A few years ago, Caryl Sortwell, a Michigan State University College of Human Medicine Parkinson's researcher, was asked by Jeff MacKeigan, a scientist at Van Andel Research Institute, or VARI, to collaborate on research that could significantly slow the progression of Parkinson's.
The primary focus of the research? Take an existing drug used in Japan for treating a blood vessel condition and see if it’s just as effective in fighting Parkinson's.
Since MacKeigan was not a specialist in Parkinson’s research, he needed a partner like Sortwell to assist him. Thus a collaboration was born between two scientists at two different research institutions, a partnership that has spanned nearly six years.
Sortwell is part of a team of Parkinson’s disease scientists who joined MSU in 2009.
“We were excited when the Michigan State Parkinson’s team came here,” MacKeigan said, who joined VARI three years earlier.
Several MSU labs, including Sortwell’s, are housed within the institute while the the university builds its new Grand Rapids Research Center down the street.
Being nearby helps, but MacKeigan and Sortwell’s collaboration works thanks in large part to their complementary backgrounds and expertise. His doctoral degree is in microbiology and immunology. Sortwell's is in neurobiology. His expertise is in discovering targets in diseased cells and then looking for existing drugs that can be repurposed to hit those targets. She specializes in Parkinson’s disease research and investigates the molecular mechanisms underlying the disease in order to develop new therapies.
“Diverse viewpoints are one of the benefits of team science, of two people working together, looking at the same problem from different perspectives to achieve the same goals,” MacKeigan said.
Sortwell added, “You have to be willing to admit what you don’t know. You have to trust, too. We don’t take a step without consulting with each other.”
The focus of their collaboration is a drug called fasudil, which for 20 years has been used in Japan for treating blood vessel spasms in the brain. Through extensive and rigorous research, Sortwell and MacKeigan have shown that fasudil also targets some of the processes in the brain that are closely linked with Parkinson’s, a neurodegenerative disease that afflicts nearly one million patients in the U.S. and 10 million worldwide, a number that is expected to increase as the baby boomer generation ages.
“We know a tremendous amount about that drug (fasudil),” MacKeigan said, referring to its long history of use in Japan. “We knew its pharmacokinetics and safety profile in patients.”
In the past six years, The Michael J. Fox Foundation for Parkinson’s Research has awarded Sortwell and MacKeigan three grants totaling $600,980 to study whether fasudil can be repurposed as a treatment for Parkinson’s. Their first grant supported work to gather evidence that the drug protects neurons in preclinical models of the disease.
“That was the first phase,” Sortwell said, “and those results turned out to be very promising.”
Under the second grant, the two studied how the drug enters the brain, how long a dose works and whether it hits the target in the brain with little or no side effects. With the third grant, which was awarded in May, they are gathering data to request specific feedback from the U.S. Food and Drug Administration to understand what will be required to approve fasudil as an “Investigational New Drug,” the first step in a long process toward clinical trials with human patients.
“Parkinson’s disease is a combination of multiple insults to the brain,” Sortwell said. “The beauty of fasudil is it has the potential to work on a number of these different insults.”
The drug appears to prevent the inflammation that results when the brain’s immune cells, called microglia, attack diseased dopamine-producing neurons. As Parkinson’s progresses, these vital cells are lost, leading to a decrease in dopamine, a neurotransmitter that is vital for smooth movement. While the inflammation is a natural immune response, in Parkinson’s it actually may contribute to the disease process.
“We have the most evidence for fasudil preventing neuroinflammation,” Sortwell said.
In addition to combating inflammation, “we believe fasudil also might directly protect the neurons,” MacKeigan said. “You want to stop neuron degeneration immediately.”
Parkinson’s disease’s hallmark symptoms—rigidity, loss of voluntary movement and tremor, for example—occur after a large number of these neurons are lost. There currently are no approved drugs that slow or stop the death of these crucial cells.
While fasudil is not seen as a cure for Parkinson’s, it has the potential to significantly slow the disease, prolonging the length of time that other drugs can effectively control its symptoms and possibly allowing patients to outlive the disease, he said.
“We’re trying to halt the disease’s progress,” MacKeigan said, “but if we also can extend the efficacy of current Parkinson’s drugs, that would be a great improvement.”
The advantage of fasudil is that it already has been shown to be safe in human patients in Japan, which could shorten the length of time required for clinical trials. Still, Sortwell said it is unlikely that the first phase of clinical trials will begin before 2019.
The search for new drugs to fight disease often is like casting a fishing line in the ocean and hoping something bites, Sortwell said.
“Repurposing an existing drug with a known safety record, such as fasudil, is like fishing in a smaller pond with hungrier fish,” she added. “It gives us a head start.”