Delivery of Therapeutic Gene Halts Heart Failure

The study appeared in the July 22, 2002, issue of Nature Medicine.

For the new therapy, researchers modified a gene called phospholamban (PLN), which regulates the strength of every heartbeat and malfunctions in heart failure. Initially, they used an inactivated adenovirus to serve as a vector, but within seven days, the body's immune system killed the virus and eliminated the mutant PLN gene. Recognizing that a feasible therapy for chronic cardiac muscle disease would need to express the target gene for many months, the researchers switched to an adeno-associated viral vector. This delivery system was not eliminated by the immune system, was found to have a high affinity for heart muscle, and in fact was attracted to it. For seven months, the progression of heart failure was halted in hamsters receiving the mutant PLN gene by this method.

PLN was chosen because defects in the heart's pumping action were linked to the gene, which acts as a brake on the calcium pump. In case of a heart attack, the PLN brake becomes defective, over-restricting calcium and weakening heart function. To overcome this problem, the researchers replaced one amino acid within PLN for another in order to form a mutant version that would inhibit its normal counterpart. In animals that received the PLN mutation, calcium activity was enhanced by more than 100%.

"In essence, we inhibited the inhibitor,” said Masahiko Hoshijima, M.D., Ph.D., first author of the study. "The PLN mutation was able to replace the defective PLN gene, generate normal cardiac contraction, and prevent heart failure.” The study was conducted by Dr. Hoshijima, senior author Kenneth Chien, M.D., Ph.D., and colleagues at the University of California, San Diego, School of Medicine (USA). The team is currently testing the therapy in pigs, and they hope to expand their study to humans in the next year or so.