Professor Simon Lovestone
King's College London
Intelligence led drug discovery for the amyloid cascade
Drug discovery in Alzheimers disease has focused on finding compounds to reduce the generation or increase the clearance of amyloid. However, other targets are almost certainly needed if we are to find a successful therapy. We have built on our work of the past ten years or more that has culminated in an understanding of the cascade pathway that links the amyloid that forms plaques with the tangles that cause neurotoxicity to generate a novel drug discovery programme. We have done this using the connectivity map; an informatics driven process that is beginning to transform drug discovery in other fields such as that of cancer. Our aim is first to use the new release of data from the connectivity map to confirm and extend our findings, second to prioritise hit compounds though in vitro screens and third to deliver further evidence for potential utility through animal studies. Our methodological approach will be to use our comparative gene expression data from experimental studies in proven cell models to interrogate the new release connectivity map. Then we will use our established secondary screens in neurons to establish compound effects on phenotypes relevant to AD including tau phosphorylation and neuronal toxicity. Finally we will use an acute amyloid injection model in the adult rat to determine compound efficacy to prevent AD pathology in vivo. The outcomes will be a portfolio of data for a set of compounds sufficient to progress the critical path for therapeutics for disease modification against AD in man.