Boosting RNA for Improved Heart Health

Researchers at the Smidt Heart Institute at Cedars-Sinai have made a significant discovery that could lead to the development of biological pacemakers, a potential alternative to traditional electronic pacemakers. In a study published in the journal Cell Reports Medicine, the researchers identified how cells that control the heartbeat, known as biological pacemaker cells, can "fight back" against therapies designed to correct abnormal heartbeat rates. The team also discovered a new method of boosting the effectiveness of RNA therapies by controlling this "fighting back" activity.

Electronic pacemakers have been used to regulate abnormal heartbeat rates since the 1950s, but they come with various limitations and side effects, including battery life, device-related infections, and system failure. In addition, electronic pacemakers can also carry risks such as infection, bleeding, blood clots, and damage to blood vessels.

The researchers used modified messenger RNA (mRNA) technology, similar to that used in developing the Pfizer and Moderna COVID-19 vaccines, to create a modified messenger RNA (CMmRNA)-encoding protein called TBX18.

When injected into laboratory mice, heart cells produced microRNAs that inhibited TBX18 protein expression, leading to an insufficient amount of TBX18 protein to support the heartbeat. While the expression of TBX18 protein was weak and temporary, the researchers were able to boost TBX18 levels by using a specific inhibitor. They also identified two microRNAs that were responsible for suppressing TBX18 expression and were able to use these microRNAs to enhance the expression of TBX18 and stabilize the heartbeat.

The researchers also found that similar microRNAs can limit the expression of another type of CMmRNA used to grow new blood vessels. By blocking these suppressive microRNAs, the researchers were able to improve the expression of genes involved in biological pacing and blood vessel growth.

"This concept that cells' fight back' against modified RNA is of practical importance, as it suggests how one might improve the effectiveness of RNA therapy," says study author Eduardo Marbán, MD, PhD, executive director of the Smidt Heart Institute and the Mark S. Siegel Family Foundation Distinguished Professor. "We now have a clearer picture of how to inhibit microRNAs, release the brake, and ultimately get better gene expression." 

This discovery could potentially improve the effectiveness of RNA therapy and provide a biological solution for stabilizing the heartbeat. The researchers plan to conduct further studies to assess their findings' long-term efficacy and safety, with the aim of eventually applying the insights to clinical trials.