Roberts, Martha Jane; (2023) Novel therapeutic strategies in Spinal and Bulbar Muscular Atrophy. Doctoral thesis (Ph.D), UCL (University College London).

Text Final Thesis_Martha Roberts.pdf - Accepted Version Access restricted to UCL open access staff until 1 January 2025. Download (16MB)

Abstract

Spinal and Bulbar Muscular Atrophy (SBMA), also known as Kennedy’s Disease, is an adult-onset degenerative neuromuscular disease caused by a polyglutamine (polyQ) encoding CAG repeat expansion in the androgen receptor gene (AR). This results in lower and bulbar motor neuron loss and atrophy of limb, facial and bulbar muscles. Recent research, including work from our lab, has suggested that SBMA pathology may initially manifest in skeletal muscle and that muscle may be a viable and accessible target for therapeutic intervention in SBMA. In this Thesis, RNA-sequencing was performed to identify disease pathways which may underly the muscle atrophy in tibialis anterior (TA) muscle of the AR100 mouse model of SBMA, which carry 100 pathogenic CAG repeats in the human AR gene. Pathway analysis of differentially expressed genes highlighted multiple key pathways with involvement in: (i) muscle regeneration, (ii) muscle contraction and (iii) muscle structure. Dysfunction in myogenesis was seen as early as 3-months in the TA of the AR100 mouse model, with a significant decrease in markers of muscle regeneration, before symptoms such as muscle atrophy and loss of muscle force manifest. We identified galectin-1 which may be beneficial in SBMA as it has also been shown previously to be protective in mouse models of other neuromuscular diseases. To test the potential of galectins to ameliorate dysfunction in myogenesis, in vitro models of SBMA muscle were characterised to examine their suitability as potential cellular models of SBMA, including an AR100Q C2C12 cell line as well as primary myotube explant cultures from SBMA AR100 adult mice. Treatment of differentiating AR100Q C2C12 cells with human recombinant galectin-1 increased myosin heavy chain protein levels and improved nuclear fusion index as well as myotube area. To test whether the beneficial effects of galectin-1 observed in vitro translated into SBMA mice in vivo, AAV vectors were optimised to deliver transgenes to skeletal muscle in wildtype mice. MyoAAV was more effective at targeting TA muscle than AAV8 and AAV9. This will allow potential treatments for muscle dysfunction and atrophy in SBMA to be tested in AR100 mice in upcoming experiments. This study identifies several crucial and important pathways involved in muscle dysfunction in the SBMA AR100 mouse model, which may be key novel therapeutic targets for SBMA.

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