Research in Mice Suggests the Drugs Block Inflammatory Molecules That Spur Disease Progression
NEW YORK (March 9, 2006) — New animal research suggests that two well-studied drugs, thalidomide and its derivative, lenalidomide, might extend the survival of patients with the neurological disorder amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease.
The drugs appear to shut down production of cytokines thought to be crucial to progression of the disease, according to a study by researchers in the Department of Neurology and Neuroscience at the Weill Medical College of Cornell University in New York City.
"While it's always a leap to go from mice to humans, we've found that these agents inhibit the production of two pro-inflammatory cytokines linked to ALS," explained lead author Dr. Mahmoud Kiaei, an Instructor in Neuroscience at Weill Cornell Medical College.
His team published its findings in this month's issue of the Journal of Neuroscience.
More than 30,000 Americans, most of them between the ages of 40 and 70, are living with ALS. ALS is a neurodegenerative disorder that attacks motor neurons in both the brain and spinal cord, causing gradual debilitation and death. While one drug, Riluzole, can alleviate symptoms and extend survival by perhaps a few months, there is no effective treatment for this uniformly fatal illness.
Part of the problem is that the disease's origins are so poorly understood, explained study co-author Dr. Susanne Petri, a Postdoctoral Research Fellow at Weill Cornell.
"While we know that a particular gene, called SOD1, can cause ALS, this is true for only about 2 percent of all cases," she said.
Research is bolstering the idea that certain pro-inflammatory molecules called cytokines play a role, however.
"Specifically, increased levels of two cytokines — tumor necrosis factor alpha (TNF-alpha) and a related cytokine, called fibroblast-associated cell-surface ligand (FasL) — may encourage nerve cells to undergo apoptosis, or programmed cell death," Dr. Petri said. "Unlike other cells, motor neurons don't get replaced when they die. The result is the gradual loss of motor function that's a hallmark of ALS."
Thalidomide and lenalidomide work to suppress these pro-inflammatory cytokines.
"We're not quite sure how they do so, but we think it's at the level of mRNA — the genetic 'messengers' that tell genes to produce a particular protein," said co-author Dr. Khatuna Kipiani, a Postdoctoral Research Fellow at Weill Cornell. "These drugs destabilize this mRNA, shutting down production of TNF-alpha and FasL."
That theory seems to have been borne out by the team's work with tissues from human ALS patients, and in mice genetically engineered to carry the ALS-generating SOD1 gene. "These mice develop a disease that is nearly indistinguishable from human ALS," Dr. Kiaei explained.
First of all, the researchers observed high levels of pro-inflammatory TNF-alpha and FasL in samples of spinal cord tissue taken from both human ALS patients and the genetically engineered mice.
"That strongly suggests that these two cytokines are key players in ALS pathogenesis," said senior researcher Dr. M. Flint Beal, the Anne Parrish Titzell Professor of Neurology and Chairman of the Department of Neurology and Neuroscience at Weill Cornell.
"It's also important to note that increased levels of TNF-alpha and FasL appear long before the onset of disease symptoms," he added.
The researchers then treated ALS-prone mice with thalidomide or lenalidomide.
"Treatment slowed the wasting and declines in motor control that we typically see with ALS," Dr. Kiaei said. "We also saw evidence of reduced neuronal death. Best of all, the mice lived significantly longer than untreated mice."
A deeper investigation of the mice's spinal cord tissue also showed reductions in active TNF-alpha and FasL, and a steep drop in related mRNA.
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