title: Drug resistance confounding prion therapeutics.
abstract: There is not a single pharmaceutical that halts or even slows any neurodegenerative disease. Mounting evidence shows that prions cause many neurodegenerative diseases, and arguably, scrapie and Creutzfeldt-Jakob disease prions represent the best therapeutic targets. We report here that the previously identified 2-aminothiazoles IND24 and IND81 doubled the survival times of scrapie-infected, wild-type mice. However, mice infected with Rocky Mountain Laboratory (RML) prions, a scrapie-derived strain, and treated with IND24 eventually exhibited neurological dysfunction and died. We serially passaged their brain homogenates in mice and cultured cells. We found that the prion strain isolated from IND24-treated mice, designated RML[IND24], emerged during a single passage in treated mice. Although RML prions infect both the N2a and CAD5 cell lines, RML[IND24] prions could only infect CAD5 cells. When passaged in CAD5 cells, the prions remained resistant to high concentrations of IND24. However, one passage of RML[IND24] prions in untreated mice restored susceptibility to IND24 in CAD5 cells. Although IND24 treatment extended the lives of mice propagating different prion strains, including RML, another scrapie-derived prion strain ME7, and chronic wasting disease, it was ineffective in slowing propagation of Creutzfeldt-Jakob disease prions in transgenic mice. Our studies demonstrate that prion strains can acquire resistance upon exposure to IND24 that is lost upon passage in mice in the absence of IND24. These data suggest that monotherapy can select for resistance, thus intermittent therapy with mixtures of antiprion compounds may be required to slow or stop neurodegeneration.
authors.affiliation: Institute 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.
authors.forename: David B
authors.initials: DB
authors.lastname: Berry
authors.forename: Duo
authors.initials: D
authors.lastname: Lu
authors.forename: Michal
authors.initials: M
authors.lastname: Geva
authors.forename: Joel C
authors.initials: JC
authors.lastname: Watts
authors.forename: Sumita
authors.initials: S
authors.lastname: Bhardwaj
authors.forename: Abby
authors.initials: A
authors.lastname: Oehler
authors.forename: Adam R
authors.initials: AR
authors.lastname: Renslo
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: DeArmond
authors.forename: Stanley B
authors.initials: SB
authors.lastname: Prusiner
authors.forename: Kurt
authors.initials: K
authors.lastname: Giles
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D055808:Drug Discovery; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D006801:Humans; D015151:Immunoblotting; D008163:Luminescent Measurements; D051379:Mice; D019636:Neurodegenerative Diseases / Q000188:drug therapy*; D011328:Prions / Q000037:antagonists & inhibitors* / Q000235:genetics; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D017931:DNA Primers; D011328:Prions; D013844:Thiazoles; C004483:2-aminothiazole
keywords: antiprion therapeutics; bioluminescence imaging; drug discovery