The first real break in solving the mystery of ALS causation came in 1993, when MDA-supported investigators linked one form of familial (genetic) ALS to a gene on chromosome 21 that gives rise to a protein called superoxide dismutase 1 (SOD1), identifying 11 disease-causing mutations in the SOD1 gene in 13 affected families. (Today, some 100 different SOD1 mutations are known to cause ALS in humans.)
Shortly after these findings, MDA grantee Mark Gurney, a biologist at Northwestern University, in Evanston, Ill., led a team that developed mice with an SOD1 mutation at position 93. The mutation, which changes the amino acid glycine to one called alanine in the SOD1 protein, caused a disease in the mice that closely resembled ALS. The mice lost muscle-controlling nerve cells (motor neurons), became paralyzed, and died by 5 to 6 months of age, far short of the usual mouse lifeof two to three years.
These G93A mutant SOD1 mice quickly became the standard model in which to test new ALS treatments and study ALS pathology, although there are mice available with a few other SOD1 mutations.
“We were lucky that the SOD1 mutant mouse disease looked a lot like human ALS,” says Denise Figlewicz, a neuroscientist and MDA research grantee at the University of Michigan in Ann Arbor. “We decided to make the most of it.” Figlewicz and many other ALS experts believe that, after the initial disease-causing event, whether a genetic mutation or something else, a similar cascade of biochemical changes leads to the death of motor neurons.
But some researchers think studying the G93A mouse as a model for sporadic ALS is like looking for your keys where the light is better instead of where you dropped them.
Since the mid-1990s, several drugs that helped the G93A mice by delaying disease onset or prolonging life failed to help patients in trials. Among the drugs that showed these “discordant” results are celecoxib (Celebrex), creatine and gabapentin (Neurontin).
Even Gregory Cox, an associate staff scientist at the Jackson Laboratory in Bar Harbor, Maine, a nonprofit facility that conducts research and supplies the G93A mouse to dozens of labs, has reservations about the scope of its applicability. The mouse, he says, develops an “incredibly reproducible motor neuron disease. It’s a great model for human SOD1 mutations, but it’s not clear how applicable what we learn is to all sporadic cases.”
One approach to increasing the usefulness of the SOD1 mutant mouse model is to apply more rigorous testing procedures.
Gwendolyn Wong, director of in vivo pharmacology at the Research Center of the ALS Therapy Development Foundation (TDF) in Cambridge, Mass., says that tighter controls would have predicted the failed clinical trial of Celebrex.
Wong thinks the SOD1 mouse is “a fabulous model of the clinical disease.” But she also believes that you have to minimize every possible cause of variability in the mouse experiments other than the test drug’s effects if you’re going to get results worth your attention.
“I firmly believe that of all the animal models out there, this is the best one to use for drug discovery in ALS,” she says.
The TDF carries out experiments using SOD1 mutant mice only after matching the treatment and nontreatment groups for litter of origin, body weight, gender, and number of copies of the mutated SOD1 gene.
When all these sources of variation were minimized, Wong says, a test of Celebrex in SOD1 mutant mice didn’t show any benefit — just as it didn’t in the patients. In Wong’s experience, “failed mouse experiments lead to failed clinical trials.” And, one hopes, with tighter controls, successes in mouse trials will predict successes in humans.
Mimicking Human Variation
Denise Figlewicz has a somewhat different take on why the SOD1 mouse results have often not predicted human results. She’s suggested that if the G93A mutation in SOD1 were bred into several different strains of mice, each with its own genetic background in other respects, the resulting mix of mice would be closer to mimicking human variation. Experimental drugs that show benefit in more than one strain would be promising. She’s now breeding such mice, with MDA support.
“The problem,” she says, “is that most of us are using the same G93A mice, which are genetically identical. It’s as if somebody cloned you and tested a drug on you and the clones and said, ‘It works!’ But there would be people unrelated to you for whom it wouldn’t work.” In a genetically diverse population, she says, any possible benefits of an experimental ALS drug to a small percentage of people with a certain genetic background are likely to be masked by the drug’s lack of effect on others with different backgrounds.
The ultimate answer probably lies in a combination of both approaches: Compounds that look very good in a rigorously controlled set of experiments would be even stronger candidates if they subsequently proved beneficial in SOD1 mutant mice from several different genetic backgrounds.
It’s unclear how applicable any results will be to non-SOD1 ALS. But Cox, for one, is encouraged by the fact that you can’t tell the difference between patients who have SOD1-caused ALS and other ALS patients without doing genetic testing, which suggests there’s considerable overlap. “We’ve got that going for us,” he says.
MDA offers four publications for people with ALS, as well as family members and caregivers. Contact your local office for information.
Everyday Life With ALS: A Practical Guide, released in May, is a revision and expansion of MDA’s ALS: Maintaining Mobility. The updated guide is designed to help readers manage their daily experiences with ALS. A free copy of the book will be provided to any person with ALS who’s registered with MDA. The book is available on CD for a fee.
Facts About ALS discusses the history, description and causes of ALS.
When a Loved One Has ALS: A Caregiver's Guide is a comprehensive manual of practical advice for meeting the medical, emotional, financial and everyday challenges faced by primary caregivers of people with ALS. The primary caregiver of anyone with a diagnosis of ALS who is registered with MDA can receive a free copy.
Meals for Easy Swallowing is no longer in print but is available on the MDA Web site at www.als-mda.org/publications/meals. The online version, which contains all of the original text, comprises a collection of recipes for people who have swallowing difficulties because of neuromuscular diseases such as ALS.