Targeting disease pathways in models of Spinal and Bulbar Muscular Atrophy

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Spinal and Bulbar Muscular Atrophy (SBMA), also known as Kennedy's disease, is an adult-onset slowly progressing degenerative neuromuscular disorder which predominantly affects males. It is caused by a polyglutamine encoding CAG expansion within the androgen receptor (AR) gene. The AR mediates the effect of androgens such as testosterone and functions as a ligand-dependent transcription factor. However, the molecular basis of muscle atrophy and motor neuron degeneration is as yet unknown. Therefore, the aim of this project is to understand the underlying disease mechanisms in the two primary sites of pathology in SBMA, spinal cord motor neurons and skeletal muscle, allowing for therapeutic targeting of these sites. A well characterised mouse model of SBMA, as well as patient derived stem cell (iPSC) will be used in this study. In particular, analysis will be undertaken on our recent RNA-seq data from laser captured motor neurons from spinal cord and hindlimb muscle of SBMA mice, as well as gene expression data from SBMA patient muscle biopsies to establish the disease pathways. This will be followed up by performing RNA-seq from human stem-cell (h-iPSC) derived motor neurons from SBMA patients. The functional consequences of the genes and pathways dysregulated in SBMA mice, patient iPSCs and patient muscle biopsies will be studied in vitro using primary mouse motor neuron and muscle cultures, as well as patient iPSCs, to establish if targeting these pathways may be a viable therapeutic approach for SBMA. We hope that identification of the genes and pathways that underlie SBMA pathogenesis will lead to in vivo testing of drug targets in a pre-clinical trial in SBMA mice to establish if they have any observable effect on disease progression. Furthermore, by testing potential therapies both in vivo and in vitro, as well in two different models of SBMA, one mouse and the other human derived stem cells, identification of viable therapeutic targets will be greatly enhanced.