As far as med tech goes, the pacemaker ranks near the top in terms of impressiveness and lives saved. Over 3 million people around the world rely on them, and each year more than 600,000 are implanted. Despite this current level of success, however, physicians, scientists, and engineers continue working on improving pacemaker technology – even to the point of not needing them anymore.
A paper published in Sunday’s issue of Nature Biotechnology describes one approach to pacing the heart without an electrical implant: genetic reprogramming. Whereas the vast majority of the heart’s 10 billion cells are cardiomyocytes, which are responsible for pumping blood through the body, the pacemaker is composed of a specialized population of ~10,000 cells with spontaneous electrical rhythm originating in the sino-atrial node (SAN).By using an adenovirus carrying the transcription factor Tbx18, the Cedars-Sinai Heart Institute team succeeded in reprogramming cardiomyocytes into induced sino-atrial node (iSAN) pacemaker cells. The engineered iSAN cells are functionally and morphologically the same as normal SAN cells, as described in the paper:
Within days of in vivo Tbx18 transduction, 9.2% of transduced, ventricular cardiomyocytes develop spontaneous electrical firing physiologically indistinguishable from that of SAN cells, along with morphological and epigenetic features characteristic of SAN cells. In vivo, focal Tbx18 gene transfer in the guinea-pig ventricle yields ectopic pacemaker activity, correcting a bradycardic disease phenotype. Myocytes transduced in vivo acquire the cardinal tapering morphology and physiological automaticity of native SAN pacemaker cells.
We contacted the Cedars-Sinai Heart Institute Director of Cellular Electrophysiology, and study’s principal investigator, Hee Cheol Cho, PhD, to learn more about the team’s work:
Shiv Gaglani, Medgadget: What are you currently working on to translate this viral-based reprogramming of cardiac myocytes from the bench to the bedside?Dr. Hee Cheol Cho: In the present work, we demonstrate the work in a small animal (guinea pig) model. In order for this technology to become a reality, we will verify the findings in a large animal model. Then, safety/toxicity/dose-response/biodistribution studies will need to be performed prior to first clinical trial. Although this may translate to a few years before the first human trial, we are making measured steps to advance this technology.Medgadget: You have engineered sinoatrial node (SAN) pacemaker cells using the transcription factor, Tbx18, which opens the doors for fixing problems with SAN activity. Do you have any leads on how to create other types of pacemaker cells to repair downstream pacemaker activity, for example atrioventricular block?
Dr. Cho: We are currently examining other transcription factors for this purpose. To achieve clinical benefit, however, the iSAN cells created in this study may suffice.
Medgadget: At the end of your paper, you suggest two potential implementations: (1) in vivo transduction of existing cardiac tissue, and (2) in vitro transduction of cells for implantation. With the first approach, how would you focally transduce only a subsection of the cardiac tissue to develop pacemaker activity, so as to avoid potential pathologies like wandering pacemaker or multifocal atrial tachycardia?
Dr. Cho: This is easily done by directly injecting the gene vector into the heart muscle as we have shown in this study. (You could not have seen this image since the image is a part of Supplementary Data which will not be available until the manuscript is released on Dec. 23rd.) We have determined this direct injection leads to focal expression of the gene vector. More importantly, we have recently demonstrated a clinically-relevant, large-animal model of delivering a gene vector in minimally-invasive manner using an intracardiac catheter. (Cingolani et al, Heart Rhythm. 2012 Aug;9(8):1310-8).
Medgadget: Many patients who require traditional pacemakers have co-occurring pathophysiologies, such as heart failure from ischemia and resulting fibrosis. Rather than converting existing, functional cardiac myocytes, can Tbx18 or other transcription factors be used to convert other cell types to iSAN pacemaker cells?
Dr. Cho: We are currently investigating on this topic.
While this research is still very much on the bench end of the bench-to-bedside continuum, Medgadget readers may recall that genetic therapy took a big step in the Western hemisphere last month with the first approval of a viral-based drug, Glybera, to treat a rare enzyme deficiency.
To learn more, read the paper in Nature Biotechnology: Direct conversion of quiescent cardiomyocytes to pacemaker cells by expression of Tbx18