Weizmann Research Shows How Copaxone Improves Heart Muscle Function After Heart Attack
Copaxone was originally developed at the Weizmann Institute of Science in the 1960s to treat multiple sclerosis. Now, decades later, a research team led by Prof. Eldad Tzahor and Dr. Rachel Sarig has uncovered a surprising new benefit of this longstanding drug: its ability to protect the heart and improve its function after a heart attack. Unlike other tissues that can regenerate, the heart has limited capacity to heal itself. After a heart attack, scar tissue forms, weakening the heart's function and potentially leading to chronic heart failure. In a study published today, the research team demonstrates that Copaxone can reduce scar tissue formation and enhance the heart’s ability to pump blood, both after a heart attack and in cases of chronic heart failure. In collaboration with Hadassah Ein Kerem Hospital, Weizmann Institute scientists conducted a clinical study testing the effects of Copaxone on heart failure patients. Although the results have yet to be published, they are expected to show significant improvements in heart function, potentially offering new hope to patients worldwide
Miyara S., Adler M., Umansky K. B., Häußler D., Bassat E., Divinsky Y., Elkahal J., Kain D., Lendengolts D., Ramirez Flores R. O., Bueno-Levy H., Golani O., Shalit T., Gershovits M., Weizman E., Genzelinakh A., Kimchi D. M., Shakked A., Zhang L., Wang J., Baehr A., Petrover Z., Sarig R., Dorn T., Moretti A., Saez-Rodriguez J., Kupatt C., Tanaka E. M., Medzhitov R., Krüger A., Mayo A., Alon U. & Tzahor E.
(2025)
Cell Systems.
16,
3,
101198.
Fibrosis remains a major unmet medical need. Simplifying principles are needed to better understand fibrosis and to yield new therapeutic approaches. Fibrosis is driven by myofibroblasts that interact with macrophages. A mathematical cell-circuit model predicts two types of fibrosis: hot fibrosis driven by macrophages and myofibroblasts and cold fibrosis driven by myofibroblasts alone. Testing these concepts in cardiac fibrosis resulting from myocardial infarction (MI) and heart failure (HF), we revealed that acute MI leads to cold fibrosis whereas chronic injury (HF) leads to hot fibrosis. MI-driven cold fibrosis is conserved in pigs and humans. We computationally identified a vulnerability of cold fibrosis: the myofibroblast autocrine growth factor loop. Inhibiting this loop by targeting TIMP1 with neutralizing antibodies reduced myofibroblast proliferation and fibrosis post-MI in mice. Our study demonstrates the utility of the concepts of hot and cold fibrosis and the feasibility of a circuit-to-target approach to pinpoint a treatment strategy that reduces fibrosis. A record of this paper's transparent peer review process is included in the supplemental information.
Aviel G., Elkahal J., Umansky K. B., Bueno-Levy H., Petrover Z., Kotlovski Y., Lendengolts D., Kain D., Shalit T., Zhang L., Miyara S., Kramer M. P., Merbl Y., Kozlovski S., Alon R., Aharoni R., Arnon R., Mishali D., Katz U., Nachman D., Asleh R., Amir O., Tzahor E. & Sarig R.
(2024)
Nature Cardiovascular Research.
3,
9,
p. 1049-1066
Myocardial injury may ultimately lead to adverse ventricular remodeling and development of heart failure (HF), which is a major cause of morbidity and mortality worldwide. Given the slow pace and substantial costs of developing new therapeutics, drug repurposing is an attractive alternative. Studies of many organs, including the heart, highlight the importance of the immune system in modulating injury and repair outcomes. Glatiramer acetate (GA) is an immunomodulatory drug prescribed for patients with multiple sclerosis. Here, we report that short-term GA treatment improves cardiac function and reduces scar area in a mouse model of acute myocardial infarction and a rat model of ischemic HF. We provide mechanistic evidence indicating that, in addition to its immunomodulatory functions, GA exerts beneficial pleiotropic effects, including cardiomyocyte protection and enhanced angiogenesis. Overall, these findings highlight the potential repurposing of GA as a future therapy for a myriad of heart diseases.
Zhang L., Elkahal J., Wang T., Rimmer R., Genzelinakh A., Bassat E., Wang J., Perez D., Kain D., Lendengolts D., Winkler R., Bueno-levy H., Umansky K. B., Mishaly D., Shakked A., Miyara S., Sarusi-Portuguez A., Goldfinger N., Prior A., Morgenstern D., Levin Y., Addadi Y., Li B., Rotter V., Katz U., Tanaka E. M., Krizhanovsky V., Sarig R. & Tzahor E.
(2024)
Nature Cardiovascular Research.
3,
8,
p. 915-932
Senescence plays a key role in various physiological and pathological processes. We reported that injury-induced transient senescence correlates with heart regeneration, yet the multi-omics profile and molecular underpinnings of regenerative senescence remain obscure. Using proteomics and single-cell RNA sequencing, here we report the regenerative senescence multi-omic signature in the adult mouse heart and establish its role in neonatal heart regeneration and agrin-mediated cardiac repair in adult mice. We identified early growth response protein 1 (Egr1) as a regulator of regenerative senescence in both models. In the neonatal heart, Egr1 facilitates angiogenesis and cardiomyocyte proliferation. In adult hearts, agrin-induced senescence and repair require Egr1, activated by the integrinFAKERKAkt1 axis in cardiac fibroblasts. We also identified cathepsins as injury-induced senescence-associated secretory phenotype components that promote extracellular matrix degradation and potentially assist in reducing fibrosis. Altogether, we uncovered the molecular signature and functional benefits of regenerative senescence during heart regeneration, with Egr1 orchestrating the process.
