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Doubling Down on Gene Therapy for Heart Failure

After a disappointing clinical trial in 2015, scientists are trying anew to mend failing hearts with a gene.
November 2, 2017
NIMR, MRC, Wellcome Images

For over a decade, scientists have been trying to reverse heart failure by delivering a new gene to the heart that makes it better at pumping blood and supplying the body with oxygen.

A major clinical trial testing this gene therapy flopped in 2015. But as gene therapy has finally become a reality for other diseases after years in the making, there’s now renewed interest in trying it again for heart failure.

A team at the Icahn School of Medicine at Mount Sinai in New York, led by Roger Hajjar, has just tested such a therapy in pigs, with encouraging results. Hajjar was a cofounder of the biotech company Celladon, which sponsored the failed clinical trial.

In a study of 13 pigs with severe heart failure, Hajjar and his colleagues gave six a gene therapy while another seven got a placebo saline solution. The gene therapy was safe and reduced heart failure by 25 percent in the left ventricle by 20 percent in the left atrium. Hajjar says most patients with heart failure have problems in the left ventricle. The treatment also reduced the size of the animals’ enlarged hearts by 10 percent.

Hajjar says pigs are good test subjects for this kind of therapy because they have hearts about the size of humans’. He plans to begin enrolling people with advanced congestive heart failure in a clinical trial next year.

About 5.7 million adults in the U.S. have heart failure, and about half of those who are diagnosed die within five years, according to the Centers for Disease Control and Prevention. Heart failure currently can’t be cured; it can only be managed with medications and behavioral changes like quitting smoking, watching your diet, and getting regular physical activity.

In heart failure, the heart doesn’t actually stop. Instead, it has trouble pumping as much blood as your body needs. It tries to make up for this by growing bigger and pumping faster, but eventually it can’t keep up. This causes fatigue and difficulty breathing.

Hajjar’s latest therapy delivers a gene meant to regulate a protein called phosphatase-1, which is found in high levels in people with heart failure. Too much of this protein interferes with the heart’s ability to contract. He thinks targeting this protein could be a way to improve the damaged heart’s pumping action.

This approach is different from traditional gene therapies for inherited conditions, which aim to repair a single genetic mutation. Hajjar instead wants to go after a common characteristic of the disease.

“By identifying molecular targets that are known across the board in all patients with heart failure, we could treat all patients instead of just patients with certain genetic mutations,” he says.

The gene is packaged in an engineered virus that makes its way to heart cells. The therapy would be injected into a major artery.

Hajjar says he and his colleagues have learned from the failure of Celladon’s gene-therapy trial. In that case, they tried to improve muscle contraction in the heart by restoring a protein that’s lacking in compromised hearts. But the therapy didn’t show a significant benefit when it was tested in 250 patients at more than 50 centers in the U.S. and Europe.

Hajjar thinks the therapy failed because it wasn’t getting to enough heart muscle cells. This time around, he says, he and his team at Mount Sinai have reengineered the viral vector to make it more effective at delivering the new gene to the heart.

Walter Koch, chair of cardiovascular medicine and director of the Center for Translational Medicine at Temple University, says the Mount Sinai study is promising. But the challenge is not only getting the virus to the heart: you have to “get it to enough cells that it’s going to make a difference” in a patient’s symptoms. Koch has been working on gene therapy for heart failure for more than a decade.

The goal is to reverse the heart failure with a single injection. “We believe only once would be enough,” he says.

Koch thinks we’re closer than ever to a gene fix for heart failure, especially now that Big Pharma is investing in the idea—something that wasn’t the case 10 years ago. Last year, Pfizer signed a deal with 4D Molecular Therapeutics, based in Emeryville, California, to develop viral vectors for cardiac disease.

Dutch company UniQure, the maker of the Western world’s first gene therapy, is also working on a gene therapy for heart failure. Bristol-Myers Squibb partnered with the company in 2015 to bring the therapy to the market. In a statement, UniQure says its gene therapy has primarily been tested in mini-pigs. The company didn’t say when clinical trials might begin.

One big question is how much a gene therapy for heart disease might cost in the market. Judging from the price of four approved gene therapies, two in Europe and another two in the U.S., Koch thinks it could be very expensive, at least at first.

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