Disparity of outcomes: the limits of modeling amyotrophic lateral sclerosis in murine models and translating results clinically

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastatingly progressive neurodegenerative disorder with multiple underlying etiological factors contributing to disease pathogenesis. Despite intensive research efforts and therapeutic development, disease presentation in ALS remains largely intractable to intervention. To date, the most common rodent model used in preclinical drug development accounts for a small proportion of the affected patient population and is predicated upon the significant overexpression of a mutant form of the human antioxidant protein, superoxide dismutase 1 (mSOD1). After more than 50 clinical trials, there is an alarming paucity of positive outcomes at the clinical level of ALS therapeutics with strong supporting pre-clinical data in mSOD1 models. Potential reasons for the negative clinical results are multifactorial in nature and include an overly reductionist model system that is heavily influenced by individual transgene level variation, as well as attempting to widely apply findings derived from a model of specific genetic causality to a patient population where the majority of cases are of unknown etiology. With such a tremendous disease burden and a lack of therapeutic options, it is critical that the research community re-evaluate the dependence on mSOD1 pre-clinical models as the gold standard prior to translating findings at the clinical level. Here we briefly review both the clinical and pre-clinical findings of select therapeutics, discuss the limitations of pre-clinical mSOD1 models, and suggest future stratagems that could aid in the clinical translation of efficacious therapeutic agents.

Effects of cannabinoids in Amyotrophic Lateral Sclerosis (ALS) murine models: a systematic review and meta‐analysis

“…It is also important to consider that only the SOD1-G93A mouse model was used in the studies included in this metaanalysis of survival time. There have been difficulties translating preclinical outcomes from the SOD1-G93A mice model to humans (Zwiegers and Shaw 2015). It is also compounded by the fact that SOD1 mutation only account for < 5% of ALS cases (Zwiegers and Shaw 2015).…”

“…There have been difficulties translating preclinical outcomes from the SOD1-G93A mice model to humans (Zwiegers and Shaw 2015). It is also compounded by the fact that SOD1 mutation only account for < 5% of ALS cases (Zwiegers and Shaw 2015).…”