New mRNA-based therapy shows promise for heart regeneration after heart attack

Heart attacks remain one of the leading causes of death and disability worldwide. The ongoing loss of heart muscle cells—cardiomyocytes—and the heart’s limited ability to regenerate often lead to chronic heart failure. Current treatment strategies manage symptoms but do not reverse the underlying damage.

Now, researchers at Temple University's Lewis Katz School of Medicine have identified a new strategy that could help repair damaged heart tissue by reactivating an important developmental gene marker.

In a study published in the journal Theranostics, a multidisciplinary team led by Dr. Raj Kishore, the Laura H. Carnell Professor, the Vera J. Goodfriend Chair in Cardiovascular Science, and a member of Temple's Center for Discovery in Aging and Cardiovascular Disease, describes how the PSAT1 gene, delivered using synthetic modified messenger RNA (modRNA), can stimulate heart muscle repair and improve heart function after a heart attack.

This study represents an important step forward in the development of regenerative treatments for coronary heart disease.

“PSAT1 is a gene that is highly expressed early in development but becomes virtually inactive in the adult heart,” said Dr. Kishore. “We wanted to investigate whether reactivating this gene in adult heart tissue could promote regeneration after injury.”

To test this hypothesis, the researchers synthesized PSAT1-modRNA and injected it directly into the hearts of adult mice immediately after a heart attack. The goal was to awaken regenerative signaling pathways—specifically those related to cell survival, proliferation, and angiogenesis—that are active during development but dormant in adults.

The results were impressive. Mice receiving PSAT1-modRNA showed significant increases in cardiomyocyte proliferation, reduced tissue scarring, improved blood vessel formation, and significantly improved cardiac function and survival compared to controls.

Mechanistically, PSAT1 was shown to activate the serine synthesis pathway (SSP), a key metabolic network involved in nucleotide synthesis and cellular stress resistance. SSP activation resulted in decreased oxidative stress and DNA damage, key factors in cardiomyocyte death after infarction.

Further investigation revealed that PSAT1 is transcriptionally regulated by YAP1, a known driver of regenerative signaling. PSAT1, in turn, promotes the nuclear translocation of β-catenin, a protein critical for cardiomyocyte cell cycle re-entry. Importantly, the study also demonstrated that inhibition of SSP abrogated the beneficial effects of PSAT1, highlighting the central role of this pathway in cardiac repair.

“Our results indicate that PSAT1 is a master regulator of cardiac repair after injury,” explained Dr. Kishore. “Activation of PSAT1 by modRNA enables regenerative programs in the heart that are not normally available in adult tissues.”

The implications of the study are broad. modRNA technology, which has recently transformed vaccine development, provides a flexible and efficient platform for delivering genes like PSAT1 with high specificity and limited side effects. Additionally, unlike viral gene therapies, modRNA does not integrate into the genome, reducing the risk of long-term complications.

“This study opens a new therapeutic perspective for coronary artery disease,” said Dr. Kishore. “It opens the door for further research into mRNA strategies to regenerate damaged organs.”

Next, the researchers plan to evaluate the safety, durability, and optimization of delivery of PSAT1-based therapy in large animal models. They also aim to improve control over the timing and localization of gene expression, which are key to clinical application.

“While this work is in the preclinical stage, it represents a transformative step toward a therapy that not only treats heart failure, but helps prevent it by repairing the heart from the inside out,” added Dr. Kishore.