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 delivered gene inhibits another gene that has higher activity in diseased hearts.
The rats were treated with a gene that generates a peptide called βARKct, which was administered to hearts in combination with recombinant-adeno-associated virus serotype 6 (rAAV6). βARKct works by inhibiting the activation of G protein-coupled receptor kinase 2 (GRK2).
In order to do this experiment the scientists first needed to know that the kinase enzyme GRK2 is expressed more in failing hearts and that it contributes to the failure. Then they needed to know which gene to use to inhibit this kinase. Then they needed a delivery vehicle for getting this gene into the heart. A lot of work went into each of these pieces of the puzzle.
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 β-adrenergic receptors,” Dr. Koch said. “The expression of βARKct 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 βARKct peptide, two groups received rAAV6 with green fluorescent protein (GFP), and the last group received a saline treatment. One of the βARKct 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 βARKct 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 βARKct was sufficient to reverse heart failure even without concomitant metoprolol.
One of the ways that cheap DNA sequencing helps is that it leads to the identification of genes that contribute to heart disease risk. Those genes then become candidates to use in gene therapy to either turn them up or turn them down or modify how they work. The expanding knowledge about which genes get more or less expressed in disease tissue will help in the identification of potential targets for gene therapy. Though there's a lot more work involved beyond just identifying which genes are turned up or down in diseased tissue.
Gene therapy has been pretty slow in coming. The problem isn't just in identifying which gene(s) to deliver but also how to package them, how to get them into only the cell types you want to treat (turning on heart genes in the liver is not a good idea), and how to do all this without damaging the genome of the targeted cells. Cancer is a real threat and some gene therapy development efforts have failed due to cancer.
The experiment above suggests some good news. If we can find a way to deliver gene therapy safely into heart cells then at least some types of heart disease can be stopped and reversed.
|Share |||Randall Parker, 2008 December 29 04:49 PM Biotech Gene Therapy|