Design, power, and interpretation of studies in the standard murine model of ALS

Autor:	Nancy Kelly, John M. Lincecum, James Heywood, Jeyanthi Ramasubbu, Alan Bostrom, Fernando G. Vieira, Janice E. Kranz, Sean Scott, Bashar M. Al‐Nakhala, Jill Theodoss, Jeff Cole, Kenneth Thompson
Rok vydání:	2008
Předmět:	Male Transgene SOD1 Mice Transgenic Mice Superoxide Dismutase-1 Species Specificity Medicine Animals Amyotrophic lateral sclerosis Mutated protein Genetics business.industry Superoxide Dismutase Amyotrophic Lateral Sclerosis General Medicine medicine.disease Survival Analysis Riluzole Disease Models Animal Neurology Murine model Research Design Female Neurology (clinical) business Neuroscience medicine.drug
Zdroj:	Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases. 9(1)
ISSN:	1471-180X
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d574462c5a43dd63d38f1e61c65069b8 https://pubmed.ncbi.nlm.nih.gov/18273714 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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