Thalidomide, Lenalidomide show promise against Lou Gehrig's disease

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.

"This suggests that, as we suspected, thalidomide and lenalidomide prevent cytokine production by destabilizing mRNA," said Dr. Beal, who is also Neurologist-in-Chief at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

The next step is "to test and see whether these drugs work in mice if we administer them at the time of disease onset," Dr. Kiaei said. "That's much more relevant for patients because that's when they would first be prescribed medications to fight ALS."

Of course, the word thalidomide recalls its past association with birth defects -- the drug was withdrawn from the market for decades after women who took it in the 1960s to alleviate pregnancy-related symptoms gave birth to severely deformed babies. In recent years, the drug has made somewhat of a comeback, having proved useful against a number of serious illnesses.

"Because pregnancy is not an issue for women with ALS, the concern with birth defects should not slow this research or thalidomide's potential use in patients," Dr. Kiaei said. "Still, we should always make sure thalidomide is used under strict conditions, should clinical trials begin."

He noted that peripheral neuropathy -- numbness and tingling in the extremities -- is usually the only major side effect noted with thalidomide use.

Dr. Kiaei stressed, however, that success in mice doesn't always mean breakthroughs for human patients.

"Drug metabolism and other factors are just so different between mice and humans, and so far, none of what's worked for ALS in animal models has translated to effective treatments," he said.

"Still, right now we have so little to offer patients battling this devastating disease," Dr. Kiaei added. "This does offer new hope."

This work was funded by grants from the Muscular Dystrophy Association, The Amyotrophic Lateral Sclerosis Association, and the National Institutes of Health.

Co-researchers include Dr. Gabrielle Gardian, Junyu Chen, and Dr. Noel Y. Calingasan -- all of Weill Cornell; Dr. Peter Schafer and Dr. George Muller, of the Celgene Corporation in Summit, N.J.; Dr. Charles Stewart and Dr. Kenneth Hensley, of Oklahoma Medical Research Foundation in Oklahoma City; and Dr. Dong-Kug Choi, of Konkuk University, South Korea.