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In EUreka‘s second article on biological pacemakers, Dr Gerard J.J. Boink from the Department of Clinical & Experimental Cardiology, Academic Medical Center (AMC) at the University of Amsterdam gives his views on the exciting progress being made in biological pacemaker research.
Electronic pacemakers have been implanted for more than fifty years, providing a safe and secure lifesaving device for millions suffering from slow heart rates. Research into the potential next iteration of treatment, provided by biological pacemakers, is yielding exciting results.
Several groups of top-tier cardiologists and basic scientists are exploring a number of biological pacemaker strategies including approaches based on: embryonic stem cells, induced pluripotent stem cells, and gene therapy with pacemaker function-related genes delivered via stem cell platforms or viral vectors. One alternative approach has been overexpression of transcription factors (e.g. TBX18) to transdifferentiate cardiac myocytes towards pacemaker-like cells; such as discussed in the previous Eureka article.
Dr Boink‘s team including among others Dr Hanno L. Tan (Cardiologist; AMC), have been working closely with Dr Michael R. Rosen‘s group at Columbia University, New York on improving gene-based biological pacemakers. Recent work has focused on combining engineered hyperpolarization-activated cyclic nucleotide variant 2 (HCN2) with skeletal muscle sodium channel 1 (SkM1). “What makes the HCN2/SkM1 strategy attractive is that you have an alternative way of inducing biological pacemaker function where the HCN2 channel still drives diastolic membrane depolarization, and the SkM1 channel is there to hyperpolarize the action potential threshold leading to faster and more stable biological pacemaker function,” he explains.
I THINK THAT IF YOU USE THE RIGHT ELEMENTS TO FINE TUNE THE EFFECT, THIS TYPE OF TECHNOLOGY IS REALLY CAPABLE OF DELIVERING A LONG-TERM PACEMAKER SIGNAL TO THE HEART.
Boink also notes that because pacemaker function is generated at more hyperpolarized potentials in HCN2/SkM1, the difference in membrane potential between pacemaker cells and surrounding myocardium is smaller, which could add to the greater stability found with this construct. “If you have a biological pacemaker that operates at more hyperpolarized potentials, it is less likely to be affected by its surroundings. I think that is one of the key advantages of this strategy,” he said.
On the potential for causing arrhythmia, Dr Boink said that they have some positive data on the use of SkM1 gene therapy. “We have data that supports that the SkM1 is less likely to generate arrhythmia. This is based on modelling studies showing that there is no accumulation of calcium. Other studies show us that SkM1 by itself can normalize areas of slow conduction, whether this translates to a less arrhythmic biological pacemaker still needs to be confirmed,” he said.
Looking forward, Dr Boink said the crucial next step is successful demonstration of safe and stable long-term biological pacemaker function. He said, “Based on the data we now have, we know that this combination of genes is highly effective and that is why now we are looking into developing long-term delivery vehicles for this strategy. A primary target in this effort is provided by adeno-associated viral vectors (AAV). These vectors can deliver long-term gene expression to the heart as is currently being explored in clinical studies targeting patients with end-stage heart failure.” A downside of AAV is the relatively small packaging size, which could be problematic for SkM1, but Boink expects them to find ways to work around this issue.
Asked about viral vector degrading and potential loss of effect, Boink explained that although the viral vectors themselves are eliminated, the genetic information delivered persists long-term. “Several different vectors have been shown to generate gene expression for years. I think that if you use the right elements to fine tune the effect, this type of technology is really capable of delivering a long-term pacemaker signal to the heart,” he said.
Considering initial potential patient populations for biological pacing, Boink suggests those in need for demand ventricular pacing as a primary target. He said, “These could be patients in permanent atrial fibrillation in combination with complete atrio-ventricular block.” He explained that if long-term function can indeed be safely demonstrated, clinical studies could follow with injection of the most promising constructs into the ventricular induction system; i.e. in the Bundle of His or bundle branch. Feasibility of this type of gene delivery has already been provided in various experimental studies and with some additional modifications should be safely applicable to human subjects.
He expects that initial human trials are likely to take a dual approach: a biological pacemaker implanted together with an electronic pacemaker. This way patients will benefit from the advantages of biological pacing such as improved autonomic modulation and optimized hemodynamic performance while also taking advantage from the established safety of electronic pacing. In addition, the biological pacemaker would prolong battery life of its electronic counterpart. Boink believes this approach may be tantalizingly close. “I could see this sort of clinical studies happening within five to seven years, if all works out well,” he said.
As research into biological pacemakers continues, Dr Boink stressed that several different groups are showing exciting progress with various strategies in preclinical, large animal models. He said, “Apart from the HCN2/SkM1 strategy, equally encouraging outcomes are being generated with pacemaker cells derived from induced pluripotent stem cells and approaches based on transcription factor overexpression (TBX18).” It is difficult to predict which of these strategies eventually will be most effective and safe. He believes that long-term animal studies are the next step in comparing different strategies either head-to-head or study-to-study reviewing their function, long-term performance and safety. Dr Boink said, “It‘s an exciting time to see how these studies eventually translate into successful therapies.”
HCN2/SkM1 Gene Transfer into Canine Left Bundle Branch Induces Stable, Autonomically Responsive Biological Pacing at Physiological Heart Rates (2013) http://content.onlinejacc.org/article.aspx?articleid=1569177
Biological Pacemakers - Are We at the Dawn of a New Treatment Era? (2013). Available here: http://content.onlinejacc.org/article.aspx?articleid=1569175&resultClick=3
Gene Therapy and Biological Pacing (2014) Available here: http://www.nejm.org/doi/full/10.1056/NEJMcibr1408897
Gene therapy creates biological pacemaker (2014). Available here http://www.nature.com/news/gene-therapy-creates-biological-pacemaker-1.15569
Heart cells transformed into biological pacemaker (2014). Available here:http://www.scientificamerican.com/article/heart-cells-transformed-into-biological-pacemaker/