How Tweaking Genes May Fix Broken Hearts

May 31, 2010— -- Replenishing the supply of a gene that controls the way heart muscle cells work appears to slow progression of heart failure, a disease that will be diagnosed in about 670,000 Americans this year.

After six months, patients who received the highest dose of the gene therapy had less worsening of a six-minute walk test, as well as evidence of less rapid enlargement or remodeling of the heart, compared with patients in the placebo group.

Patients who receive the high dose gene therapy were also likely to have shorter hospitalizations -- an average of 0.2 days versus 2.1 days for patients in the placebo group.

But the gene therapy didn't reduce breathlessness, fatigue, or pain associated with advanced heart failure, nor did it make patients feel better or have improved quality of life.

In announcing preliminary results of the first study of gene therapy for treatment of heart disease, Dr. Barry Greenberg of the University of California tried to balance optimism for what has been called a breakthrough treatment against the reality that the results were less than stunning.

Greenberg reported the findings to fellow heart failure researchers gathered in Berlin for the Heart Failure Congress.

Of the 39 patients in the study, just nine received the high-dose gene therapy that Greenberg and his colleagues have identified as demonstrating enough efficacy for it to be investigated in a larger study.

The gene used in the study is called Mydicar, which is a bioengineered or recombinant version of an enzyme called SERCA 2A that is found in heart muscle cells. This enzyme regulates two critical functions: the transport of calcium between cells and the contractility or squeezing power of a heart muscle cell.

Heart failure occurs when the heart loses its ability to efficiently pump blood through the body. As a result the heart enlarges and fluid builds up in the lungs. Earlier studies have suggested that SERCA 2A plays a key roll in this process -- as the cellular supply or level of this enzyme diminishes the heart begins to fail.

Conversely, Greenberg said, replacing the gene with the manmade version might slow or reverse that process.

Mydicar is given as a one time infusion directly into the coronary arteries via a catheter using technology that is commonly used to obtain angiographic images of the heart or to open open blocked vessels using balloons or stents.

In the study reported by Greenberg, eight patients received low dose Mydicar, eight were treated with a medium dose, and nine were assigned to high dose Mydicar. The remaining 14 patients underwent angiography but had no infusion.

Dr. Andreas Zeiher of the University of Frankfurt, who served as discussant for the CUPID trial, offered generous praise for the findings but he also sounded a note of caution about the delivery system for the therapy. The in order to enter cells, the gene needs to be wrapped in a virus that "infects" the cells with the gene.

Mydicar uses an adeno-assisted virus vector from the virus family that produces the common cold as well as pneumonia, bronchitis, and croup. As a result, Zeiher said that about 40 percent of heart failure patients have developed antibodies to this virus, which means that the Mydicar could not be given to those patients unless the patient underwent a process called leukapheresis in which white cells are removed from the blood.

If additional studies confirm a benefit for this gene therapy, it would be a boon for Celladon, the La Jolla, Calif., company that is developing Mydicar, and be an even bigger boon for the beleaguered United States health care system. According to the U.S. Centers for Disease Control and Prevention, about 5.8 million people in the U.S. have heart failure, and this year the cost of heart failure treatment, medicines and lost productivity will top $39 billion.