Reprogramming of heart muscle cells into pacemaker cells in a large animal
Slow heartbeats caused by age or heart disease are treated by implantation of a pacemaker, a device that delivers precisely timed electrical impulses to the heart muscle. While these are widely used and generally effective, they can fail or cause complications such as infections or damage to the surrounding tissues caused by device migration. An alternative means of restoring normal heart rate that is no more invasive than pacemaker implantation (a minor surgery performed under local anesthesia) would avoid such complications. However, targeting such futuristic therapies, either stem cell-derived pacemaker cells or genes to convert heart muscle cells to pacemaker cells, to a small area of the heart (necessary to induce synchronous beating) represents a major challenge.
A research team at Cedars-Sinai Heart Institute led by Eugenio Cingolani has made a major advance towards this goal, demonstrating restoration of beating in pig hearts with experimentally induced heart block by a virally delivered gene that reprograms heart muscle cells. Most importantly, this induction of endogenous pacemaking was achieved via a minimally invasive procedure; the viral vector was introduced to the heart muscle via a steerable catheter.
Specifically, Yu-Feng Hu (the study’s first author) and co-workers delivered transcription factor T-box 18 (TBX18), previously demonstrated to convert heart muscle cells to pacemaker cells (also called sinoatrial node cells) in vitro and in guinea pigs. This intervention restored normal heart rate (75-80 bpm) in pigs with heart block induced by radio frequency ablation of the atrioventricular node (in which animals heart rate was 60-65 bpm) from days 5-8 following gene transfer, after which time heart rate decreased, suggesting that transduced cells had begun to be eliminated. (Virally transduced cells are known to be cleared by the immune system.) Restoration of heart rate supported increased physical activity.
While this study demonstrates the feasibility of genetic reprogramming as a therapeutic approach, and is a convincing preclinical basis for human trials of a therapy that would provide temporary pacemaker function, other gene delivery vehicles are needed to allow retention of reprogrammed cells. Current research in nanomedicine, either involving synthetic nanoparticles or engineered viruses or cells, could lead to such vehicles. Nonetheless, even a temporary effect would be clinically relevant, as it would allow normal heart function between removal of an electronic pacemaker following complications and implantation of another.