A breakthrough in mRNA therapies could lead to biological heart pacemakers

"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."
Deena Theresa
Single strand of RNA.
Single strand of RNA.

luismmolina/iStock 

Researchers from the Smidt Heart Institute have unveiled a novel concept - they harnessed modified messenger RNA (mRNA) technology used in creating the Pfizer and Moderna Covid-19 vaccines, which can be a significant step in the evolution and creation of biological pacemakers.

The investigators identified how biological pacemaker cells could "fight back" against therapies to biologically correct abnormal heartbeat rates. They've also found a new way to "boost the effectiveness" of RNA therapies by controlling the "fighting back" activity, they said in a release.

Creating a biological solution to stabilize the heartbeat

"We are all born with a specialized group of heart cells that set the pace for our heartbeats," Eugenio Cingolani, MD, senior author of the study and director of the Cardiogenetics Program in the Smidt Heart Institute at Cedars-Sinai, said in a statement. "But in some people, this natural heartbeat is too slow, leading to the need for an electronic pacemaker."

Electronic pacemakers have a ton of limitations and side effects that include device-related infections, and system failure. Alongside, swelling, bleeding, and blood clots, all pose much danger to the individual. 

"But the biggest problem is that the machines do not cure the problem," Cingolani said. "They only allow you to find a way around it. Our intention is to create a biological solution, cells that we can reprogram within the heart to naturally stabilize the heartbeat." 

How did they go about it?

It is to be noted that an mRNA vaccine is a code that tells a cell to make a specific protein when it enters it.

The investigators first injected laboratory mice with chemically-modified mRNA. It expressed a protein called TBX1 - and in doing so, the heart cells can fight back. According to the release, they "inhibited TBX18 protein expression by producing microRNAs, nature’s regulatory molecules that specifically fine-tune gene expression". Therefore, the amount of TBX18 protein produced was not sufficient to support the heartbeat.

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The suppressive effect of the microRNAs had to be bypassed. The investigators identified the precise microRNAs involved and used "chemical antagonists" to suppress the microRNAs. This helped - it increased TBX18 protein expression, and stabilized the heartbeat.

Working on the efficacy of mRNA therapy in clinical trials

"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," said study author Eduardo Marbán, MD, Ph.D., 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."

Next, the team plans additional studies to examine the long-term efficacy and safety. The insights could then help improve the efficacy of mRNA therapy in clinical trials.

The research was published Tuesday in Cell Reports Medicine.