Gray, AL; (2015) Investigation of disease progression, outcome measures and therapeutic intervention in a mouse model of spinal and bulbar muscular atrophy (SBMA). Doctoral thesis , UCL (University College London).

Abstract

Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy’s Disease, is a late-onset, X-linked, progressive neuromuscular disease, which predominantly affects males. There is currently no effective treatment for this disease. SBMA is caused by a CAG repeat expansion in the gene that encodes the androgen receptor (AR) protein. Disease manifestation is androgen dependent and results at least in part from a toxic gain of AR function. AR100 transgenic mice which carry 100 CAG repeats in the human AR gene develop lower motor neuron degeneration with accompanying progressive neuromuscular phenotype, which closely recapitulates the human disease. In this Thesis, a longitudinal physiological and histological characterisation of disease progression in AR100 mice was conducted. The experiments described show that the disease first manifests in skeletal muscle, prior to any motor neuron degeneration, which only occurs in late stage disease. These findings challenge the prevailing view that SBMA is primarily a motor neuron disorder, and suggest that muscle-targeted therapeutics may be effective in SBMA. The effects of a potential therapeutic agent on disease progression in AR100 mice were examined. SBMA is a hereditary disease in which individuals carrying the mutation can be genetically identified prior to symptom onset, allowing for commencement of early treatment. Therefore AR100 mice were treated with arimoclomol, a pharmacological co-inducer of the heat shock response (HSR), from the point at which motor deficits first manifest. Treatment of mice with arimoclomol had no beneficial effect on disease. These results are surprising, as treatment of AR100 mice with arimoclomol from a post-symptomatic time point has previously been shown to modify disease progression. The final Results Chapter describes the development of MRI to monitor disease progression in AR100 mice and evaluates its potential as an outcome measure in preclinical trials, focusing on imaging of lower hindlimb muscles. This technique is directly translatable to the clinical setting and may provide a more direct transition between preclinical trials and patients.

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