December 29, 2008
Gene Therapy Reverses Heart Deterioration In Rats

If you can just flick the right switch you can stop a heart from deteriorating.

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

thomass said at December 30, 2008 2:31 PM:

F.. still years away... I probably have this (dad and granddad had CHF but they had clogged arteries so it was hard to tell if it was genetic.. now I have it and I don't have circulation problems / CAD)... hurry up. :)

Randall Parker said at December 30, 2008 2:35 PM:


You might be able to get this sort of therapy sooner in less regulated countries. I'm expecting to see a lot more therapies come to market first in countries that do not have heavy regulation of therapies.

thomass said at December 30, 2008 3:39 PM:

Thanks. Yeah, but the getting it into cells thing is an issue (with the attendant cancer risk).

They do have a couple safer new not really available therapies that I might go down to South America for. One involves bone marrow cells injected into the heart and another uses adult (re: your own) stem cells. Both seem to help with some muscle regrowth and both do not seem to have serious side effects.

B Dubya said at December 30, 2008 6:06 PM:

I found out how I am going to die 6 years ago, when I had a heart attack.
I got used to it. In my case, there wasn't a lot of pain and it wasn't nearly as frightening as I thought it would be. I was, and am, very lucky.
But if somebody figures out a gene therapy to rapair my heart, or figures out a nanotech method of clearing my coronary arteries, then maybe I stll have a chance at being shot climbing out of a second story bedroom window, by a jealous husband, when I'm 90...

Toadal said at December 30, 2008 11:05 PM:

Does anyone know of any forms of gene therapy that have been successful in within the brain?

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