Integrated in vitro and in vivo testing of drugs in prion diseases: screening, development and mechanisms of novel therapeutics

Projektinformationen

STOPTSES

ID Finanzhilfevereinbarung: QLK3-CT-2001-00283

Projekt abgeschlossen

Startdatum 1 Januar 2002

Enddatum 31 Dezember 2004

Finanziert unter

• Specific Programme for research, technological development and demonstration on "Quality of life and management of living resources", 1998-2002

Gesamtkosten

€ 2 532 114,00

EU-Beitrag

€ 1 755 292,00

Koordiniert durch

UNIVERSITY OF GLASGOW
United Kingdom

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Leistungen

Assessment of quinacrine as potential therapeutic for prion diseases

Quinacrine was proposed as a potential therapeutic agent for prion diseases. This drug was selected in a defined programme of screening tests starting with cell-free in vitro tests for its anti-fibrillogenic activity against PrP peptides and extending to in vivo models. The results showed favourable effects in the initial cell-free system but non-significant effects in tissue culture models of prion disease and no significant effects in defined animal models. These results accurately predicted the outcome of subsequent clinical trials in man.

Cell-free assay for screening drugs that disrupt protein fibril formation

Pepscan produces defined peptides on a commercial basis for use by the scientific research community. In this project, defined PrP peptides were developed and an in vitro, cell-free screening system using these peptides to test the potential efficacy of anti-prion drugs was also developed. This work is published in peer-review journals.

Model for PrP fibril formation

The nature of the infectious agent of prion disease remains to be fully defined. This model was developed to account for the known physical properties of the prion protein and its behaviour in NMR, MS, CD and other physical chemistry testing modalities. The model can now be used to provide testable hypotheses on the nature of strain variation of a protein-only infectious agent.

Defining effects of amyloid-associated proteins on prion pathogenesis

Studies of the pathology of prion diseases and Alzheimer's disease identified several molecules that co-located with amyloid (PrP or A-beta) deposition. These molecules include elements of the complement cascade, serum amyloid P, ApoJ. Their potenial modifying effects on prion disease pathogenesis and capacity to interfere with potential anti-prion therapeutics was investigated.

in vitro assessment of cholesterol-reducing drugs as potential prion therapeutic

Most investigations of anti-prion drugs focus on the physical nature of prions and drugs that disrupt the fibrillar structure of the infectious protein. The approach of anti-cholesterol drugs in prion therapeutics is an alternative approach seeking to disrupt the cellular trafficking, processing and formation of prions. Efficacy has been demonstrated in tissue culture models and infected cell lines; this is now being translated to in vivo models.