In animal studies, scientists at Johns Hopkins have developed what is believed to be the first successful gene therapy that mimics the action of calcium channel blockers, agents widely used in the treatment of heart diseases, including angina, arrhythmias, hypertension and enlarged heart.
Their findings - published in the latest edition of Circulation Research, online July 8 - may lead to a gene therapy alternative to calcium channel blockers and their sometimes severe side effects, but also further interest in the development of gene therapies unique - as in this case - to one particular organ.
Using guinea pigs, the Hopkins team increased production of a key protein involved in heart conductivity, called G-protein Gem, by injecting a virus carrying the gene that codes for the protein into the animals' heart muscles. Increased levels of Gem decreased calcium current densities - the chemical action of calcium channel blockers - by 30 percent to 90 percent, when compared to a control group. Indeed, when heart muscle was electrically stimulated to reproduce the effects of an irregular heartbeat, Gem infusion helped steady the heartbeat, returning it to a normal rhythm, just like calcium channel blockers do. No adverse side effects were observed.
"Calcium channel blockers are a valuable tool in combating arrhythmias and other forms of heart disease, but they can cause low blood pressure, heart block and constipation," said study lead author and cardiovascular physiologist Eduardo Marbán, M.D., Ph.D., professor and chief of cardiology at The Johns Hopkins University School of Medicine. Marbán is also director of the Hopkins Institute of Molecular Cardiology and editor in chief of Circulation Research. "Our basic research is trying to find new ways of harnessing the benefits of calcium channel blockers, while avoiding the negative side effects of existing pill therapies, especially on other organs of the body. Our initial results with gene therapy are very promising."
The researchers were drawn to investigating the role of Gem because of its key role in an enzyme pathway - it is a GTP-binding protein of the Ras pathway - that suppresses a particular way of transporting calcium across cell membranes. This suppression, in turn, helps control calcium levels within cells. Calcium, an essential chemical in the process of muscle contraction, is directly involved in the electrochemical reactions that allow muscle cells to contract as part of a regular heartbeat. In the researchers' experiments, standard adenoviral transfer of the Gem gene was made to the AV node of heart muscle, which is where the heartbeat originates.
Calcium is vital to maintaining good health, as it is involved in many everyday cellular processes, including gene regulation, memory and cell death. However, excessive levels of calcium can lead to arrhythmias, as well as hypertrophy (uncontrolled growth of muscle tissue), apoptosis (programmed cell death) and cardiac remodeling.