Investigators from the Smidt Heart Institute in Cedars-Sinai have determined how biological pacemaker cells — the cells that control your heartbeat — can “fight” against therapies aimed at biologically correcting abnormal heart rates. The research also uncovered a new way to increase the effectiveness of RNA therapies by controlling this “fighting” activity.
This new concept, published today in the peer-reviewed journal Cell Reports MedicineIt is an important step in the evolution and creation of biological pacemakers, aiming to one day replace traditional electronic pacemakers.
D., senior author of the study and director of the Smidt Heart Institute Cardiogenetics Program at Cedars-Sinai. “We are all born with a special set of heart cells that determine the rate of our heartbeats,” said Eugenio Cingolani. “But in some people, this natural heartbeat is too slow, leading to the need for an electronic pacemaker.”
While electronic pacemakers have saved many lives since they were invented in the 1950s, there are limitations and side effects such as battery life, device-related infections, and system failure. They also carry risks such as infection, swelling, bleeding, blood clots, damage to adjacent blood vessels, and in some cases, lung collapse.
“But the biggest problem is that machines don’t fix it,” Cingolani said. said. “They just let you find a way to get around it. Our intention is to create a biological solution, cells that we can reprogram within the heart to naturally stabilize the heartbeat.”
In the most recent research study, Cingolani and his team took advantage of the same modified messenger RNA (mRNA) technology used to create the Pfizer and Moderna COVID-19 vaccines. MRNA carries information from genes to make proteins, the building blocks of life.
An mRNA vaccine is essentially a code that once it enters a cell tells it to make a certain protein.
In their latest research study, the researchers injected laboratory mice with chemically altered mRNA to express a protein called TBX18. In doing so, they found that the heart cells were “fighting against”: They specifically inhibited TBX18 protein expression by producing microRNAs, nature’s own regulatory molecules that fine-tune gene expression. As a result, the amount of TBX18 protein produced was insufficient to support the heartbeat.
The team looked for a way to bypass the suppressive effect of microRNAs. After identifying the precise microRNAs of interest, the researchers used chemical antagonists to specifically suppress these microRNAs, increase TBX18 protein expression and stabilize the heartbeat.
“This concept, where cells ‘fight’ against altered RNA, is of practical importance as it suggests how the efficacy of RNA therapy can be increased,” said study author Eduardo Marbán, executive director of the Smidt Heart Institute and PhD. Mark S. Siegel Family Foundation Distinguished Professor. “We now have a clearer picture of how to block microRNAs, release the brake, and ultimately achieve better gene expression.”
Equally important, the researchers found that a similar reaction (the cells’ ability to counteract) is involved in limiting the expression of VEGF-A, an alternative type of chemically modified messenger RNA used to grow new blood vessels.
As a next step, Cingolani, Marbán and team plan additional studies to evaluate long-term efficacy and safety with the aim of ultimately applying the insights to improve the effectiveness of mRNA therapy in clinical trials.