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Remember the Ice Bucket Challenge? During an eight-week period in 2014, the effort raised $115 million for the ALS Association. Behind that good news lurks an insidious disease.
Amyotrophic lateral sclerosis attacks motor neurons, disabling the brain’s ability to control muscles throughout the body. Patients lose the capacity to walk, eat and, eventually, breathe.
ALS is fatal and quick moving. The typical survival time is three to five years after the onset of symptoms—and there’s no way to halt or reverse the disease’s progression. That’s partly because ALS’ pathology is difficult to decipher and partly because it’s an “orphan disease.”
That’s the term the medical community gives to rare diseases that are abandoned by pharmaceutical companies, wary of investing millions of research dollars in products for a small number of patients. Despite its recent turn in the spotlight, ALS is one of those rare diseases. According to ALSA, approximately 6,000 people in the United States are diagnosed with the disease each year. Contrast that with the 600,000 people diagnosed with Parkinson’s every year.
Big Pharma’s limited interest in ALS makes crowdsourced funding all the more important. The Ice Bucket Challenge allowed ALSA to funnel a whopping $77 million into research. Part of that came to the Main Line.
In July 2015, Dr. Mel Reichman, a senior investigator at the Lankenau Institute for Medical Research in Wynnewood, received a three-year $240,000 grant from ALSA to find drugs that could stop the disease in its tracks. If Reichman’s hypothesis proves correct, it would be a scientific breakthrough.
Reichman’s target is the SOD1 protein. In most people, SOD1 is a two-molecule dimer. When SOD1 mutates, it disintegrates into a one-molecule monomer. That monomer version of SOD1 has been connected to ALS. Only 10 percent of ALS cases have been proven to have a genetic link. But of those, 20 percent have been traced to SOD1’s mutated monomer.
Reichman’s goal is to find a drug that prevents the separation of mutated SOD1 proteins. He’s not creating a new drug; he’s combining drugs already approved by the FDA for different diseases. This combinatorial method may be a medical moonshot, but it’s worth trying. Because physicians don’t know what causes 90 percent of ALS cases, it’s possible that a drug proven effective in stopping another disease might work on this one.
Forward-thinking problem solvers endorsed the efforts Reichman made with previous combinatorial methods. In 2012, he was awarded a grant from
the Bill & Melinda Gates Foundation to research drugs that might fight malaria. “There are thousands and thousands of potential compounds with which we may find unexpected synergies,” Reichman says. “With malaria, it was a particularly challenging problem, and the technology did not work out, but there was a glimmer of concept validation. We told them that it was high-risk but had a potentially high reward.”
That’s the mindset Reichman brought to the ALS project. Since receiving the grant, he has unleashed a pharmaceutical arsenal of more than 100,000 combinations at SOD1. He and the LIMR staff started with the FDA-approved compounds that are safest, with minimal side effects.
None of those stabilized SOD1, but Reichman is not disheartened. He and the LIMR staff continue to combine drugs into what he calls “Whitman’s samplers of pharmacology.” If that doesn’t produce a hit, Reichman will expand the search. “We’d go into the wide world of chemical diversity,” he says. “Only 1,600 drugs have been approved by the FDA since World War II. With all the grandfathered drugs, it may be close to 4,000 compounds.
But in the world, there are 2.5 million to 5 million compounds that we could deploy.”
But Reichman is hoping to find success with drugs that are FDA approved. “If there’s no reason to believe the combination would produce ill effects, and if you are sticking to the recommended dosages, you can go straight to Phase II efficacy trials,” he says. “If you’re working on something like high cholesterol, for which there are plenty of existing drugs, there are strict standards. But for something like ALS, for which there is no effective treatment, the standard is more flexible.”
ALS’ lethality may make the FDA, physicians and patients more open to side effects, as long as they aren’t worse than the illness. But could Reichman’s work cure ALS? “A realist would say that, at this point, the goal is to better prolong the quality of life,” he says. “We still don’t know for sure the root causes of any neurodegenerative diseases, so we can’t completely halt their progression, let alone reverse them.”
Reichman’s research may only be a drop in the bucket, but every drop counts.
