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Title: Preclinical testing of potential therapeutics for Amyotrophic Lateral Sclerosis
Author: Kaneb, Hannah Marlene Jostock
ISNI:       0000 0004 2724 4275
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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Amyotrophic Lateral Sclerosis (ALS) is a fatal neurological disorder caused by the selective degeneration of upper and lower motor neurons, for which there are currently no effective treatments. 10% of ALS cases are familial, of which 15-20% are caused by mutations in the copper/zinc superoxide dismutase gene (SOD1). The primary triggers for motor neuron degeneration in ALS are unknown, but research in patients and SOD1 models has revealed several mechanisms which may contribute. These include: oxidative stress, mitochondrial abnormalities, inflammation and protein aggregation. This study focused on the pre-clinical testing of two-potential therapeutics for ALS in the SOD1G93A murine model of the disease; metformin, an anti type II diabetes drug which has been shown to have anti-inflammatory and anti-oxidant properties and the ability to bring about mitochondrial biogenesis, and trehalose, a chemical chaperone and enhancer of autophagy, which has been shown to reduce protein misfolding and aggregation. We performed an initial study in which oral metformin administration from 35 days increased the survival of functional motor units in the hindlimbs of male and female SOD1G93A mice at 100 days. Consequently we performed a dose-response survival study in SOD1G93A mice with longitudinal monitoring of weight and neurological score. Surprisingly, metformin had no effect in males and brought about a dose-dependent negative effect on the onset of neurological symptoms and on disease progression in females. We hypothesise this negative effect may have resulted from a metformin-induced reduction in oestrogen production. Oral trehalose administration was tested using the same survival study format. Although trehalose treatment brought about a dose-dependent delay in weight-loss in males, it had no effect on the onset or progression of neurological symptoms or on survival in male or female mice. We conclude that neither metformin nor trehalose represent strong candidates for clinical trial in ALS patients when administered orally.
Supervisor: Wells, Dominic ; de Belleroche, Jackie Sponsor: Medical Research Council ; Association Française contre les Myopathies
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral