Repurposed drugs show promise in heart muscle regeneration

An underlying cause of heart failure is the inability of the adult myocardium — the muscle layer that helps the heart pump blood — to regenerate after injury, such as a heart attack. Now researchers at UT Southwestern Medical Center (UTSW) have demonstrated that two FDA-approved drugs, paromomycin (Paro) and neomycin (Neo), improved left ventricular systolic function and decreased scar formation in both small and large animal models after a cardiac injury. The medications, when given in combination, target two proteins that regulate the heart muscle’s regeneration capabilities.

“Our study suggests that pharmacological targeting of the transcription factors Meis1 and Hoxb13 can be a viable therapeutic option for patients with heart failure,” said study leader Professor Hesham Sadek. “Heart muscle regeneration is present in mammals in utero and for a brief window of time after birth but is lost shortly thereafter because it is blocked by Meis1 and Hoxb13. By inhibiting the transcriptional activity of these proteins … we can induce cardiac muscle replication and stimulate heart regeneration.”

Paro and Neo are naturally occurring antimicrobials used to treat parasitic and bacterial skin infections and to decrease the risk of infection after intestinal surgery, among other indications. The drugs were identified from a group of hundreds of potential medications via the study group’s unique platform for detecting FDA-approved drugs that can be repurposed to target new diseases.

Paro and Neo were tested on animals to determine their effectiveness. The researchers discovered that combining the drugs was most effective in turning off the proteins’ regulation of cell growth. Importantly, the effectiveness of these two drugs in inducing regeneration in large animals holds promise for their potential use in human clinical trials.

The findings build on more than a decade of research at UTSW to identify the capacity of the heart to regenerate myocardial muscle. Earlier studies looked at factors that mediate loss of this regenerative capacity, including the identification of Meis1 and Hoxb13 as key regulators. The latest study, published in the journal Nature Cardiovascular Research, is the first to show a drug combination that can induce heart regeneration in small and large mammals.

“The fact that these are FDA-approved drugs with established safety profiles makes it much easier to start testing this in humans in the near future,” Sadek said. “Further studies can help us better understand the efficacy of pro-regenerative therapeutics and accelerate their delivery to the clinical setting.”

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