In mammals, including humans, the cells that contract the heart muscle and enable it to beat do not regenerate after injury. After a heart attack, there is a dramatic loss of these heart muscle cells, and those that survive cannot effectively replicate. With fewer of these contractile cells, known as cardiomyocytes, the heart pumps less blood with each beat, leading to the increased mortality associated with heart disease.
Researchers have used mouse models to demonstrate a new approach to restart replication in existing cardiomyocytes — an injectable gel that slowly releases short gene sequences known as microRNAs into the heart muscle. Though the reasons cardiomyocytes don’t regenerate aren’t fully understood, the researchers used microRNAs that target signaling pathways related to cell proliferation and were able to inhibit some of the inherent “stop” signals that keep cardiomyocytes from replicating. This resulted in cardiomyocytes reactivating their proliferative potential. With more heart cells dividing and reproducing, mice treated with this gel after heart attack showed improved recovery in key clinically relevant categories.
MicroRNA-based therapies have been studied in the past but delivering the right dose to the right place has been a consistent challenge. Biologic drugs turn over very fast — the microRNAs used in tests last less than eight hours in the bloodstream, so having a high local concentration has strong advantages.
Their short lifespan means that if patients were treated systemically, they would need to be injected frequently with large doses to ensure that a sufficient amount of microRNAs reaches their target in the heart. And because these microRNAs are designed to promote cell proliferation, there would be a risk of tumor-producing, off-target effects.
The most important traits of the gel are that it is shear-thinning and self-healing. Shear-thinning means it has bonds that can be broken under mechanical stress, making it more fluid and allowing it to flow through a syringe or catheter. Self-healing means that when stress is removed, the gel’s bonds re-form, allowing it to stay in place within the heart muscle. In addition to the bonds that give the gel its consistency, the gel features attachment sites that keep the microRNAs in place. As the gel breaks down, it loses its grip on the microRNAs, which can slip out of the gel and into the cardiomyocytes.
While encapsulated, the microRNAs are also protected from degradation, maximizing the time period that they can be effective without the risk of invading off-target cells.
Next steps involve testing human heart cells in vitro, and conducting physiological experiments in animals with more human-like hearts, such as pigs. More than a potentially life-prolonging treatment itself, the microRNA-gel approach represents a new, more direct avenue for precision regenerative medicine.