The year, 2008. The journal, Amyotrophic Lateral Sclerosis – a small journal in the neuroscience world. The paper? One of the most important studies published in ALS drug development in the past 15 years.  

Titled “Design, power, and interpretation of studies in the standard murine model of ALS,” it was the product of several years of work by the ALS Therapy Development Institute (ALS TDI) and supported by partner statisticians at the University of California, San Francisco. The paper reviewed the quality of ALS mouse studies and retested eight treatments that had been reported to extend the lifespan of these mice (1).

The result? Not one of these eight compounds worked as reported. Not one extended the lifespan of ALS mouse models by a significant margin. It was unlikely that any of them held true promise as a potential treatment for people with ALS.

In today’s Science Sunday, we look back to ALS TDI’s first ever published study to explore the state and standardization of SOD1 mouse model studies, the importance of reproducibility in science, and how in the drug development world, everything has value – even failed tests and negative results.

 

The Background: Modeling ALS

Let’s back up and start at the beginning. Mouse, or murine, models are a common tool used to study the efficacy of different therapeutic compounds in treating ALS symptoms and prolonging lifespan. The mice used in the ALS TDI lab represent the most commonly used mouse model for ALS - the SOD1G93A mouse model.

ALS is not typically seen in mice, so these mice are genetically modified to develop ALS. The mice are engineered to have approximately 23 copies of a mutated human SOD1 gene. Mutations in the SOD1 gene are associated with about 2% of people with ALS and are one of several mutated genes identified in familial ALS (FALS) patients. When given this SOD1 transgene – “transgene” meaning any artificially introduced gene – the mice develop ALS symptoms similar to those experienced by people with ALS; they progressively lose