A totally new class of drug just might become a "one-size-fits-all" silver bullet for many neuro-inflammatory conditions.
Developed in the lab of D. Martin Watterson, PhD, at Northwestern University’s Feinberg School of Medicine, the drugs have already been patented, set for commercial development, and safety tested in a Phase 1 human trial.
Neuroinflammation is a type of brain inflammation that seems to be a common denominator in the progressive neurological damage characteristic of diseases such as Alzheimer’s, multiple sclerosis, and Parkinson’s, brain injury, and stroke. And it is thought to play a role in neuro-endocrine-immune conditions such as chronic fatigue syndrome (ME/CFS) and fibromyalgia.
A Novel Treatment Strategy for Alzheimer's
By addressing neuroinflammation, the new class of drugs - represented by MW151 and MW189 - offers an entirely different therapeutic approach to Alzheimer’s than current ones being tested to prevent the development of beta amyloid plaques in the brain.
The plaques are an indicator of the disease but not a proven cause.
MW151 and MW189 - both orally-administered drugs that easily cross the blood-brain barrier - work by preventing the damaging overproduction of brain proteins called proinflammatory cytokines.
Scientists now believe overproduction of these proteins contributes to the development of many degenerative neurological diseases, as well as to the neurological damage caused by traumatic brain injury and stroke.
• When too many of the cytokines are produced, the synapses of the brain begin to misfire.
• Eventually the entire organization of the brain falls into disarray, like a computer failing.
• The neurons lose their connections with each other and can eventually die.
• The resulting damage in the cortex and hippocampus can compromise memory and decision-making.
• Similarly, in MS, proinflammatory cytokines directly or indirectly damage the coverings of nerve cells that transmit signals from the brain down the spinal cord
Stopped Alzheimer’s Progression in Animals
“In Alzheimer’s disease, many people now view the progression from mild cognitive impairment to full-blown Alzheimer’s as an indication of malfunctioning synapses, the pathways that allow neurons to talk to each other,” Dr. Watterson says. “And high levels of proinflammatory cytokines can contribute to synaptic malfunction.”
A new preclinical study published July 25 by the Journal of Neuroscience, reports that, when one of the new Northwestern-developed drugs is given to a mouse genetically engineered to develop Alzheimer’s, it prevents the development of the full-blown disease. (“Early Stage Drug Treatment that Normalizes Proinflammatory Cytokine Production Attenuates Synaptic Dysfunction in a Mouse Model….”)
Definite Therapeutic ‘Time Window’
The study identifies the optimal therapeutic time window for administering the drug.
“This could become part of a collection of drugs you could use to prevent the development of Alzheimer’s,” says Dr. Watterson, a coauthor of the animal study with Linda Van Eldik, PhD, director of the Sanders-Brown Center on Aging at the University of Kentucky. According to their report:
• A mouse model of Alzheimer’s received MW151 three times a week starting at six months of age, right at the time the proinflammatory cytokines began to rise. This would be the comparable stage when a human patient would begin to experience mild cognitive impairment.
• When the mice brains were later evaluated at 11 months (at a time when disease pathology is usually present), cytokine levels in the mice receiving the drug were restored to normal levels and their synapses were functioning normally.
• The inflammatory cytokine levels of the mice not receiving the drug, however, were still at abnormally high levels, and the mice had misfiring synapses.
“The drug protected against the damage associated with learning and memory impairment,” Dr. Van Eldik notes. “Giving this drug before Alzheimer’s memory changes are at a late stage may be a promising future approach to therapy.”
Biotech Co. Has Completed Phase 1 Human Trial
Northwestern reports it has recently been issued patents for MW151 and MW189, and has licensed the commercial development to "a biotech company" which recently completed a Phase 1 clinical trial to assess the drug’s safety in humans. The results of the Phase 1 trial are yet to be published. The human safety assessment is the first step in the process of winning approval for clinical use of a new drug.
Success in Animal MS & Brain Injury Studies Too
In previous and ongoing animal studies, the same drug:
• Inhibited the development of a multiple sclerosis-like disease.
• And reduced the neurological damage caused by closed-head traumatic brain injury.
• In both cases, as with Alzheimer’s the studies show the therapy time window is critical.
Animal MS Trials Ongoing (Human Trial Subject to Results)
In MS, overproduction of the proinflammatory cytokines damages the central nervous system and the brain. Although the brain is the site of the inflammation, in MS the proinflammatory proteins (directly or indirectly) destroy the insulation or coverings of the nerve cells that transmit signals down the spinal cord to the body. When the insulation is stripped, messages aren’t properly conducted down the spinal cord.
When mice that were induced to develop an MS-like disease received MW151 orally, they did not develop disease as severe.
“We inhibited the development of the disease,” says William Karpus, PhD, a specialist in MS research at the Feinberg School.
“Now we need to learn if the drug can prevent relapses of MS,” Dr. Karpus adds, and the results of these ongoing studies in mice will determine whether a patient trial will be planned.
The only current oral drug treatment for MS acts at the level of the lymph nodes, Dr. Karpus points out. But because the brain is the site of the inflammation and damage, a drug that works in the brain is an ideal therapy.
Animal Trials of Protection after Brain Injury
After a traumatic brain injury, the glia cells in the brain become hyperactive and release a continuous cascade of proinflammatory cytokines that - in the long term - can result in cognitive impairment and epilepsy. As a result of this hyperactivity, researchers believe the brain is more susceptible to serious damage following a second neurological injury.
In a study with mice, Mark Wainright, MD, professor of pediatric neurology at the Feinberg School, showed that when MW151 is given during an early therapeutic window three to six hours after the injury, it blocks glial activation and prevents the flood of proinflammatory cytokines after a traumatic brain injury.
“If you took a drug like this early on after traumatic brain injury or a even a stroke, you could possibly prevent the long-term complications of that injury including the risk of seizures, cognitive impairment and, perhaps, mental health issues,” Dr. Wainwright says.
Brief & Focused Therapy Seen for Stroke
Stroke causes inflammation in the brain that may also be linked to long-term complications including epilepsy and cognitive deficits. As in traumatic brain injury, this inflammatory response is part of the recovery mechanisms used by the brain, so the use of brief and focused treatments like MW151 could:
• Prevent the harmful effects of inflammation,
• While allowing the protective effects to occur unimpeded.
In another study, Dr. Wainwright demonstrated that MW151, when given after a traumatic brain injury, prevented the increased risk of epileptic seizures.
Overall, “We need more studies of therapeutic time windows in models of these other diseases so we can better plan future clinical trials,” Dr. Watterson notes.
Source: Based on Northwestern University Feinberg School of Medicine news release, Jul 25, 2012; by Marla Paul, health sciences editor (firstname.lastname@example.org)