Title: Using targeted repurposing to discover novel neuroprotective treatments for Parkinson’s disease

Abstract:

Parkinson’s disease is a neurodegenerative disorder accompanied by motor symptoms which result from degeneration of dopaminergic neurons in the nigrostriatal pathway. While current treatments aimed at replenishing lost dopamine transmission help restore movement, these treatments do not combat the ongoing neurodegeneration so motor symptoms continue to progressively worsen. There currently remains no neuroprotective treatment for use in Parkinson’s disease. We previously reported that direct intracerbral infusion of fibroblast growth factor 20 (FGF20), a neurotrophic factor which supports dopaminergic neurones, was neuroprotective in the 6-hydroxydopamine (6-OHDA) lesion rat model of Parkinson's disease. Given the difficulties associated with growth factor infusion in patients, we looked for an alternative way to boost endogenous FGF20 levels to achieve this neuroprotection. Specifically, we adopted a targeted repurposing approach to screen for candidate FDA-approved drugs with potential to enhance endogenous FGF20 production. In silico interrogation of the Broad Institute’s Connectivity Map database revealed 16 candidate drugs that increased FGF20 transcription, were blood brain barrier penetrant and not contra-indicated for use in Parkinson’s disease. Through in-vitro screening, 4 drugs were found to significantly elevate FGF20 protein levels, as determined by ELISA, in both MCF-7 cells and ventral mesencephalic primary cultures. Of these, salbutamol and triflusal significantly elevated FGF20 levels in the nigrostriatal tract in rats treated orally for 7 days and afforded a modest but significant protection against against nigral cell loss in the 6-OHDA-lesion rat. These daa support targeted repurposing as a powerful strategy to help the timely identification of neuroprotective treatments for Parkinson’s disease.  

Biography:

Susan Duty completed her PhD from the University of Manchester and undertook postdoctoral studies at the Universities of Sydney and Manchester before achieving an academic appointment at King’s College London in 1995. Susan is now Head of Department of Pharmacology & Therapeutics and Primary Investigator in the Wolfson Centre for Age-Related Diseases. She has published more than 49 papers and is a long-standing committee member of the British Pharmacological Society. Research in Susan’s laboratory is currently funded by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie Grant Agreement No 764860, Parkinson’s UK and Innovate UK.