Most of the UK population has been exposed to BSE prions through contaminated food, and no one knows how many people will eventually develop the fatal brain disease variant CJD. This matters because prion diseases are always fatal, and there is currently no treatment. The central problem is that a normal brain protein, PrPc, can be converted into a misfolded, infectious form that accumulates and destroys brain tissue. The researchers have identified a strategy: find small molecules that lock PrPc into its healthy shape, preventing it from being recruited into the disease process. If prion replication can be slowed below the brain's natural clearance rate, infection could be cured. The researchers have secured unprecedented access to GlaxoSmithKline’s massive compound library for high-throughput screening. If this collaboration succeeds, it could produce the first drug capable of treating or preventing human prion infection. Given that prion incubation periods can span decades, a treatment developed now could intervene before the majority of those silently infected begin showing symptoms. The impact would be direct: saving lives from a currently untreatable disease, and reducing the risk of secondary transmission through medical procedures and blood supplies.
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BackgroundThe majority of the UK population have potentially been exposed to BSE prions, the causative agent of variant CJD. The number infected, eventual epidemic size and secondary transmission dynamics are unknown. The central molecular event in prion replication is the conversion of a neuronal glycoprotein (PrPc) into a conformational isomer that accumulates as aggregated material (PrPs) in a self-propagating process. The availability of PrPc substrate is an absolute requirement for prion propagation and pathogenesis. We propose to identify and characterise novel small molecules that stabilise the native conformation of PrPc and inhibit its ability to be recruited into PrP$0. Inhibition of prion replicationkinetics to below those of natural clearance mechanisms should cure prion infection. The MRC Unit has developed an effective collaboration with GlaxoSmithKline R&D Ltd, performed successful pilot stage studies and produced further experimental underpinning of our therapeutic strategy. We now aim toexpand this productive collaboration to allow for the full-scale application of high-throughput screening methods to identify Lead compounds, their chemical optimisation, and proof of principle assessment in cellular and animal models to the stage where human clinical trials can be considered for prion disease.Access to the GSK compound collection, one of the largest in existence in the pharmaceutical industry, is highly regulated and its use within this type of collaboration is without precedent. The combined experience, expertise and resources now marshalled within the two organisations will allow the realisticdiscovery of practical drums to treat and prevent human prion infection.AimsHISTORIC PROJECT - Entire abstract transferred from the previous database into the [Scientific summary background] field of this database.Plan of InvestigationHISTORIC PROJECT - Entire abstract transferred from the previous database into the [Scientific summary background] field of this database.Potential ImpactHISTORIC PROJECT - Entire abstract transferred from the previous database into the [Scientific summary background] field of this database.Policy RelevanceThe BSE epidemic in cattle has been a disaster for UK and EU agriculture, costing the taxpayer £billions, and also damaging public confidence in food production and in Government risk assessment and risk management. Even more importantly, there is now a consensus that BSE prions are a human pathogen,BSE-like prions being the causative agent of the novel human prion disease, variant CJD. It is probable that the majority of the UK population and a lesser proportion of continental European and other populations have been exposed to BSE prions via dietary and other routes. While the number of clinicallyrecognised cases of this fatal neurodegenerative disease, although showing an upward trend, remains small to date, the number of currently infected individuals and the eventual epidemic size are unknown. Human prion disease incubation periods, as evidenced by kuru, may span decades. The risk of secondarytransmission via medical and surgical procedures is also unquantifiable at present, causing major disruption to the blood supply nationally and internationally and concern about the contamination of surgical instruments. The primary importance of TSE therapeutics research has been firmly andrepeatedly emphasised by the UK Government's advisory bodies, official spokespersons and relevant ministers, and the development of an effective treatment for human prion infection is considered a national strategic priority. The long incubation periods of prion disease in humans provides a window ofopportunity to 'get ahead of the curve' and develop such a therapeutic before the majority of those currently infected by BSE prions enter the clinical phase and develop symptoms of the disease.
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