Since their introduction in the 1950s, implantable cardiac devices such as permanent pacemakers have become an integral part of modern cardiovascular medicine. The growing number of evidence-based indications for cardiac devices coupled with an aging world population predicts a continued increase in the implantation of such devices. Although pacemaker devices have prolonged the lives of countless patients, they also place these same patients at risk for a number of complications, including infection. Particularly in an aging population, cardiac pacemaker device complications carry substantial morbidity and mortality rates. Whether systemic or localized to the pocket, complete removal of hardware is the universally accepted, definitive treatment for pacemaker infection; incomplete removal of all hardware is associated with an approximately 50% incidence of infection recurrence. While the infection is treated, the need to maintain an adequate heart rate is provided by temporary external pacing devices. Temporary pacing devices sustain the vital hemodynamic needs during antibiotic treatment, but expose the patients to continued infection risks since generally a new external lead is utilized. This is the target population for our gene therapy.
The goal of this proposal is to develop a biological pacemaker for clinical use, replacing the currently utilized electronic pacemaker devices that consist of a generator and leads. We seek to pace the heart with a straightforward injection of human stem cell-derived biological pacemaker. We propose to introduce the biological pacemaker in patients in whom the electronic pacemaker device has been infected and they are admitted to the hospital for treatment of this infection. Biological pacemaker is designed to provide a heart rhythm in the complete absence of external pacing devices without lead wires running in to the patients’ body. The technology capitalizes on our ability to guide human embryonic stem cells into spontaneously-beating heart cells, and to optimize the beating heart cells to pace the heart consistently and effectively. We seek to replace the temporary electronic pacing devices with a human stem cell-derived biological pacemaker during an antibiotic therapy upon the removal of infected permanent pacemaker devices.
Statement of Benefit to California:
Cardiovascular disease remains the leading cause of death and disability in Americans. The death toll from cardiovascular disease is greater than that for cancer, chronic respiratory diseases, accidents, and diabetes combined. Aside from the human costs, cardiovascular disease exacts a tremendous fiscal toll. All taxpayers must bear the economic burden of resulting death and disability. Clearly, virtually all Californians stand to benefit, directly or indirectly, from the development of more effective treatments of cardiovascular disease.
Among the different arrays of heart diseases, cardiac arrhythmias are particularly deadly; disturbances of heart rhythm are often the final disease that kills the patient. Many of the patients with bradycardia (abnormally slow rhythm) are clinically indicated to receive implantable electronic pacemaker devices in order to pace their diseased heart and maintain the hemodynamic needs. However, the pitfalls associated with device-driven management of cardiac rhythm are numerous; such devices are expensive, and implantation involves a number of acute (pulmonary collapse, hemorrhage) and chronic risks (bacterial infection, lead or generator failure). With the populace aging rapidly and indications growing steadily, the present pitfalls are predicted to enlarge into a critical burden on delivery of health care.
We seek to capitalize on the intrinsic ability of human embryonic stem cells to become differentiated, spontaneously beating (i.e., pacemaker) heart cells. The treatment would be “allogeneic”: a single defined cell product (we call “BioPace-ES”) will be available to off-the-shelf to benefit the patients in need immediately. Although the BioPace-ES are derived from human embryonic cells, the final product is fully differentiated heart cells. Thus, the concerns associated with stem cell injection (e.g., differentiation of the injected stem cells into unwanted lineage, formation of teratoma, etc.) are, in principle, not applicable to BioPace-ES. If our studies are successful, it may offer a radically cost-effective way to reduce the tremendous financial damage to Californians inflicted by cardiac arrhythmias. This in turn may also reduce the economic burden presently borne by taxpayers who support the health care systems in California. In addition to the public health benefits, spinoff technology developed by this disease team will benefit existing California-based biotechnology companies, leading to fuller employment and an enhanced tax base.