Finding a cure for amyotrophic lateral sclerosis (ALS)--also known as Lou Gehrig's disease--has been a frustrating and elusive quest. Even after decades of research, the biological roots of ALS are only partially understood. Now a new form of treatment offers fresh hope.
Trophos, a company based in Marseilles, France, has discovered a drug compound that appears to protect neurons from the effects of ALS, a rapidly debilitating degeneration of motor neurons in the brain and spinal cord. These effects lead to muscle atrophy and, ultimately, complete loss of motor control. The company's researchers have found that a compound named olesoxime promotes survival and regeneration of neurons deprived of neurotrophic factors--proteins essential for maintaining healthy neurons. This deprivation is similar to what occurs in the neurons of ALS patients.
The company is currently conducting Phase II clinical trials to test the drug's efficacy in ALS patients. Although the compound's mechanism of action isn't exactly clear, researchers believe it acts like a molecular "stopper," preventing motor neurons from dying off by blocking a key structure that triggers the degeneration of nerve cell mitochondria.
For the past decade, researchers have increasingly focused on mitochondria as a potential target for treating ALS and other neurodegenerative diseases. Often referred to as the powerhouse of cells, mitochondria churn out ATP, a nucleotide that transfers the energy needed by cells. Researchers have found that in ALS patients, something causes the mitochondria to swell up and burst. Scientists believe that the accumulation of dead mitochondria deprives neurons of energy. This causes the neurons to die and thus lose their connection with associated muscles.
It's unclear how mitochondria become dysfunctional in ALS patients in the first place, but over the past two years, scientists have identified a tiny pore within a membrane that may act as a fatal floodgate, letting in unwanted molecules that destabilize mitochondria. This gateway, called the mitochondrial permeability transition pore (mPTP), forms when two proteins within the inner and outer membrane come together. The resulting channel lets in a flood of calcium and other molecules, the source of the swelling in mitochondria.
Lee Martin, a professor of pathology and neuroscience at Johns Hopkins University in Baltimore, who was not involved with the research, says this mitochondrial opening may have evolved in order to get rid of damaged cells and make way for new, healthy cells. However, in diseases such as ALS, membrane proteins may come together more often, and the resulting pore may stay open longer than normal, causing otherwise healthy mitochondria and neurons to die off. "Normally this pore is in a state of flicker," says Martin. "However, in disease states, this flicker may be transformed into a more permanent, more stable opening, and this is really bad."
Martin and others believe that designing drugs to block mPTP from forming may prevent neuron death, and thus slow the progression of diseases such as ALS, Huntington's, and Parkinson's disease. Scientists at Trophos have found that olesoxime binds with a membrane protein in mitochondria that is responsible for forming mPTP. "Our compound binds to the outer membrane of mitochondria, and prevents the pore from opening in pathological conditions," says Trophos CEO Damian Marron. "This is how we believe [the compound] prevents neuronal cell death."
The company screened thousands of compounds before discovering the drug. The researchers' method involved depriving motor neurons of their neurotrophic factors in order to produce neurons that resemble those found in ALS. They then studied the effects of thousands of compounds on these neurons, and found that olesoxime, a cholesterol-like molecule, was best at promoting neuron survival and growth.
In tests on mice with ALS, olesoxime significantly improved survival rates. Researchers went on to determine the drug's safety performance in healthy volunteers and ALS patients. The company determined the drug to be safe in both groups, and is now going forward with an 18-month clinical trial in Europe, testing the drug's efficacy in 480 ALS patients.
Marron says that in the European trial, the compound will be used in combination with riluzole, the only drug currently approved by the U.S. Food and Drug Administration to treat ALS. Riluzole, which is marketed as Rilutek in the United States, has been found to increase survival in patients by three to five months. "What we're looking for is a 12 percent improvement over 18 months, which is a six-to-nine-month increase in survival in patients," says Marron. "We've set a high hurdle, but we feel that if that could be provided, it would be clinically worthwhile."
Other researchers caution that there is more work to be done to tease out the exact mechanism of the drug. "This molecule has great potential for delaying the disease progress in ALS patients, but still, there is a lot more to be done," says Hemachandra Reddy, assistant professor of physiology and pharmacology at Oregon Health and Science University, who investigates the role of mitochondria in neurodegenerative diseases. "If we know the mechanism, then this molecule can be used not just for ALS patients, but also for a broad range of diseases like Parkinson's and Huntington's."
By Jennifer Chu