Long-term gene therapy resulted in improved cardiac function and reversed deterioration of the heart in rats with heart failure, according to a recent study conducted by researchers at Thomas Jefferson University's Center for Translational Medicine. The study was published online in Circulation.
The rats were treated with a gene that generates a peptide called beta ARKct, which was administered to hearts in combination with recombinant-adeno-associated virus serotype 6 (rAAV6). beta ARKct works by inhibiting the activation of G protein-coupled receptor kinase 2 (GRK2).
GRK2 is a kinase that is increased in heart failure myocardium. Enhanced GRK enzymatic activity contributes to the deterioration of the heart in heart failure, according to Walter J. Koch, Ph.D., the W.W. Smith Professor of Medicine and the director of the Center for Translational Medicine at Jefferson Medical College of Thomas Jefferson University. Dr. Koch's research team carried out the study, which was led by Giuseppe Rengo, M.D., a post-doctoral fellow.
"The theory is that by inhibiting this kinase, the heart will recover partially due to reversal of the desensitization of the beta-adrenergic receptors," Dr. Koch said. "The expression of beta ARKct leads to a negative neurohormonal feedback that prevents the heart from continuing on the downward slope during heart failure. This was one novel finding of the study."
Dr. Koch and his colleagues used five groups of rats in their study. Two groups received rAAV6 with the beta ARKct peptide, two groups received rAAV6 with green fluorescent protein (GFP), and the last group received a saline treatment. One of the beta ARKct groups and one of the GFP groups also received the beta blocker metoprolol concurrently.
Twelve weeks after receiving the treatment, the rats who received the beta ARKct had a significantly increased left ventricular ejection fraction. The treatment also reversed the left ventricular deterioration and normalized the neurohormonal status. Dr. Koch said that targeting the GRK2 enzyme with beta ARKct was sufficient to reverse heart failure even without concomitant metoprolol.
The rats that received GFP or saline alone experienced more deterioration of cardiac function during the course of the study. This deterioration was prevented, but not reversed, with the concomitant metoprolol.
"Our data show that beta blockers and the beta ARKct peptide are compatible and can be given together," Dr. Koch said. "Although beta blockers are effective at stopping the downward progression of the disease, they do not reverse the damage already done. That is where the beta ARKct gene therapy comes in."
In future trials in humans, the beta ARKct peptide will be administered with beta blockers, which are the standard treatment. However, Dr. Koch said that if a pharmaceutical inhibitor can be developed, then a new class of drugs to treat heart failure could possibly even replace beta blockers.
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