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CUMC Collaborates to Develop Biological Pacemaker
A cardiac pacemaker based on gene and cell therapies may one day be possible

Michael R. Rosen, M.D
Columbia University Medical Center, Guidant Corporation and Stony Brook University will collaborate to study a new gene and cell therapy that may ultimately provide better understanding of how genetically engineered cells can help pace the heart. This work builds on recent basic research conducted at the universities.

Research to date at the universities suggests the possibility of developing a biological pacemaker, one that can vary the heart's beats to fit the body's needs, as is required during variations in exercise or emotional state.

"The opportunity to translate this important technology from basic research into human therapy fits in with our mission at Columbia University Medical Center," says Gerald D. Fischbach, M.D., executive vice president and dean. "We look forward to collaborating with Guidant and Stony Brook and harnessing the potential of this new treatment." Based in Indianapolis, Guidant designs and develops cardiovascular medical products.

Research will be conducted in four laboratories at the universities: those of Michael R. Rosen, M.D., Gustavus A. Pfeiffer Professor of Pharmacology and professor of pediatrics at Columbia; Richard B. Robinson, Ph.D., professor of pharmacology at Columbia; Ira S. Cohen, M.D., Ph.D., Leading Professor of Physiology & Biophysics and professor of medicine at Stony Brook; and Peter R. Brink, Ph.D., professor and chairman of physiology and biophysics at Stony Brook. The research grew out of collaborations between Columbia's Center for Molecular Therapeutics, headed by Dr. Rosen, and Stony Brook's Institute of Molecular Cardiology, headed by Dr. Cohen. Columbia's Office of Science and Technology Ventures, supported by Stony Brook's Office of Technology Licensing, played an important role in negotiating the arrangement between the universities and Guidant.

"The partnership provides a chance for us to attempt the translation of basic research done in our laboratories into a clinical therapy," Dr. Rosen says. "Guidant's commitment is central to making this happen."

The normal heartbeat is initiated by a pacemaker region of the right atrium. This pacemaker, the sinoatrial node, is a relatively small group of cells that spontaneously initiates an electrical impulse or action potential. This impulse then is conducted to the remainder of the heart, providing the basis for its rate and rhythm of contraction. The intrinsic rhythmicity of the sinoatrial node is the result of an ion current determined by the HCN family of genes.

In approximately 250,000 patients per year in the United States alone, disorders occur in the initiation or the conduction of the heartbeat – many of which are potentially lethal. Treatment for these individuals is usually an electronic pacemaker consisting of an electrode placed in one or two of the cardiac chambers and attached to a power pack inserted under the collarbone. While this has become the standard for therapy, it has a number of limitations that have led investigators to seek alternatives.

The team of investigators at Columbia and Stony Brook has devised a therapy based on delivering genes of the HCN family to specific locations in the heart. In the research program that now includes Guidant, adult human mesenchymal stem cells are used as a platform to deliver the therapy.

Adult human mesenchymal stem cells are not to be confused with human embryonic stem cells, which have different properties and are obtained from different sources. Since the mesenchymal stem cells do not carry the HCN gene, it is first necessary to load them with the gene, via a process called electroporation. This avoids concerns raised by the use of viral vectors in many forms of gene therapy.

The resultant ion current, when studied biophysically, has properties nearly indistinguishable from those of the native pacemaker current. When the stem cells are placed in proximity with heart muscle cells in culture or in the heart itself, they form gap junctions, regions of low resistance and tight apposition, with the myocardial cells.

These gap junctions enable the pacemaker current generated in the stem cells to initiate action potentials in the heart muscle cells, thereby providing a pacemaker function. Therefore, the cell pair, consisting of stem cell and heart muscle cell act in functional unity: the former generating the pacemaker current and the latter responding to it by initiating the action potential that excites the remainder of the heart.

The investigators are optimistic such a pacemaker can be developed, based on the positive results of this cell pairing in cell cultures as well as in experimental animal models. "Some of the partnership's research goals now are to fine-tune the pacemaker gene function, test the longevity and the possible toxicity of the therapy, and compare it directly with electronic pacemaker therapy," Dr. Rosen says.

—Matthew Dougherty