When it comes to assessing the damage caused by natural disasters, experts often think in terms of primary and secondary effects.
A primary effect of a flood, for example, would include the damage to homes and buildings caused by the rushing waters, while a secondary effect would be power outages resulting from downed trees and utility poles.
A similar one-two punch occurs in patients who suffer an ischemic stroke—one that occurs when a blood clot cuts off the supply of oxygenated blood to part of the brain.
First there is the primary damage done by the stroke itself, which includes the rapid death of brain cells surrounding the area where the clot formed. Then there is the secondary damage that occurs over the next few days in areas of the brain that were impacted—but not killed—during the stroke.
This secondary damage involves the overproduction of a naturally occurring enzyme, 12/15-lipoxygenase. At normal levels, the enzyme is harmless to the brain. However, when its production increases following a stroke, it can compound the damage done by the stroke itself.
12/15-lipoxygenase binds to mitochondria in neurons and kills the cells from the inside out. It also breaks down the integrity of the blood-brain barrier, which can lead to brain bleeding that kills more brain cells.
Klaus van Leyen, PhD Investigator, Neuroprotection Research Laboratories, Massachusetts General Hospital Associate Professor of Radiology, Harvard Medical School
Klaus van Leyen, PhD, an investigator in the Laboratory of Neuroprotection at Massachusetts General Hospital, has spent the last fifteen years developing strategies to reduce these damaging secondary effects.
Working in collaboration with Ted Holman, PhD, of the University of California Santa Cruz, van Leyen has identified molecular compounds that bind to the enzyme and limit its effect on brain cells and the blood-brain barrier.
The team recently received funding through the NIH Blueprint Neurotherapeutics Grant Program to support the further development of these compounds, with the goal of creating new treatments for stroke patients.
A Doubly Beneficial Treatment Strategy
An inhibitor of 12/15-lipoxygenase could benefit stroke patients in two ways, van Leyen explains.
For one, it would help to stop the damaging secondary effects of stroke resulting from the overproduction of that enzyme.
It could also help to limit the primary damage caused by the stroke itself. Ischemic stroke patients are currently treated with tissue plasminogen activator (tPA), which help to break up clots in the brain, but also increase the risk of cerebral bleeding—a risk which is compounded by the breakdown of the blood-brain barrier caused by 12/15-lipoxygenase.
Thus patients can only be treated with tPA for a short time before the risk of bleeding becomes too great. By treating patients with a 12/15-lipoxygenase inhibitor at the onset of stroke, it may be possible to use tPA at later time points, or under conditions where tPA cannot currently be used because the patient has an increased risk of bleeding, e.g., when on anticoagulant therapy.
Laboratory experiments testing this treatment strategy have been promising so far. Mice that are treated with a 12/15-lipoxygenase inhibitor following a stroke have infarcts (areas of dead tissue in the brain) that are up to 40% smaller than mice that did not receive the treatment.
“This is the approach we are trying to translate into the clinic, but there are significant obstacles,” van Leyen explains.
One obstacle has been the reluctance of the pharmaceutical industry to pursue the development of new stroke treatments following the high-profile failure of the SAINT II clinical trial in 2005-06, which was testing an initially promising treatment for ischemic stroke.
“That trial was over 10 years ago, and some [industry members] are now starting to come back, but it is still a long, hard path,” van Leyen says. “To translate our findings into clinical reality, we need industry support.”
Blueprint Grant Provides Crucial Support
The NIH’s Blueprint Grant will help van Leyen and the research team further develop and refine their compounds so they have a better chance of attracting industry partners.
“The idea is that the NIH hires subcontractors that can do the kinds of experiments that are not feasible in an academic lab; such as toxicology studies, first in human testing and learning more about the compound’s uptake, metabolism and distribution throughout the body,” van Leyen says.
“It is a back and forth between us and these contractors and the NIH to first get these compounds tested and then get them as far along as possible toward a clinical study.”
If the team reaches their project milestones during this first year of the grant program, they will receive four more years of support. The goal is to make a strong case for moving the drug into commercial development where it can benefit stroke patients.
“By then you have de-risked your molecules to the point that industry has seen that they have gone through extensive rounds of testing, the compounds look good, and it looks like they have a chance of working in the clinic.”
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