Cardiac Gene Therapy Reverses Heart Damage That Occurs In Heart Failure

by Dr Sam Girgis on July 21, 2011

Heart failure, also termed congestive heart failure, results when damage to the heart from heart attack, toxins, or genetic disease cause it to pump blood less efficiently.  The damaged heart is weakened and cannot pump blood forward to organs to maintain the normal physiologic processes of the body.  As a result, fluid can accumulate in the lungs, legs, and abdomen.  In addition, the weakened heart is more prone to abnormal heart rhythms or arrhythmias which can lead to early death.  In the United States, there are an estimated 6 million people who are currently living with heart failure with 300,000 deaths occurring each year from the disease.  Five years after the initial diagnosis of heart failure, more than half of patients will have died of the disease.  Currently, medical treatment focuses on symptomatic treatment with the use of diuretics to eliminate excess fluid, ACE inhibitors to prevent heart remodeling, and beta blockers to decrease catecholamine toxicity.  Despite these treatments, heart failure remains a chronic and progressive disease that almost always goes on to kill the afflicted individual.  We have previously discussed the use of stem cells to reverse heart damage due to heart attack in mice.  Heart attack remains the leading cause of heart failure and stem cell therapy may help prevent heart failure caused by the damage of a heart attack.  Recently, researchers lead by Dr. Patrick Most have shown that gene therapy using a calcium regulatory protein can reverse the damage cause by heart attack and prevent heart failure.  The results of their research were published online in the journal Science Translational Medicine.  In their study, the researchers induced a heart attack in pigs by balloon occlusion of the left circumflex coronary artery.  After 2 weeks, the pigs displayed significant heart dysfunction due to the heart attack with decreased heart contraction and decreased left ventricular ejection fraction indicative of heart failure.  The investigators used an adeno-associated virus vector carrying the gene for S100A1 as gene therapy for the undamaged heart tissue of the pigs.  S100A1 is a calcium regulatory protein that has been shown to be markedly decreased in the hearts of heart failure patients.  At 14 weeks time, the untreated pigs showed significantly decreased heart S100A1 expression levels with decreased heart function and cardiac remodeling.  The pigs that had received the gene therapy showed normal heart muscle calcium handling and metabolism, as well as S100A1 levels.  In addition, the gene therapy treatment prevented and reversed the functional and structural changes that occur in heart failure.  The authors of the study wrote, “This translational study shows the preclinical feasibility of long-term therapeutic effectiveness of and a favorable safety profile for cardiac AAV9-S100A1 gene therapy in a preclinical model of heart failure. Our results present a strong rationale for a clinical trial of S100A1 gene therapy for human heart failure that could potentially complement current strategies to treat end-stage heart failure”.  This study is important because it utilized a large animal model of heart failure which more closely resembles the physiology of human heart failure.  As a result, these results could potentially be obtained in humans.  The next step will be the application of this gene therapy in phase 1 clinical trial in humans.


Sven T. Pleger et al. “Cardiac AAV9-S100A1 Gene Therapy Rescues Post-Ischemic Heart Failure in a Preclinical Large Animal ModelSci Transl Med 20 July 2011: Vol. 3, Issue 92, p. 92ra64 DOI: 10.1126/scitranslmed.3002097

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