Somatic Reprogramming May Create Biological Pacemakers

GUADALAJARA, Mexico — “Somatic reprogramming is a strategy in which we are not modifying a single part of the cell, but we are reprogramming a normal cell to transform it into a pacemaker cell,” said Eugenio Cingolani, MD, director of the Cardiogenetics-Familial Arrhythmia Clinic at Cedars Sinai Medical Center in Los Angeles. “Those specialized cells in our sinoatrial node, which are few, can be reprogrammed and recreated starting from a normal heart cell.”

Cingolani made these remarks during the session titled “Biological Pacemakers: Are We There Yet?” at the Annual Congress of International Cardiology CADECI 2023.

The specialist indicated that the first biological pacemaker was described by Eduardo Marbán, MD, PhD, in the journal Nature in 2002. Cingolani explained that a normal heart beats more than 2 million times during a lifetime, but when the system that generates the synchronization of the beats fails, pacemakers can compensate.

“And while pacemakers have evolved from the first one in 1968 to wireless pacemakers, which are very useful in some patients, there are still limitations and complications. They have no true autonomic response, electrode fractures and dysfunction can occur, the generator may also malfunction, electrodes can be misplaced and will need to be repositioned, there can be infections, there can be pacemaker-induced cardiomyopathy, and they are also problematic in the pediatric population,” he said.

Marbán and colleagues created a mutation in the ion channel of a current that normally slows down myocardial depolarization. “By inducing this genetic change in animals, they have spontaneous antipolarizations and a parasystolic beat, as can be seen on the electrocardiogram. Alternative strategies to pacemakers have been sought,” said Cingolani.

These strategies include functional re-engineering, which consists of introducing changes in ionic currents to produce the spontaneous oscillation of normal cells. Transplantation of hematopoietic progenitor cells can capture the myocardium and thus generate pacemaker activity. A hybrid system uses cells to transplant a gene that is taken to the normal myocyte and enable it to oscillate.

Cingolani’s work has focused on somatic reprogramming using the gene TBX18. “It turns out that a spike in TBX18 in embryonic life is responsible for generating the sinoatrial node. So, having this knowledge of embryology, we thought of reintroducing TBX18 into an adult cardiac cell and thus reprogramming it to generate pacemaker activity,” he said.

The aforementioned studies were conducted on small animals, so the next question was whether TBX18 could be delivered to patients in a minimally invasive system.

“We conducted a protocol in which we used pigs in the initial phase with a basal electrocardiogram. A cow’s pacemaker was implanted, and the animals underwent radiofrequency ablation of the atrioventricular node. After this, the pigs were left with dependent pacemakers, and anatomical mapping was done to deliver the biological pacemaker,” explained Cingolani, adding that the next step was to randomize two arms: one with TBX18 and the other with GFP, a fluorescent gene that allows localization but has no biological activity.

“The animals were followed up with continuous telemetry to see the dynamics of this pacemaker. On day 14, which was the follow-up of this initial study, mapping, arrhythmia induction, and histological and molecular techniques were performed to see the distribution and reprogramming of these animals,” he said.

Cingolani reported that the heart rate of animals injected with TBX18 was significantly higher, “and as a result of that, the use of the cow pacemaker was minimal in the pigs during follow-up. That is, the biological pacemaker could pace them, and because of that, the electronic pacemaker was inhibited and they didn’t need it to remain viable.”

In addition to the heart rate itself, the researchers wanted to know whether the animals were feeling better. “I learned the hard way that exercising a pig is quite complicated. They don’t like to exercise, they don’t want to do it no matter how many times you try. So, we decided to implement an accelerometer like the one we all have today in our phones to see the activity. These results were very interesting, because the activity levels in the animals implanted with the pacemaker were higher than those in the placebo group.”

The investigators transferred TBX18 with a viral form of adenovirus. Cingolani mentioned that he is also conducting studies with modified RNA, a technology similar to that used in some COVID-19 vaccines.

He concluded that to carry out a study in humans with this technology, the following steps would be required: having a clinical grade viral vector, having toxicology and biodistribution studies, replicating efficiency data, and receiving approval by the United States Food and Drug Administration.

Cingolani has disclosed no relevant financial relationships.

Follow Pablo Hernández Mares of Medscape Spanish Edition on Twitter @pablohmares

This article was translated from the Medscape Spanish Edition.

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