March 1, 2002

Inhibiting cardiac protein through gene therapy improves heart cell function

Blocking a key protein involved in calcium regulation can improve the function of failing heart cells, according to an MGH study featured in the Feb. 26 issue of Circulation. The work holds promise for treating congestive heart failure. "We set out to inhibit a protein that blocks normal calcium flow in the heart," explains principal investigator Roger Hajjar, MD, (pictured at right) of the MGH Heart Failure Center and the Cardiovascular Research Center. "Usually with gene therapy, you add something, but here the strategy was to take something away."

Hajjar says heart failure in the aged is a result of abnormal calcium levels in heart muscle cells. The current study focuses on phospholamban, a protein that regulates a molecular pump controlling calcium flow within cells. In a failing heart, in which the pump's activity is already reduced, phospholamban's natural action may further inhibit the cardiac muscle from relaxing and the heart from filling with blood appropriately.

The study's first author, Federica del Monte, MD, PhD, of MGH Cardiology, took cells from failing hearts and injected them with single-strand DNA. The DNA then binds to the RNA message encoded by the phospholamban gene, completing the approach called "antisense strategy." The technique prevented formation of phospholamban, and the cultured heart cells began to contract normally. The researchers — who include G. William Dec, MD, of MGH Cardiology — hope the treatment strategy eventually can be used to correct heart failure and reduce the need for heart transplants.