How to heal a broken heart
US scientists have identified a drug candidate to restore heart muscle function following a heart attack, in a breakthrough which has been described as a game changer for people living with heart disease.
They say time heals all wounds, but for those who have suffered a heart attack, the reality could not be more different. Even if one is lucky enough to survive such an ordeal, part of the heart muscle dies and the associated scarring interferes with the heart’s ability to effectively pump blood. No drug currently exists to restore this muscle function.
While regenerative medicine has so far focused on cell-, gene- and tissue engineering-based therapeutics, the development of small molecule regenerative medicine therapies is an emerging area. Scientists at the MDI Biological Laboratory sought to further explore this arena, recently undertaking a study in zebrafish to identify small molecules capable of stimulating tissue repair and regeneration processes.
“Small molecules offer potential advantages over other regenerative medicine therapeutic strategies including reduced complexity and regulatory hurdles, ready reversibility of the therapy, lack of ethical concerns and likely lower treatment costs,” the researchers wrote in the journal npj Regenerative Medicine. “However, small molecule discovery and development has to date been constrained by limited understanding of the molecular mechanisms underlying regenerative processes.”
The zebrafish already has regenerative capabilities, with the ability to restore the form and function of almost any body part. The researchers aimed to accelerate this process, amputating the caudal fins of adult zebrafish and then giving the creatures daily intraperitoneal (IP) injections of either vehicle or candidate compounds.
The most successful candidate was found to be a small molecule called MSI-1436, described by the study authors as “a potent and highly selective inhibitor of the ubiquitous protein tyrosine phosphatase 1B (PTP1B)… [which] dephosphorylates and inactivates receptor activated tyrosine kinases”.
Originally isolated from the liver of the dogfish shark, 0.125 mg/kg of MSI-1436 was found to increase the rate of caudal fin regeneration by 200–300%, without apparent tissue overgrowth or malformation. Study co-author Viravuth P Yin said this was “definitely a ‘Eureka!’ moment” and was so astonished that he repeated the study several times under different conditions.
With accelerated regeneration confirmed in the zebrafish’s fin, Yin decided to test the process again — this time in the creature’s heart. Adult fish were subjected to a partial ventricular resection, removing about 20% of the ventricular mass, and subsequently given daily IP injections of either vehicle or MSI-1436 at 0.125 mg/kg for three days. Without interference, regeneration was expected to be complete within two months.
“To determine whether MSI-1436 increases the rate of heart regeneration, we quantified the expression of Tropomyosin, a muscle specific marker expressed in differentiated cardiac sarcomeres, by immunohistochemistry,” the scientists said. Their research showed MSI-1436 treatment increased Tropomyosin expression nearly two-fold within the injury zone.
The third step of the study was to test the molecule in the heart of a mouse — a creature that is separated from the zebrafish by approximately 450 million years of evolution. The researchers noted that while the neonatal mouse heart regenerates in a manner similar to that of the adult zebrafish, this capacity is lost approximately one week after birth.
“Ischemic heart injury was induced in 6- to 8-week-old mice by permanent ligation of the left anterior descending (LAD) coronary artery,” the study authors said. “These mice were then administered MSI-1436, at either 0.125 or 1.25 mg/kg, or vehicle only, via IP injections.”
After four weeks of treatment, MSI-1436 administration increased survival from 55% in vehicle-treated control animals to 70 and 80% in mice administered 0.125 or 1.25 mg/kg MSI-1436, respectively. Other benefits included a two- to threefold improvement in heart function; a 53% reduction in infarct size (0.125 mg/kg); reduced ventricular wall thinning; and a fourfold increase in cardiomyocyte proliferation. The drug was also used to stimulate satellite cell activation in injured mouse skeletal muscle, increasing proliferation twofold without inducing aberrant tissue regeneration.
The authors believe MSI-1436 to be the first drug candidate that has been shown to reduce scarring and induce heart regeneration in an adult mammal. And while it has not yet been tested in the human heart, it has been utilised in Phase 1 and 1b obesity and type 2 diabetes clinical trials, with PTP1B identified as a major pharmaceutical target for possible treatment of these diseases; a PTP1B inhibitor such as MSI-1436 was thus seen as ideal.
“Data consistent with inhibition of PTP1B were reported and the molecule was shown to be well tolerated by patients,” Yin and his fellow study authors noted. They added that doses shown to be effective in stimulating tissue regeneration were 5–50 times lower than the maximum well-tolerated human dose.
Other potential applications include the regeneration of skeletal muscle tissue in Duchenne muscular dystrophy, the stimulation of wound healing and regeneration of multiple other tissues, including nervous tissue.
In collaboration with spinoff company Novo Biosciences, MDI Biological Laboratory is now looking to move MSI-1436 into human clinical trials. The next step will be to test the drug in pigs, the animal whose heart most closely resembles that of humans.
“The path from laboratory bench to patient bedside can be long and difficult,” said study co-author Kevin Strange, president of the MDI Biological Laboratory and CEO/co-founder of Novo Biosciences. “But the fact that MSI-1436 has been shown to be safe for use in humans shaves years off the drug development process.”
The researchers view their study results as a validation of the MDI Biological Laboratory’s and Novo Biosciences’ approach to regenerative medicine, which focuses on decoding the ‘instruction manual’ for repair and regeneration that has been conserved in human DNA for hundreds of millions of years.
“If we can decode the instruction manual for regeneration in highly regenerative species, we can use drug therapies to reignite our own dormant regenerative capacity,” said Yin. “Our research in these highly regenerative species is showing that regenerating damaged or lost tissues and organs could be as simple as taking a drug.”
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