(Press-News.org) Heart attacks remain a leading cause of death and disability worldwide. The permanent loss of heart muscle cells—known as cardiomyocytes—and the heart’s limited regenerative capacity often led to chronic heart failure. Current treatment strategies manage symptoms but do not repair the underlying damage. Now, researchers at the Lewis Katz School of Medicine at Temple University have identified a new strategy that may help repair damaged heart tissue by reactivating an important developmental gene.
In a study published in Theranostics, a multidisciplinary team led by Raj Kishore, PhD, Laura H. Carnell Professor, Vera J. Goodfriend Chair in Cardiovascular Research, Chair of Cardiovascular Sciences, and a member of the Aging + Cardiovascular Discovery Center at Temple, describes how a gene known as PSAT1, delivered through synthetic modified messenger RNA (modRNA), can stimulate heart muscle repair and improve cardiac function following heart attack. The study represents a major step forward in the effort to develop regenerative therapies for ischemic heart disease.
“PSAT1 is a gene that is highly expressed during early development but becomes virtually silent in the adult heart,” said Dr. Kishore. “We wanted to explore whether reactivating this gene in adult heart tissue could promote regeneration after injury.”
To test this hypothesis, the researchers synthesized PSAT1-modRNA and delivered it directly into the hearts of adult mice immediately following a heart attack. The goal was to reawaken regenerative signaling pathways—particularly those related to cell survival, proliferation, and angiogenesis—that are active during development but dormant in adulthood.
The results were striking. Mice treated with PSAT1-modRNA showed robust increases in cardiomyocyte proliferation, reduced tissue scarring, improved blood vessel formation, and significantly enhanced heart function and survival compared to untreated mice. 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 led to reduced oxidative stress and DNA damage, which are key contributors to cardiomyocyte death following a heart attack.
Further investigation revealed that PSAT1 is transcriptionally regulated by YAP1, a known driver of regenerative signaling. PSAT1 in turn promotes nuclear translocation of β-catenin, a protein critical for cell cycle re-entry in cardiomyocytes. Importantly, the study also demonstrated that inhibition of SSP negated the beneficial effects of PSAT1, highlighting the pathway’s central role in heart repair.
“Our findings suggest that PSAT1 is a master regulator of cardiac repair after injury,” Dr. Kishore explained. “By activating PSAT1 through modRNA, we can jumpstart regenerative programs in the heart that are otherwise inaccessible in adult tissues.”
The implications of the study are wide-ranging. ModRNA technology, which has recently transformed vaccine development, provides a flexible and efficient platform for delivering genes such as PSAT1 with high specificity and limited side effects. In addition, unlike viral gene therapies, modRNA does not integrate into the genome, reducing the risk of long-term complications.
“This study introduces a novel therapeutic avenue for ischemic heart disease,” Dr. Kishore noted. “It opens the door to further exploration of mRNA-based strategies aimed at regenerating damaged organs.”
Looking ahead, the researchers plan to evaluate the safety, durability, and delivery optimization of PSAT1-based therapies in larger animal models. They also aim to refine control over the timing and localization of gene expression, which are key considerations for clinical translation.
“Although this work is still in the preclinical phase, it represents a transformative step toward therapies that don’t just treat heart failure—but help prevent it by repairing the heart at its source,” Dr. Kishore added.
Other researchers who contributed to the study include Ajit Magadum, Vandana Mallaredy, Darukeshwara Joladarashi, Charan Thej, Zhongjian Cheng, Maria Cimini, May Truongcao, Adam Chatoff, Claudia V. Crispim, Carolina Gonzalez, Cindy Benedict, and Nathaniel W. Snyder, Aging+Cardiovascular Discovery Center and Department of Cardiovascular Sciences, Lewis Katz School of Medicine; Vagner O.C. Rigaud and Mohsin Khan, Center for Metabolic Disease Research, Lewis Katz School of Medicine; Celio X.C. Santos and Ajay M. Shah, King’s College London British Heart Foundation Centre, School of Cardiovascular Medicine & Sciences, United Kingdom; and Rajika Roy and Walter J. Koch, Department of Surgery, Division of Cardiovascular and Thoracic Surgery, Duke University School of Medicine.
The study was supported in part by grants from the National Institutes of Health and the British Heart Foundation.
END
New mRNA-based therapy that shows promise in heart regeneration after heart attack
2025-07-31
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