Use of Cell- and Gene-Based Therapies for Providing Cardiac Biological Pacing
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Wolfson, David
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Abstract
Each heartbeat, pumping blood throughout the body, is initiated by an electrical impulse from the heart’s natural pacemaker. However, a number of diseases/syndromes can hamper our pacemaker’s ability to generate consistent action potentials, requiring the implantation of an artificial pacemaker device for treatment. However, complications inherent to the indwelling hardware give pause to categorical use of device therapy for a subset of populations, including pediatric patients or those with temporary pacing needs. In this dissertation, I demonstrated the use of new gene- and cell-based therapies for the generation of de novo pacemaker cells, capable of raising the heart rate of animals with bradycardia, thus providing temporary biological pacing and reducing patient dependence on artificial pacemaker devices. For cell-based therapies, I used activation of retinoic acid signaling to direct differentiation of human pluripotent stem cells toward cardiomyocytes with a more pacemaker-like genotype and phenotype. Delivery of these cells to rats with complete heart block significantly increased their heart rate. For gene-based therapies, I used in vitro transcribed modified mRNA, encoding the transcription factor T-box18 to reprogram chamber cardiomyocytes into induced pacemaker cells. I demonstrated the health and safety benefits in vivo of using mRNA for gene transfer, rather than traditional recombinant adenoviral vectors. Moreover, myocardial injection of TBX18 mRNA in rodent and clinically-relevant porcine models of complete heart block created rate-adaptive cardiac pacing for one month, which strongly correlated to the subject’s sinus rhythm and physical activity. Altogether, this dissertation provides strong evidence for the ability of cell- and gene-based therapies for use in cardiac rhythm management.
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Date
2022-01-04
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Dissertation