Preclinical research into amyotrophic lateral sclerosis : a comparison of established and novel techniques and models

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressing degenerative disease which leads to muscular atrophy via the degeneration of both upper and lower motor neurons with the majority of patient death resulting from respiratory failure. The majority (~90-95%) of ALS cases are non-inherited or sporadic ALS (sALS), with the remaining 5-10% inherited or familial ALS (fALS). ALS presents with a broad heterogeneity, as age of onset, symptoms and rate of disease progression are highly variable among patients, and this is further compounded by recent findings that ALS sits on a spectrum of diseases together with frontotemporal dementia (FTD) and being referred to as ALS-frontotemporal spectrum disorder. Only one drug is currently widely approved for the treatment of ALS (Riluzole) with many other drug candidates failing in clinical trials after seeing success in preclinical animal models for the disease. One of the factors potentially contributing to the discrepancy between outcomes of preclinical testing and clinical trials for a new treatment candidate is the impact of the laboratory environment on ALS mouse models. The work presented in this thesis shows that mouse handling and mouse cage systems used for ALS transgenic mouse models can impact on anxiety and behaviours such as fear-associated learning and sensorimotor gating. These findings can have implications for the validity of these mouse models for research into human diseases as well as the particular experimental strategy chosen. Additionally, my work provides new insights into ALS-relevant gene-gene interactions that are capable of influencing behavioural phenotypes in established mouse models for the disease. Finally, I provide evidence that administration of 50mg/kg CBD as a novel treatment is not effective in female SOD1G93A mice with the chosen parameters. Ultimately, laboratory environments / procedures should always be considered as potential test confounders and therefore be specifically selected for any preclinical research project. It is important to realise that these factors can impose on the validity of mouse models for ALS - even small alterations to the onset or progression of disease-relevant phenotypes can impact on experimental outcomes and thereby influence the translational potential of e.g. novel treatments in diseases with narrow treatment windows such as ALS.

Date of Award	2021
Original language	English