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Project grant

Refinement of therapeutic intervention in a mouse model of amyotrophic lateral sclerosis

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At a glance

Completed
Award date
May 2008 - May 2011
Grant amount
£164,730
Principal investigator
Dr Andrew Grierson
Institute
University of Sheffield

R

  • Refinement
Read the abstract
View the grant profile on GtR

Application abstract

The objective of this project is to minimise the number of mice undergoing procedures of substantial severity when testing therapeutic strategies in mouse models of amyotrophic lateral sclerosis (ALS). We will use two complementary approaches to achieve this: (i) Application of new in vivo molecular assays. Using in vitro models we have identified novel therapeutic agents that can reduce oxidative damage or restore axonal transport in the presence of mutant SOD1. These are two of the key pathogenic processes in ALS. We have designed an in vivo molecular approach to test the efficacy of these drugs in motor neurons in G93A mice. This has the potential to identify the drugs that should be taken forwards into formal clinical testing in G93A mice at an early stage and in a small number of animals. Importantly, it also identifies drugs that are ineffective in vivo, and so leads to an overall reduction in the number of mice used for research. (ii) Determining clinical benefit in ALS mouse models prior to the onset of substantial severity. One widely used measure of therapeutic effect in ALS mouse studies is lifespan extension. However this requires cohorts of mice to undergo scientific procedures of substantial severity. We believe that robust and disease-relevant behavioural and pathological markers of early motor neuron dysfunction can be used to refine this approach. We will test this hypothesis by comparing the effects of therapeutic agents in our short model with historical published data on lifespan extension.

We will also investigate the effects of antioxidants and axonal transport drugs identified in the first part of this study. One application of this work is the development of novel methods for screening for efficacy of drugs in vivo prior to testing their clinical benefits. We hope that the overall reduction in numbers of animals, as well as laboratory time and expense, will demonstrate to our scientific peers the added value of this approach. We will also demonstrate the use of a refined mouse model of ALS, which will potentially be taken up across many international laboratories. We also hope that the results obtained in this project will lead to the identification of novel therapeutic approaches in ALS targeting oxidative damage and axonal transport.

Publications

  1. Bennett EJ et al. (2014). Early detection of motor dysfunction in the SOD1G93A mouse model of Amyotrophic Lateral Sclerosis (ALS) using home cage running wheels. PLoS ONE 9(9):e107918. doi: 10.1371/journal.pone.0107918
  2. Mead RJ et al. (2011). Optimised and Rapid Pre-clinical Screening in the SOD1G93A Transgenic Mouse Model of Amyotrophic Lateral Sclerosis (ALS). PLoS ONE 6:e23244. doi: 10.1371/journal.pone.0023244
  3. Grierson AJ et al. (2011). The role of mitochondria in the pathogenesis of Amyotrophic Lateral Sclerosis. Neuropathology and Applied Neurobiology 37(4):336-52. doi: 10.1111/j.1365-2990.2011.01166.x 
  4. Grierson AJ et al. (2009). Direct evidence for axonal transport defects in a novel mouse model of mutant spastin-induced hereditary spastic paraplegia (HSP) and human HSP patients. Journal of Neurochemistry 110:34-44. doi: 10.1111/j.1471-4159.2009.06104.x