Design, power, and interpretation of studies in the standard murine model of ALS
Abstract
Identification of SOD1 as the mutated protein in a significant subset of familial amyotrophic lateral sclerosis (FALS) cases has led to the generation of transgenic rodent models of autosomal dominant SOD1 FALS. Mice carrying 23 copies of the human SOD1(G93A) transgene are considered the standard model for FALS and ALS therapeutic studies. To date, there have been at least 50 publications describing therapeutic agents that extend the lifespan of this mouse. However, no therapeutic agent besides riluzole has shown corresponding clinical efficacy. We used computer modeling and statistical analysis of 5429 SOD1(G93A) mice from our efficacy studies to quantify the impact of several critical confounding biological variables that must be appreciated and should be controlled for when designing and interpreting efficacy studies. Having identified the most critical of these biological variables, we subsequently instituted parameters for optimal study design in the SOD1(G93A) mouse model. We retested several compounds reported in major animal studies (minocycline, creatine, celecoxib, sodium phenylbutyrate, ceftriaxone, WHI-P131, thalidomide, and riluzole) using this optimal study design and found no survival benefit in the SOD1(G93A) mouse for any compounds (including riluzole) administered by their previously reported routes and doses. The presence of these uncontrolled confounding variables in the screening system, and the failure of these several drugs to demonstrate efficacy in adequately designed and powered repeat studies, leads us to conclude that the majority of published effects are most likely measurements of noise in the distribution of survival means as opposed to actual drug effect. We recommend a minimum study design for this mouse model to best address and manage this inherent noise and to facilitate more significant and reproducible results among all laboratories employing the SOD1(G93A) mouse.
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Inappropriate data cleaning has the potential to bias study outcomes.
“Inappropriate data cleaning has the potential to bias study outcomes [53]; providing the reasoning for removing data points enables the distinction to be made between responsible data cleaning and data manipulation.”
From Reporting animal research: Explanation and elaboration for the ARRIVE guidelines 2.0 (2020) · cites this paper as [53]
The ALS Therapy Development Institute rigorously retested more than 100 drug candidates in the SOD1 mouse model and could not replicate many previously reported preclinical efficacy findings.
“The ALS Therapy Development Institute rigorously retested more than 100 drug candidates in the superoxide dismutase 1 (SOD1) mouse model, and they were unable to replicate many of the previously reported preclinical efficacy findings85.”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [85]
Lack of reproducibility in preclinical models and lack of translation from SOD1 mouse efficacy to ALS patients explain why drug profiling in the SOD1 mouse poorly translated into clinical efficacy.
“Lack of reproducibility in preclinical models and lack of translation from preclinical efficacy for drugs tested in the SOD1 mouse model to patients with ALS explain why the profiling of drug candidates in the SOD1 mouse model poorly translated into clinical efficacy85.”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [85]
Reproducibility of preclinical results has been problematic in amyotrophic lateral sclerosis.
“The reproducibility of preclinical results has been problematic in the field of amyotrophic lateral sclerosis (ALS).”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [85]
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- Authors
- Scott, S., Kranz, J. E., Cole, J., Lincecum, J. M., Thompson, K., Kelly, N., Bostrom, A., Theodoss, J., Al‐Nakhala, B. M., Vieira, F. G., Ramasubbu, J., & Heywood, J. A.
- Affiliations
- Amyotrophic Lateral Sclerosis Therapy Development Institute (US)
- University of California, San Francisco (US)
- Corresponding author
- Scott, Sean
- Venue
- Amyotrophic Lateral Sclerosis
- Publisher
- Informa UK Limited
- Published
- 2008-01
- Volume
- 9
- Issue
- 1
- Pages
- 4-15
- ISSN
- 1471-180X (ISSN-L)
- 1748-2968
- OpenAlex
- W2087656730
- Cited by
- 504
- References
- 40
- Citations by year
- 2026: 10 · 2025: 15 · 2024: 20 · 2023: 11 · 2022: 21 · 2021: 22 · 2020: 33 · 2019: 30 · 2018: 27 · 2017: 34 · 2016: 37 · 2015: 40 · 2014: 47 · 2013: 35 · 2012: 30
- FWCI
- 18.86
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Amyotrophic Lateral Sclerosis (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Genetics › Neurogenetic and Muscular Disorders Research
- Keywords
- SOD1 G93A mice, familial ALS, research design, statistical power, confounding variables, survival analysis, drug efficacy, riluzole, minocycline, ceftriaxone, thalidomide, celecoxib, 4-phenylbutyric acid, creatine, statistical noise, reproducibility
- MeSH terms
- Superoxide Dismutase-1, Amyotrophic Lateral Sclerosis, Animals, Disease Models, Animal, Female, Male, Mice, Transgenic, Research Design, Species Specificity, Superoxide Dismutase, Survival Analysis, Mice
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