Biological pacemakers created from human embryonic stem cells or transcription factor-driven reprogramming in a preclinical model of heart block
New Faculty Physician Scientist
Electronic Pacemakers (EP) have been used for over 50 years for the treatment of cardiac conditions associated with slow heart rates,such as complete heart block. Despite continuous refinement,the presence of a foreign body increases the risk of hardware related infections. This serious complication is associated with an increased risk of generalized infection,and death. Treatment of these infections often requires complete removal of all hardware and treatment with intravenous antibiotics for over two weeks. In some patients,inserting a temporary pacing device to maintain an adequate heart rhythm until the infection is cleared and a permanent device re-implanted, is required. Biological pacemakers (BioPs) have been developed as an alternative to EP to treat these conditions. By using stem cell-based approaches, the patient's own pacemaker cells can be regenerated, avoiding the need for an EP. We have developed a clinically-applicable delivery technique to study different BioPs strategies experimentally.In the case of device-related infections,a BioP could provide the patient with adequate heart rates while the infected device is removed and infection is cleared. This could improve the therapeutic efficacy by removing any possible nidus of infection associated with a temporary pacing device. Development of a BioP for the focused "bridge to device" application could open the way for more ambitious applications such as definitive replacement of EP by biological surrogates.
Statement of Benefit to California:
The numbers of cardiac pacemakers and defibrillators implantations for treating cardiac rhythm disorders continue to rise steadily in the United States.Despite continuous refinement, complications such as device malfunction and infection occur.Device-related infections have been rising in the past decade not only due to the increase in device implantations, but also due to a higher incidence of bacterial infections in the US and worldwide.Current treatment for these conditions involves admission to the hospital,removal of all infected hardware,placement of a temporary pacing device (in those pacer-dependent patients),and treatment with systemic antibiotics.This increases the risk of generalized infections, hospitalization length, patient’s discomfort, and health care costs.New and more effective treatment modalities for these conditions are needed. Clearly, all Californians stand to benefit, directly or indirectly, from the development of more effective treatment modalities for heart rhythm disorders. The present work seeks to provide the scientific basis for regulatory filings that would allow regenerating the patient’s own pacemaker cells avoiding the need for an electronic pacing device.This could potentially offer a more effective treatment option for Californians inflicted by pacemaker-related complications.By reducing hospitalization length, this may also reduce the economic burden presently borne by taxpayers who support the health care systems in California.
Executive Summary This proposal aims to develop a biological pacemaker that would serve as a temporary bridge between electronic pacemakers in cases where infection has necessitated removal of a previous device. The applicant plans to test two approaches for generating biological pacemaker activity: a virally delivered regulatory gene that induces many pacemaker related proteins in working myocytes (BioP) and a human embryonic stem cell (hESC) derived biopacemaker candidate (hESC-BioP). The applicant plans to first elect an hESC-BioP from multiple candidate hESC sources including those cells that have been genetically modified to acquire pacemaker like properties. The BioP and hESC-BioP candidate approaches will then be tested in vitro for their ability to control the beating of primary cardiomyocytes. Next the applicant will optimize methods by which the candidates can be delivered to a relevant preclinical model of conduction disease. Finally, the two BioP candidates will be tested for efficacy and safety in the model. Research Plan - Reviewers questioned what would be learned by the applicant’s comparison of gene therapy and xenogeneic cell therapy approaches. They noted that different sets of expertise are required to develop these two approaches. A panelist suggested that comparing two candidates within a single therapeutic class would be more informative. - Reviewers were divided regarding the proposal’s rationale for a bridge to new device approach. Some expressed significant reservation regarding both the unmet need and the clinical appropriateness of transplanting allogeneic cells during an infection, while others felt this may be a useful initial application for biopacemakers that could advance the field. - Risks of the proposed candidate therapies weren’t well considered including that of teratoma formation, viral integration and immune rejection. Further, acute rejection of the hESC-BioP could render the “bridge” duration inadequate. - A discussant cautioned that expression of the regulatory gene does not fully recapitulate the pacemaker phenotype. - A panelist questioned the rationale for treating both sinoatrial node (SAN) and atrioventricular node (AVN) failure with same pacemaker cell type, as these structures have divergent properties. Principal Investigator - The PI is a well-trained cardiologist with a strong background in cardiac electrophysiology and a relevant publication record in this area. However, s/he lacks the hESC expertise required to support the proposed hESC-BioP studies and technically challenging hESC-BioP transplants. This led reviewers to question whether the applicant would be able to achieve the proposed goals. - The applicant has an established relationship with the primary mentor, who has provided a very strong letter of support. However, the career development plan is weak and the poorly written application suggested to reviewers that the PI was not receiving adequate guidance. Institutional Commitment - The applicant will have protected research time and the institution is very committed to, and well equipped to translate stem cell research. However, the institutions commitment specifically to the individual applicant in terms of dedicated lab space and start up funds is unclear. Responsiveness - Reviewers found the proposal to be mostly responsive to the RFA as it seeks to advance a therapeutic candidate. However, some reviewers questioned the responsiveness of the gene therapy approach and felt the hESC component was merely included to render the application technically responsive to the RFA.