Research ArticleHeart Disease

Cardiac AAV9-S100A1 Gene Therapy Rescues Post-Ischemic Heart Failure in a Preclinical Large Animal Model

Science Translational Medicine  20 Jul 2011:
Vol. 3, Issue 92, pp. 92ra64
DOI: 10.1126/scitranslmed.3002097

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Paving the Way for a Gene Therapy Trial for Heart Failure

Heart failure, also known as congestive heart failure, results when, for any number of reasons, the heart no longer pumps enough blood to keep organs perfused and oxygenated. Common in the Western world, heart failure’s first-line treatment is diuretics, which help to remove the excess fluid that pools in the body during heart failure, and β-adrenergic receptor–blocking drugs to interfere with the deleterious effects of the excess catecholamines that accompany this disease. These treatments are effective but do not restore normal heart function; more than half of patients with heart failure die within 5 years. The authors of Pleger et al. now present evidence that a gene therapy approach to augmenting the failing heart’s damaged ability to handle intracellular calcium produces marked improvements in heart function in pigs with heart failure. These results provide enough evidence, the authors say, to justify a clinical trial to see whether this approach could improve patient’s quality of life and survival when added to current treatments.

The investigators injected an adenovirus gene therapy vector (AAV9) carrying the gene for S100A1 into pigs experiencing heart failure, induced by the experimental occlusion of a coronary artery. They chose to deliver S100A1 to the failing heart because this calcium-binding protein becomes depleted as the heart fails and is needed for proper regulation of the calcium dynamics within myocardial cells. Two weeks after infarction, the vector (under control of a cardiac-specific promoter) was delivered to non-infarcted regions of the heart (which would eventually fail without treatment). Twelve weeks later, S100A1 protein expression increased and heart function improved. By several measures, calcium handling within the cardiomyocytes was improved, as were markers of mitochondrial energy production. The authors saw no toxic effects of the therapy and verified the cardiac-specific expression of the vector.

Although similar gene therapy tests were shown previously to be effective in mice, a test in a large animal model was especially important to verify that this approach is likely to be safe and effective in patients. The volume of successfully transduced tissue in a pig heart is similar to that required for humans. Unlike the rodent, the pig’s heart rate, sarcomeric proteins, and cardiomyocyte calcium handling are all similar to human, and therapeutic vector delivery through a percutaneous catheter, which will be required in patients, could be mimicked in pigs. If the value of this therapy is confirmed in clinical trials, it would be available for patients already suffering heart failure. It would likely prove most useful as an adjunct therapy to currently existing drugs where it could augment the strength of the heart’s contraction.


  • * These authors contributed equally to this work.

  • Citation: S. T. Pleger, C. Shan, J. Ksienzyk, R. Bekeredjian, P. Boekstegers, R. Hinkel, S. Schinkel, B. Leuchs, J. Ludwig, G. Qiu, C. Weber, P. Raake, W. J. Koch, H. A. Katus, O. J. Müller, P. Most, Cardiac AAV9-S100A1 Gene Therapy Rescues Post-Ischemic Heart Failure in a Preclinical Large Animal Model. Sci. Transl. Med. 3, 92ra64 (2011).