Investigating the effects of xyloside and TD874 on chondroitin sulfate proteoglycan levels in spinal cord injured rats
Abstract
Chondroitin sulfate proteoglycans (CSPGs) inhibit of neural regeneration in the central nervous system after injury. Our laboratory identified SRY-BOX Transcription Factor 9 (SOX9) as a key driver of genes involved in CSPG synthesis. Conditional SOX9 ablation reduces CSPG levels and improves locomotor recovery post-spinal cord injury (SCI) in mice by enhancing axon sprouting. This thesis identifies and evaluates novel small molecule inhibitors of SOX9, focusing on the lead compound TD874. Through in silico screening and in vitro assays, we identified several SOX9 inhibitors and assessed their effects on SOX9 target gene expression and metabolic stability. TD874 emerged as the most promising candidate, significantly inhibiting SOX9 target genes and showing favourable pharmacokinetic properties in vivo. TD874 treatment markedly reduced SOX9 target gene expression in the injured spinal cord, highlighting its potential as a therapeutic agent for SCI. Future studies will optimize TD874 formulations, and evaluate its pharmacodynamics and efficacy.