The U.S. Department of Health and Human Services has called regenerative medicine the “vanguard of 21st-century healthcare.”
For more than 15 years, regenerative medicine research has focused primarily on developing stem cell- and tissue engineering-based therapies to regenerate, replace or repair damaged tissues and organs. Despite extensive research, however, these approaches remain challenged by their complexity and expense, by problems with efficacy and by ethical and regulatory hurdles.
But what if there were another approach? What if we could simply take a drug to stimulate the regeneration of lost and damaged tissues and organs?
By contrast with stem cell and tissue engineering approaches, few resources have been devoted to the development of regenerative medicine drug therapies, despite the fact that they offer many advantages. These include reduced complexity, reduced cost, reversibility (a drug can simply be discontinued), fewer regulatory hurdles and the absence of ethical concerns like those that have challenged the stem cell field.
They are also easy to administer, which is why drugs and their herbal counterparts have been the mainstay of medicine for thousands of years.
At the MDI Biological Laboratory, we are pioneering new approaches to regenerative medicine.
Our research is focused on defining the gene and signaling networks that control regeneration in diverse animals like zebrafish and salamanders that have the natural ability to regenerate injured or lost tissues. We now know that humans possess these same genes and signaling pathways, yet our ability to regenerate lost and damaged tissues is limited. Our goal is to understand why these pathways are dormant in humans and then develop drugs that will activate them.
The example of heart disease
Heart disease, the world’s leading killer (taking the lives of 17.5 million people per year, according to the World Health Organization), offers an example of the benefits of our approach to regenerative medicine.
When a patient suffers a heart attack, a portion of the heart muscle is deprived of oxygen and dies. The dead tissue and associated scarring interfere with the heart’s ability to pump blood effectively, leading to disability and possibly to heart failure and death. Standard treatment for a heart attack is focused on preventing a secondary attack and heart failure. No drugs exist to regenerate damaged heart muscle tissue in humans – yet.
In the early 2000s the promise of stem cells generated tremendous enthusiasm, including for the treatment of heart disease.
However, despite more than 15 years of research and the investment of hundreds of millions of dollars, stem cells have largely failed to deliver on their promise.
Our scientists are taking a different tack. We are seeking to harness the body’s natural ability to heal and regrow tissues. Early indications are that it’s working. In just three years and with limited investment, our unique approach has yielded a drug candidate, MSI-1436, for regenerating damaged heart muscle that we are working to move into clinical development through a spinoff company, Novo Biosciences.
A great moment in the laboratory
Voot P. Yin, Ph.D., remembers well the day in the summer of 2012 that a student who was screening potential drug candidates in his laboratory found that MSI-1436 increased regeneration in the tail fin of the zebrafish by 300 percent. Yin was so astonished by the results that he had the student repeat the experiment several times and under different conditions.
“That was definitely a great moment in the laboratory,” says Yin, an assistant professor and co-founder of Novo Biosciences along with MDI Biological Laboratory President Kevin Strange, Ph.D., and co-inventor of MSI-1436 with Strange and collaborator Michael Zasloff, M.D., Ph.D.
Yin followed the zebrafish study with a mouse study that also showed dramatic effects on heart muscle regeneration. Those results were recently published in the journal npj Regenerative Medicine. The next step is to test MSI-1436 in pigs, the animal model whose heart most closely resembles that of humans. If that study is successful, Novo Biosciences plans to pursue clinical trials in humans.
Though MSI-1436 has enormous potential, Strange cautions that drug development is a perilous process. “Ninety percent of the drug candidates that make it into human clinical testing fail — they don’t produce the expected results or they are toxic,” he says. “Still, we think MSI-1436 is very promising.”
MSI-1436 has two significant advantages that could help smooth the path to clinical applications. The first is that it works in both zebrafish and mice, which are separated by more than 450 million years of evolution. The fact that the drug candidate works in two such disparate species is a strong indicator that it might work in humans as well.
The other is that MSI-1436 has already been found to be safe in Phase 1a and 1b human clinical trials that tested the drug as a possible treatment for obesity and type 2 diabetes. The trials found that it was well tolerated by patients at doses 5 to 50 times higher than those that stimulate regeneration in zebrafish and mice.
“This is extremely significant,” says Strange. “The fact that MSI-1436 is well tolerated by humans shaves years off the drug development process.”
If MSI-1436 proves to be effective in humans, it will change the lives of millions of people who are disabled by heart disease. It also holds the potential to stimulate would healing, reduce wound scarring and stimulate the regeneration of multiple other tissues, including nervous and skeletal muscle tissue.
“Evolution is smarter than you are”
While other regenerative medicine therapies focus on transplanting stem cells or creating new tissues and organs in a dish, we are taking our cues from nature. Our goal is to reactivate the instruction manual for the repair and regeneration of tissue that has been conserved by evolution in our DNA for hundreds of millions of years.
Yin is fond of quoting the late British biochemist, Leslie Orgel, whose studies of early life on Earth contributed to a now widely accepted theory about the development of DNA. “Evolution,” Orgel said, “is smarter than you are.”
“If we can decode the instruction manual for regeneration in highly regenerative species,” Yin says, “we should be able to develop drug therapies that will activate our own dormant regenerative capacity.”
This post is excerpted from “Breaking Through,” the MDI Biological Laboratory’s biannual news magazine. Subscribe to “Breaking Through” here.