Most strokes occur when a blood vessel carrying oxygen to the brain is blocked by a blood clot. A drug called tissue plasminogen activator (tPA) can dissolve the clot and restore blood flow, but only a small percentage of stroke patients get this treatment due to the risks associated with it. Stroke is currently the fifth leading cause of death and the leading cause of long-term disability in the United States.
Holman has been collaborating with Klaus van Leyen at Massachusetts General Hospital to develop a new type of drug that can protect brain cells from the damaging effects of a stroke. When a stroke interrupts the flow of blood in the brain, the affected area of the brain is deprived of oxygen and brain cells begin to die. Abilities such as movement or speech that were controlled by the damaged parts of the brain are then impaired, sometimes permanently.
But if blood flow and its associated oxygen are restored fast enough, the patient enters a “grey zone” where doctors could potentially rescue the brain tissue, Holman said. That grey zone is where his team’s new drug, called ML351, comes in.
ML351 works to inhibit an enzyme known as 12/15-lipoxygenase, which is produced in large amounts when brain tissue is under oxidative stress. Lipoxygenase, which Holman has been studying since 1993, is a major contributor to irreversible cell death during strokes. By inhibiting the enzyme’s activity in the aftermath of a stroke, the new drug treatment could protect brain cells and reduce the amount of damage in the brain.
“We can induce strokes in mice, and if we give them our drug, we can reduce the damaged area by 40 percent,” Holman said. “Even lowering damage by 20 percent can have clinically significant outcomes—like restoration of the patient’s verbal skills.”
Holman said he envisions the new drug being used in combination with tPA or possibly on its own. The problem with tPA is that it has to be given promptly, but it can seriously harm patients with strokes caused by a ruptured artery (hemorrhagic stroke) rather than a blood clot (ischemic stroke). And if given too late, it can even cause bleeding in brain tissue already damaged by an ischemic stroke. Therefore, the decision to administer tPA or not must often be made before doctors can perform the tests needed to differentiate an ischemic stroke from a hemorrhagic stroke.
It is this dilemma that has limited the use of tPA to fewer than 10 percent of stroke patients. Holman said the new drug might give doctors more time to conduct tests and make an informed decision.
“Our hope is that it will replace tPA,” he said. “TPA may be needed eventually to remove the clot, but our hope is that the new drug will become a stand-alone therapy that can be given immediately to both ischemic and hemorrhagic stroke patients.”
ML351 is currently the lead compound, but the researchers are still working to optimize its pharmacological properties. Getting a drug from this experimental phase to clinical trials involving human subjects is very costly, and van Leyen and Holman have had a hard time getting pharmaceutical companies interested in ML351.
“You’d think the drug companies would be falling all over themselves to tap into that market, but they aren’t because getting a drug candidate through clinical trials is too expensive,” Holman said. “Klaus and I talked to three different companies, and they won’t touch it with a ten-foot pole.”
Now, the National Institutes of Health (NIH) has stepped in, awarding the duo $1.5 million in direct funding, with another $8.5 million in support funds, to bring their lipoxygenase inhibitor drug to Phase I clinical trials in the next five years.
According to Holman, the NIH usually doesn’t get involved in clinical discovery, but the agency developed a funding stream called the Blueprint Neurotherapeutics Network to support discovery and development efforts for neurotherapeutic drugs that pharmaceutical companies often hesitate to invest in. Since the network’s inception in 2011, it has funded 23 projects—about three per year.
Holman called this grant the “golden ticket” that will enable him and van Leyen to take their drug from the lab bench to clinical trials and, eventually, to the marketplace.
“I appreciate the NIH is rolling the dice on this,” Holman said. “Now the pressure’s on—we have to solve the stroke dilemma.”
Source : UC Santa Cruz