For Failing Hearts: Gene therapy stops decline in animals

Tests in hamsters have raised hopes for creating a gene therapy to stop the common downward spiral of chronic heart failure.

What distinguishes the proposed treatment is a novel version of a calcium-regulating gene plus an improved way of getting that gene into heart cells, says Kenneth Chien of the University of California, San Diego. In a laboratory breed of hamsters that commonly develops progressive heart failure, the treatment arrested the decline for the 7 months that the experiment ran, Chien and his colleagues report in the August Nature Medicine.

If testing continues to go well, Chien says, he hopes to design within months a version of the therapy to test in people. Also, he speculates that the new delivery system might work for other genes. “This opens the door,” Chien says.

Some 4.5 million Americans a year find that their hearts are losing the pumping power that keeps blood flowing properly. Drugs can ease symptoms and slow the decline but can’t stop it, says Chien. The only complete fix is to find a new pump, either a transplanted heart or a mechanical device.

Earlier work by Chien and others suggested that fiddling with a small molecule, called phospholamban, within muscle cells might revive failing hearts. Chien says that phospholamban acts as a brake on the normal ebb and flow of calcium that drives heart contractions. In diseased hearts of lab mice, deactivating that brake has had a beneficial effect.

Chien’s team slightly modified the gene for phospholamban so that it encodes a molecule with less-than-normal braking effect. To get the gene into heart cells, the researchers hitched it to rAAV, a biologically engineered virus related to ones that cause the common cold. Many previous gene therapies have relied on injections of gene-carrying viruses directly into targeted tissue, but Chien administered the rAAV and its novel cargo through the bloodstream. The biotech company Celladon of La Jolla, Calif., in which Chien owns an interest, is working to commercialize this technique.

In their recent work, the researchers treated 30 hamsters that already showed signs of cardiac decline. No inflammation flared up, the Chien team reports, and tests indicated that more than 60 percent of the cells in heart-ventricle muscle expressed the modified gene.

“That’s a real advance,” says Elizabeth Nabel of the National Heart, Lung, and Blood Institute in Bethesda, Md. The effectiveness of the modified phospholamban gene is another significant contribution of this research, Nabel says.

Chien’s team reports that starting 5 weeks after the treatment, the hamsters’ heart muscle stabilized. In contrast, heart muscle of 28 hamsters without the treatment continued to weaken dramatically.