January 25, 2008

ALS Mice Variability Probably
Distorted Study Results

Failure to recognize differences in the genetic makeup of mice used to test drugs for amyotrophic lateral sclerosis (ALS) may have biased studies conducted in rodents in a way that made ineffective drugs look beneficial, investigators say.

When researchers at the ALS Therapy Development Institute (ALS TDI) in Cambridge, Mass., tested more than 70 drugs in mice with mutated SOD1 genes that cause a genetic form of ALS, they found that all the drugs that previously seemed to extend survival time in the mice failed to show such benefit in more tightly controlled studies.

Sean Scott, president of ALS TDI, said scientists have only recently learned that there is far more variability in the number of mutated SOD1 genes bred into mice used in ALS studies than previously assumed, leading to a much greater variability in the severity of disease than investigators have estimated. (The mice are bred to have 23 copies of the mutated gene, but some examined at ALS TDI had as few as 10 to 14.)

In addition to the number of copies of the mutant gene a mouse has, ALS TDI found that other factors, such as gender and genes shared among siblings, can also confound the results of small drug trials. These factors must be taken into account when the trials are planned so that test groups and control groups are balanced.

If drugs are tested in small numbers of mice with differing genetic backgrounds and degrees of disease severity, the likelihood of an inaccurate result is high. If, for instance, a group of mice receiving the experimental drug lives longer on average than an untreated group, it could be that the treated mice by chance had fewer mutated genes and a less severe disease, rather than that they benefited from the treatment.

“This important study highlights the need to better understand and to standardize the field’s use of this mouse model of ALS, particularly when it’s used as the basis for launching a human clinical trial,” said Sharon Hesterlee, MDA’s vice president of translational research.

The ALS TDI studies were conducted with larger numbers of mice that all had the same number of mutated SOD1 genes and were matched in the treated and untreated groups with respect to gender and litter of origin.

Hesterlee said that it’s the Institute’s capacity to conduct industrial-scale research that led MDA to form a three-year, $36 million research collaboration with it last year.