Researchers at Cedars-Sinai’s Smidt Heart Institute have identified how pacemaker biological cells; the cells that control your heartbeat; can “fight back” against therapies to biologically correct abnormal heart rhythms. Research has also uncovered a new way to increase the effectiveness of RNA therapies by controlling this “fight back” activity.
This new concept, published today in the peer-reviewed journal Medicine Reports Unitis an important step in the evolution and creation of biological pacemakers, which aim to one day replace traditional electronic pacemakers.
“We are all born with a specialized group of heart cells that regulate our heartbeats,” said Eugenio Cingolani, MD, lead study author and director of the cardiogenetics program at Cedars-Sinai’s Smidt Heart Institute. “But in some people, this natural heartbeat is too slow, requiring an electronic pacemaker. »
Although electronic pacemakers have saved many lives since their invention in the 1950s, there are limitations and side effects, including battery life, device-related infections, and system failures. They also carry risks, including infection, swelling, bleeding, blood clots, damage to nearby blood vessels, and in some cases, a collapsed lung.
“But the biggest problem is that machines don’t solve the problem,” Cingolani said. “They just allow you to find a way around it. Our intention is to create a biological solution, cells that we can reprogram in the heart to naturally stabilize the heartbeat. »
In the latest research study, Cingolani and his team leveraged 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, when it enters a cell, tells it to make a specific protein.
In their latest research study, the researchers injected lab mice with mRNA chemically modified to express a protein called TBX18. In doing so, they discovered that heart cells “fighted back”: they inhibited the expression of the TBX18 protein by producing microRNAs, nature’s own regulatory molecules that specifically fine-tune gene expression. As a result, the amount of TBX18 protein produced was insufficient to sustain heart rate.
The team looked for a way to circumvent the suppressive effect of microRNAs. After identifying the precise microRNAs involved, the researchers used chemical antagonists to specifically suppress these microRNAs, increasing TBX18 protein expression and stabilizing heart rhythm.
“This concept that cells ‘fight back’ against altered RNA is of practical importance, as it suggests how one might improve the efficacy of RNA therapy,” said study author Eduardo Marbán. , MD, PhD, Executive Director of the Smidt Heart Institute and Professor Emeritus of the Mark S. Siegel Family Foundation. “We now have a clearer picture of how to inhibit microRNAs, release the brake, and ultimately achieve better gene expression. »
Of equal importance, the researchers found a similar reaction – the ability of cells to fight back – is at play in limiting the expression of VEGF-A, an alternative type of chemically modified messenger RNA that has been used to grow new blood vessels.
As a next step, Cingolani, Marbán and team plan additional studies to assess long-term efficacy and safety, with a view to eventually applying the knowledge to improve the efficacy of mRNA therapy in trials. clinics.