Currently, over 350,000 patients per year with abnormal heart rhythm receive electronic pacemakers to restore their normal heart beat. Electronic pacemakers do not respond to the need for changing heart rate in situations such as exercise and have limited battery life, which can be resolved with biopacemakers. In this proposed project, we will examine methods that improve the generation of pacemaking cells from human induced pluripotent stem cells as candidates for biopacemaker.
This proposal aims to generate pacemaking cells through facilitated differentiation from human induced pluripotent stem cells that may serve as biopacemakers. Over 350,000 patients a year in the U.S. require the implantation of an electronic pacemaker to restore their heart rhythm, with more than 3 million patients that are dependent on this device. At the cost of $58K per pacemaker implantation, the healthcare burden is greater than $20 billion a year. However, the cost associated with these electronic devices does not end with surgery for implantation. These devices require a battery change every 5 to 10 years that involve another surgical procedure. With California being the most populated state, this can be very costly to the Californians. It also does not give the patients the quality of life by having to endure repeated surgeries. The possibility of biopacemaker that requires no future battery replacements and other advantages such as physiological adaptation to the active state of the patient make biopacemakers a truly desirable alternative to electronic devices. Moreover, one in 20,000 infants or preemies with congenital sinoatrial node dysfunction are also inappropriate candidates to receive electronic pacemakers because they are physically too small and require a proportional increase in the length of pacing leads with their significant growth rate. Therefore, there is a great need for biopacemakers that may overcome the deficiencies of electronic devices.
This is a proposal to study the development of pacemaker cells from human induced pluripotent stem cells (hiPSC) in order to enable generation of long lasting, biological pacemakers. The plan focuses upon the role of a group of proteins in this process for which a small molecule activator has been identified. The group will first test a specific mechanism by which the activator might enhance induction of pacemaker differentiation. Next, they plan to determine pathways downstream of the activated proteins of interest responsible for pacemaker cell formation.
Significance and Innovation
- Reviewers praised the concept of a biological pacemaker and highlighted that while pacemaker devices are currently available, they require replacement and are not appropriately sized for pediatric patients.
- Pharmacological induction of pacemaker differentiation represents a feasible approach to drive differentiation of this cell type, which is otherwise generated at very low frequency.
Feasibility and Experimental Design
- Reviewers expressed concern that many of the proposed experiments rely on a small molecule activator that is not specific to the proteins of interest. This was not addressed in the plan and was seen as a flaw in the proposal.
- Reviewers suggested the proposal would be strengthened by incorporating genetic manipulation of the protein of interest to confirm its role in pacemaker formation.
- The proposal lacked a clear plan describing how to ensure retention of the pacemaker cell phenotype over time and did not address cardiomyocyte maturity.
- The proposal is well written and provides appropriate preliminary data.
- Principal Investigator (PI) and Research Team
- While the applicant is a promising investigator, the panel expressed concern regarding both his/her relative inexperience as an independent investigator and limited publication record.
- Reviewers were puzzled by the dual institution appointment and expressed strong concerns that this could jeopardize the PIís ability to lead this effort.
- The PI has assembled a team of co-investigators with demonstrable expertise in stem cell biology, cardiovascular biology and imaging that are required to execute the program.
Responsiveness to the RFA
- The proposal is responsive to the RFA.
- PROGRAMMATIC REVIEW
- A motion was made to move this application into Tier 1, Recommended for Funding. It was noted that while there were technical flaws in the plan, it addressed an important topic, and that if granted, this award could help launch the PIs independent career. However, the PIs track record remained a concern. The motion failed.