Scientists at Cedars-Sinai Medical Center have developed an experimental synthetic RNA drug called TY1 that strengthens the body’s ability to clear damaged DNA and promote tissue healing. Described in a paper in Science Translational Medicine, the treatment could improve recovery from heart attacks and certain inflammatory or autoimmune conditions by enhancing the activity of a key DNA-processing gene in immune cells.
Scientists at Cedars-Sinai say the development of TY1 marks a notable advance in regenerative therapeutics, offering a new approach to tissue repair that does not rely on transplanting stem cells.
Led by Eduardo Marbán, MD, PhD, executive director of the Smidt Heart Institute at Cedars-Sinai and senior author of the study, the research team reported their findings in an article published December 3 in the journal Science Translational Medicine titled “Augmentation of DNA exonuclease TREX1 in macrophages as a therapy for cardiac ischemic injury.”
“By probing the mechanisms of stem cell therapy, we discovered a way to heal the body without using stem cells,” Marbán said, according to a Cedars-Sinai news release distributed via outlets including Medical Xpress and EurekAlert!. “TY1 is the first exomer—a new class of drugs that address tissue damage in unexpected ways.”
According to Cedars-Sinai, the path to TY1 grew out of more than two decades of work on heart-derived cells and their molecular signals. Earlier research from Marbán’s group had shown that certain cells taken from heart tissue could support cardiac repair, in part by releasing microscopic sacs called exosomes that carry RNA and other cargo.
Ahmed Ibrahim, PhD, MPH, a Cedars-Sinai investigator and lead author of the Science Translational Medicine paper, and colleagues analyzed the RNA content of these exosomes and identified one small Y RNA species that was especially abundant. Laboratory studies in animal models of heart attack suggested this naturally occurring RNA could promote tissue healing.
TY1 is a laboratory‑engineered version of that RNA molecule, designed to resemble the structure of RNA medicines already in clinical use. The Science Translational Medicine report and institutional summaries describe TY1 as a noncoding RNA drug that upregulates a gene called TREX1, a DNA exonuclease that helps immune cells—including macrophages—degrade cytosolic DNA.
By boosting TREX1 activity in macrophages, TY1 enhanced the clearance of damaged DNA in preclinical models of myocardial infarction, the study found. In these models, TY1 treatment reduced scar size, lessened DNA damage in heart tissue and improved healing after ischemia/reperfusion injury. When macrophages were depleted or TREX1 was inhibited in these cells, the protective effects of TY1 were lost, supporting a central role for TREX1‑expressing macrophages in the drug’s mechanism of action.
Cedars-Sinai reports that TY1’s ability to enhance DNA repair and dampen damaging inflammation suggests potential applications beyond heart attack, including autoimmune or inflammatory diseases in which the immune system attacks healthy tissue. “By enhancing DNA repair, we can heal tissue damage that occurs during a heart attack,” Ibrahim said in the institutional statements, adding that the same pathway may be relevant in other conditions.
The study was supported by grants from the National Heart, Lung, and Blood Institute (R01 HL164588, T32 HL116273 and R01 HL142579) and by the California Institute for Regenerative Medicine through grant TRAN1-15317, according to Cedars-Sinai and the Science Translational Medicine article. In addition to Ibrahim and Marbán, co‑authors included Alessandra Ciullo, Hiroaki Komuro, Kazutaka Miyamoto, Xaviar M. Jones, Shukuro Yamaguchi, Kara Tsi, Jessica Anderson, Joshua Godoy Coto, Diana Kitka, Ke Liao, Chang Li, Alice Rannou, Asma Nawaz, Ashley Morris, Cristina H. Marbán, Jamie Lee, Nancy Manriquez, Yeojin Hong, Arati Naveen Kumar, James F. Dawkins and Russell G. Rogers.
Researchers say the next step is to evaluate TY1 in clinical trials to see whether the benefits observed in preclinical models translate to patients. The therapy remains experimental and has not yet been approved for use in humans.
