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PRECLINICAL STUDY

Percutaneous Cardiac Recirculation-Mediated Gene Transfer of an Inhibitory Phospholamban Peptide Reverses Advanced Heart Failure in Large Animals

David M. Kaye, MD, PhD^_*,1,2,_*, Arthur Preovolos, BS^_*,1,3, Tanneale Marshall, BS^_*, Melissa Byrne, PhD^_*,1,3, Masahiko Hoshijima, PhD, Roger Hajjar, MD, Justin A. Mariani, MD^_*, Salvatore Pepe, PhD^_*, Kenneth R. Chien, MD, PhD and John M. Power, PhD^_*,1,2

^_* Baker Heart Research Institute, Melbourne, Australia
Institute of Molecular Medicine, University of California–San Diego, La Jolla, California
Massachusetts General Hospital, Cardiovascular Research Center, Harvard Medical School, and the Harvard Stem Cell Institute, Boston, Massachusetts.

Manuscript received December 4, 2006; revised manuscript received March 22, 2007, accepted March 28, 2007.

^_* Reprint requests and correspondence: Prof. David M. Kaye, Wynn Department of Metabolic Cardiology, Baker Heart Research Institute, P.O. Box 6492, St. Kilda Road Central, Melbourne, VIC 8008, Australia. (Email: david.kaye{at}baker.edu.au).

Objectives: The purpose of this study was to develop a clinically applicable high-efficiency percutaneous means of therapeutic gene delivery to the failing heart.

Background: Substantial advances in the understanding of the cellular and molecular basis of heart failure (HF) have recently fostered interest in the potential utility of gene and cell therapy as novel therapeutic approaches. However, successful clinical translation is currently limited by the lack of safe, efficient, and selective delivery systems.

Methods: We developed a novel percutaneous closed-loop recirculatory system that provides homogeneous myocardial delivery for gene transfer in the failing large animal heart. After 4 weeks’ rapid pacing in adult sheep to induce HF, the animals were randomly allocated to receive either adenovirus expressing a pseudophosphorylated mutant (AdS16E) of phospholamban (PLN) or Ad–ß-galactosidase (AdLacZ).

Results: Two weeks after gene delivery, in the presence of continued pacing, left ventricular (LV) ejection fraction had significantly improved in the AdS16E-treated animals (27 ± 3% to 50 ± 4%; p < 0.001), whereas a further decline occurred in the AdLacZ group (34 ± 4% to 27 ± 3%; p < 0.05). In conjunction, AdS16E delivery resulted in significant reductions in LV filling pressures and end-diastolic diameter (both p < 0.05). In conjunction, AdS16E-treated animals showed significant improvement in the expression of PLN and Ca²⁺-adenosine triphosphatase activity. In separate animals, recirculating AdLacZ delivery was shown to achieve superior myocardial gene expression in contrast to intracoronary delivery and was associated with lower systemic expression.

Conclusions: We report the development of a novel closed-loop system for cardiac gene therapy. Using this approach delivery of AdS16E reversed HF progression in a large animal HF model.

Abbreviations and Acronyms   Ad = adenovirus   HF = heart failure   LacZ = ß-galactosidase   LVEF = left ventricular ejection fraction   PLN = phospholamban   S16EPLN = serine-to-glutamate "pseudo-phosphorylated" phospholamban mutant   SERCA = sarcoplasmic reticulum Ca2+-ATPase   SR = sarcoplasmic reticulum

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