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Updated: May 6, 2026
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Real-time Quaking-induced Conversion Assay for Detection of CWD Prions in Fecal Material
Published on: September 29, 2017
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Drug resistance confounding prion therapeutics
David B Berry1, Duo Lu, Michal Geva
1Institute for Neurodegenerative Diseases, Departments of Neurology and Pathology, and Small Molecule Discovery Center and Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94143.
Summary
The 2-aminothiazole IND24 extended survival in mice with prion diseases but also selected for drug-resistant prion strains. Intermittent therapy with multiple compounds may be needed to effectively treat neurodegenerative diseases.
Area of Science:
- Neurodegenerative diseases
- Prion biology
- Drug discovery
Background:
- No current pharmaceuticals halt or slow neurodegenerative diseases.
- Prions are implicated in many neurodegenerative diseases, making them key therapeutic targets.
- Scrapie and Creutzfeldt-Jakob disease prions are of particular interest.
Purpose of the Study:
- To evaluate the efficacy of 2-aminothiazoles IND24 and IND81 in treating prion diseases.
- To investigate the emergence of prion resistance to therapeutic agents.
- To explore strategies for overcoming drug resistance in prion disease treatment.
Main Methods:
- Treatment of scrapie-infected mice with IND24 and IND81.
- Serial passage of prions in mice and cultured cells to isolate and characterize resistant strains.
- Testing prion infectivity and drug susceptibility in cell lines (N2a, CAD5).
Main Results:
- IND24 and IND81 doubled survival times in scrapie-infected mice.
- A new prion strain, RML[IND24], emerged in IND24-treated mice, exhibiting resistance to IND24.
- IND24 was effective against some prion strains (RML, ME7, CWD) but not Creutzfeldt-Jakob disease prions.
- Drug resistance acquired in vitro was lost upon passage in untreated mice.
Conclusions:
- Monotherapy with antiprion compounds like IND24 can select for resistant prion strains.
- Intermittent or combination therapy using mixtures of antiprion compounds may be necessary to effectively manage prion diseases.
- Understanding prion strain adaptation is crucial for developing sustainable therapeutic strategies.
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