Exactly how amyotrophic lateral sclerosis works—how it degrades motor neurons, causing muscle atrophy, paralysis and eventually death—has long eluded scientists. Although ALS (commonly known as Lou Gehrig’s disease) was first described more than 140 years ago, most major advances in understanding the disease have come only during the past decade or so. Yet new therapies are in rapid development, thanks in part to Merit Cudkowicz, Massachusetts General Hospital’s chief of neurology and director of the hospital’s Neurology Clinical Trials Unit and ALS Center. In addition to her own research into the disease, Cudkowicz has almost single-handedly revolutionized ALS clinical trials by helping to form clinical networks devoted to the search for treatments.

Q: ALS has a very low incidence rate‚ about 5,600 people in the United States are diagnosed each year. Has that been a stumbling block in finding new treatments?
A: Absolutely. Yet while ALS is considered a rare disease, the lifetime risk isn’t all that low. For a man who lives a normal life span, there’s a 1 in 500 risk, and for a woman, 1 in 1,000.

Q: In 1995 you co-founded the Northeast ALS Consortium, a clinical trials network that has grown to include more than 100 academic sites worldwide. What inspired the move?
A: At the time, ideas were beginning to form about which drug compounds to test—the first gene for ALS had been identified two years earlier—but ALS wasn’t grabbing the attention of the pharmaceutical industry. People had never really thought of ALS as a disease that you could do anything about.

Q: What did you do to change that perception?
A: To push forward, it was clear that academic centers would need to lead the way. When you enter a field that’s never had clinical trials, you’re starting from ground zero. We studied how other disease networks were structured, how they brought together scientists, clinicians, patients and disease foundations, and how they developed new investigators. For rare serious illnesses, there’s always limited time and resources; the network was a boon in allowing us to share ideas, data and results. Gaining experience in conducting trials helped us get grants from the National Institutes of Health, private foundations and industry partners. Moreover, the science is attracting researchers from other disciplines, such as neuroscientists who are studying how our bodies make proteins from RNA, which plays a role in this disease. Our network brings those scientists together with clinicians.

Q: What have you learned about ALS in the past 17 years?
A: Sixteen gene discoveries have allowed the creation of laboratory models to study which pathways are involved. And we know much more about what can go wrong in the brain that causes motor neurons to die. We know, for example, that the glutamate pathway, important in mental activity and neurotransmission, is abnormal in patients with ALS and other neurodegenerative diseases.

Q: Any drugs in the clinical trials pipeline showing promise?
A: There are two drugs we’re particularly excited about, both of which are in the final phase of testing in patients; the results will determine whether the drugs will be submitted for FDA approval. One of them, dexpramipexole, is thought to target mitochondria and improve cellular energy metabolism—there is evidence that mitochondria do not work efficiently in ALS. The other drug, ceftriaxone, helps clear glutamate, excessive amounts of which can destroy neurons.

Q: If one or both of these drugs succeed, what would that mean for ALS research?
A: Not only would it provide another treatment option for patients—there are only two FDA-approved ALS drugs—but it would lend evidence that the pathway is worth targeting, which, in turn, would lead to continued growth in research by academia and industry.

Q: Last year you helped propose a smaller consortium that investigates a number of neurological diseases.
A: The National Network for Excellence in Neuroscience Clinical Trials consists of 25 clinical centers across the United States. One of our goals is efficiency: The network has a single institutional review board, and all sites signed on via one contract. These steps will speed trials by seven months to a year.