Failure to recognize differences among mice with mutated SOD1 genes may be the key to understanding why so many medications that looked good in mouse studies later failed to benefit humans with ALS, say researchers at the MDA-supported ALS Therapy Development Institute (ALS TDI) in Cambridge, Mass.
Another possible explanation for why mouse-study results have consistently failed to pan out in human trials may be that ALS caused by an SOD1 gene mutation isn’t the same as non-SOD1 ALS. (See “Are SOD1 Mice Good Models of Human ALS?” in the July-August 2007 issue.)
ALS TDI president Sean Scott says overlooking factors such as mouse gender, litter of origin, and number of mutated SOD1 genes per cell, as well as not putting enough mice into a study and including mice with infections or other conditions, may have affected study results and caused investigators to misinterpret “noise” in the system as an actual survival benefit conferred by an experimental medication.
When the ALS TDI repeated trials using mice with SOD1 mutations, using more mice and tighter controls, they found that the drugs that failed to benefit human patients also failed to show benefit in the animals. They repeated trials of minocycline, creatine, Celebrex and others, and found none of them effective in the mice.
“I’m of the camp that believes everything we have seen in the mice clinically, molecularly and cellularly matches up to humans,” says John Lincecum, associate director of research biology at ALS TDI.
He says the mouse model predicts the human response very well, albeit negatively, which is “a very different conclusion from saying the mouse model doesn’t work.”
“We’ve become more sophisticated, and we have better tools,” Lincecum says. “We have a lot more resources available than we did 13 years ago, when this mouse model became available.” In his view, “the bar needs to be set a little higher before people jump from a mouse model to a human trial.”
Not everyone agrees with the TDI findings, including MDA grantee M. Flint Beal at Weill Medical College of Cornell University in New York. “I believe that they are very well-intentioned,” Beal said of the TDI group. “The fact, however, that they cannot replicate the data of any other academic laboratory within the United States gives one great concern.”
Sharon Hesterlee, MDA vice president of translational research, says, “this is obviously a very touchy subject, but it bears further investigation.
“The information that academic laboratories have given us by studying smaller numbers of SOD1 mice over the last several years has produced several good leads, but we need to make absolutely sure that the results from mouse studies are airtight before we go to humans. Every time you launch a large, multicenter human clinical trial, there are ‘opportunity costs’ in the form of other research projects that can’t be funded or other trials that may not have enough participants. We owe it to those we serve to make wise choices.”