Abstract
The feasibility of gene therapy for cardiomyopathy, heart failure and other chronic cardiac muscle diseases is so far unproven. Here, we developed an in vivo recombinant adeno-associated virus (rAAV) transcoronary delivery system that allows stable, high efficiency and relatively cardiac-selective gene expression. We used rAAV to express a pseudophosphorylated mutant of human phospholamban (PLN), a key regulator of cardiac sarcoplasmic reticulum (SR) Ca2+ cycling in BIO14.6 cardiomyopathic hamsters. The rAAV/S16EPLN treatment enhanced myocardial SR Ca2+ uptake and suppressed progressive impairment of left ventricular (LV) systolic function and contractility for 28–30 weeks, thereby protecting cardiac myocytes from cytopathic plasma-membrane disruption. Low LV systolic pressure and deterioration in LV relaxation were also largely prevented by rAAV/S16EPLN treatment. Thus, transcoronary gene transfer of S16EPLN via rAAV vector is a potential therapy for progressive dilated cardiomyopathy and associated heart failure.
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Acknowledgements
We thank J. Chrast and J. Lam for experimental assistance. This work was entirely supported by the Jean Le Ducq Foundation.
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K.R.C., M.H. and Y.W. have equity in a startup company, Celladon, that holds the intellectual property for the mutant phospholamban (PLN) gene therapy strategy including S16EPLN outlined in this paper.
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Hoshijima, M., Ikeda, Y., Iwanaga, Y. et al. Chronic suppression of heart-failure progression by a pseudophosphorylated mutant of phospholamban via in vivo cardiac rAAV gene delivery. Nat Med 8, 864–871 (2002). https://doi.org/10.1038/nm739
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DOI: https://doi.org/10.1038/nm739
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