Sat 2nd Aug, 2025
Heart attacks are a significant contributor to mortality and disability globally, primarily due to the irreversible loss of cardiomyocytes, which leads to chronic heart failure. Traditional treatments focus on symptom management rather than addressing the underlying cardiac damage.
Researchers at the Lewis Katz School of Medicine at Temple University have pioneered a novel approach aimed at repairing damaged cardiac tissue by reactivating a crucial developmental gene. Their findings, published in Theranostics, detail how the gene PSAT1 can be delivered through synthetic modified messenger RNA (modRNA) to stimulate heart muscle regeneration and enhance cardiac function following a heart attack.
Dr. Raj Kishore, the lead researcher and a prominent figure in cardiovascular research at Temple University, explained that PSAT1 is significantly expressed during early heart development but becomes inactive in adult hearts. The research team sought to determine if reactivating this gene could trigger regenerative processes in adult cardiac tissue following injury.
To explore this hypothesis, the team synthesized PSAT1-modRNA and administered it directly into the hearts of adult mice immediately after inducing a heart attack. Their goal was to reinitiate regenerative signaling pathways that promote cell survival, proliferation, and angiogenesis–processes typically active during early development but dormant in adult tissues.
The outcomes were compelling. Mice receiving the PSAT1-modRNA treatment exhibited notable increases in cardiomyocyte proliferation, decreased tissue scarring, enhanced blood vessel formation, and improved heart function and survival rates compared to untreated controls.
Investigations into the mechanisms revealed that PSAT1 activates the serine synthesis pathway (SSP), a critical metabolic network linked to nucleotide synthesis and cellular stress resistance. The activation of SSP resulted in reduced oxidative stress and DNA damage, both of which contribute to cardiomyocyte death following myocardial infarction.
Furthermore, the study established that PSAT1 is transcriptionally regulated by YAP1, a known promoter of regenerative signaling. PSAT1 also facilitates the nuclear movement of ?-catenin, a protein essential for cardiomyocyte cell cycle re-entry. Notably, inhibiting SSP negated the positive effects of PSAT1, underscoring the pathway’s vital role in cardiac repair.
The implications of these findings are significant. The modRNA technology, which has recently revolutionized vaccine development, offers a flexible and efficient means of delivering genes like PSAT1 with high specificity and minimal side effects. Unlike traditional viral gene therapies, modRNA does not integrate into the host genome, thereby reducing the risk of long-term complications.
This research opens a new therapeutic pathway for ischemic heart disease, signaling a shift towards mRNA-based strategies aimed at regenerating damaged organs. The team plans to further investigate the safety, durability, and delivery optimization of PSAT1-based therapies in larger animal models. They also intend to refine the timing and localization of gene expression, crucial factors for clinical implementation.
Although still in preclinical stages, this work represents a significant advancement toward therapies that not only address heart failure but also aim to repair the heart at its fundamental level.