Gao, Abhijit Dasgupta, Giuseppe Rengo, Andrew Remppis, Hugo A. Katus, Andrea D. Eckhart, Joseph E. Rabinowitz, Walter J. Koch

Research output: Contribution to journalArticle

Abstract

BACKGROUND - The incidence of heart failure is ever-growing, and it is urgent to develop improved treatments. An attractive approach is gene therapy; however, the clinical barrier has yet to be broken because of several issues, including the lack of an ideal vector supporting safe and long-term myocardial transgene expression. METHODS AND RESULTS - Here, we show that the use of a recombinant adeno-associated viral (rAAV6) vector containing a novel cardiac-selective enhancer/promoter element can direct stable cardiac expression of a therapeutic transgene, the calcium (Ca2+)-sensing S100A1, in a rat model of heart failure. The chronic heart failure-rescuing properties of myocardial S100A1 expression, the result of improved sarcoplasmic reticulum Ca2+ handling, included improved contractile function and left ventricular remodeling. Adding to the clinical relevance, long-term S100A1 therapy had unique and additive beneficial effects over β-adrenergic receptor blockade, a current pharmacological heart failure treatment. CONCLUSIONS - These findings demonstrate that stable increased expression of S100A1 in the failing heart can be used for long-term reversal of LV dysfunction and remodeling. Thus, long-term, cardiac-targeted rAAV6-S100A1 gene therapy may be of potential clinical utility in human heart failure.

Original languageEnglish
Pages (from-to)2506-2515
Number of pages10
JournalCirculation
Volume115
Issue number19
DOIs
Publication statusPublished - May 2007

Fingerprint

Genetic Therapy
Heart Failure
Transgenes
Ventricular Remodeling
Sarcoplasmic Reticulum
Therapeutics
Adrenergic Receptors
Pharmacology
Calcium
Incidence

Keywords

  • Gene therapy
  • Heart failure
  • Long-term care
  • S100A1 protein

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Pleger, S. T., Most, P., Boucher, M., Soltys, S., Chuprun, J. K., Pleger, W., ... Koch, W. J. (2007). Stable myocardial-specific AAV6-S100A1 gene therapy results in chronic functional heart failure rescue. Circulation, 115(19), 2506-2515. https://doi.org/10.1161/CIRCULATIONAHA.106.671701

Stable myocardial-specific AAV6-S100A1 gene therapy results in chronic functional heart failure rescue. / Pleger, Sven T.; Most, Patrick; Boucher, Matthieu; Soltys, Stephen; Chuprun, J. Kurt; Pleger, Wiebke; Gao, Erhe; Dasgupta, Abhijit; Rengo, Giuseppe; Remppis, Andrew; Katus, Hugo A.; Eckhart, Andrea D.; Rabinowitz, Joseph E.; Koch, Walter J.

In: Circulation, Vol. 115, No. 19, 05.2007, p. 2506-2515.

Research output: Contribution to journalArticle

Pleger, ST, Most, P, Boucher, M, Soltys, S, Chuprun, JK, Pleger, W, Gao, E, Dasgupta, A, Rengo, G, Remppis, A, Katus, HA, Eckhart, AD, Rabinowitz, JE & Koch, WJ 2007, 'Stable myocardial-specific AAV6-S100A1 gene therapy results in chronic functional heart failure rescue', Circulation, vol. 115, no. 19, pp. 2506-2515. https://doi.org/10.1161/CIRCULATIONAHA.106.671701
Pleger, Sven T. ; Most, Patrick ; Boucher, Matthieu ; Soltys, Stephen ; Chuprun, J. Kurt ; Pleger, Wiebke ; Gao, Erhe ; Dasgupta, Abhijit ; Rengo, Giuseppe ; Remppis, Andrew ; Katus, Hugo A. ; Eckhart, Andrea D. ; Rabinowitz, Joseph E. ; Koch, Walter J. / Stable myocardial-specific AAV6-S100A1 gene therapy results in chronic functional heart failure rescue. In: Circulation. 2007 ; Vol. 115, No. 19. pp. 2506-2515.
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