Calls Now Open
2026 Scholar-Innovator, Harrington Prize and ADDF-Harrington
Cardiovascular, Regenerative
Inhibition of IncExACT1 to Promote Cardiac Function, Repair and Regeneration
2023 Harrington Scholar-Innovator
Cardiologist, Anthony Rosenzweig, MD encounters many diseased hearts. Curious to deeply understand what makes hearts healthy, he and his team conducted genomic studies to compare RNA pathways in cardiomyocytes (muscle cells) in exercised healthy hearts and diseased hearts of mouse models. They identified and validated a pathway driven by a noncoding RNA molecule they named lncExACT1 (pronounced “link exact one” for long noncoding Exercise-Associated Cardiac Transcript). lncExACT1 increases in human and animal hearts in disease, where overexpression induces pathological growth and heart failure. It decreases in the exercised hearts, however, and its chemical inhibition promotes cardiomyocyte repair and regeneration. With Harrington support, the team hopes to demonstrate further proof of concept, validating lncExACT1 in cell models of human heart disease.
“lncExACT1 signaling through the downstream effector, DCHS2, acts as a master switch,” explains Dr. Rosenzweig. “We hope that targeting that switch in patients who can’t exercise sufficiently themselves—and turning it off—can capture some of the benefits of exercise and improve heart function and decrease the burden of heart disease.”
Interventions such as modified nucleic acid antisense drugs, approved by the US Food and Drug Administration (FDA) for other indications, can effectively inhibit lncExACT1 in animal models. Dr. Rosenzweig and his team are now testing drug candidates to inhibit lncExACT1 in human induced pluripotent stem cell (iPSC)-derived cardiomyocytes.
“If we can mimic the effects of exercise through this druggable target, we can improve heart function,” Dr. Rosenzweig says. “Our Harrington team’s support and drug development expertise are essential as we refine lncExACT1 inhibition strategies—foundational to preclinical large animal studies and future clinical trials of lncExACT1 inhibition in heart disease.”
Other key contributors to this work include Dr. Haobo Li of Massachusetts General Hospital, and Drs. Jon and Christine Seidman of Harvard Medical School.