Drug resistance confounding prion therapeutics
David B. Berrya, Duo Lua,1, Michal Gevaa,2, Joel C. Wattsa,b, Sumita Bhardwaja, Abby Oehlerc, Adam R. Renslod, Stephen J. DeArmonda,c, Stanley B. Prusinera,b,3, and Kurt Gilesa,b Author Affiliations
aInstitute for Neurodegenerative Diseases, Departments of bNeurology and cPathology, and dSmall Molecule Discovery Center and Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94143 Contributed by Stanley B. Prusiner, September 11, 2013 (sent for review August 16, 2013)
Significance As people live longer, the prevalence and economic impact of neurodegenerative diseases rise. No cures or effective treatments exist for any of these fatal disorders, so identifying potential therapeutics that extend survival in animal models is vital. Many neurodegenerative illnesses have been shown to be caused by the accumulation of self-propagating misfolded proteins—the hallmark of prion diseases. We report the efficacy of 2-aminothiazoles, which were identified in cell-based screens as antiprion compounds, in extending the lives of prion-infected animals. Efficacy was limited by the development of drug-resistant prions, which is likely to have important implications for creating therapeutics in many different neurodegenerative diseases.
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.
drug discovery antiprion therapeutics bioluminescence imaging Footnotes ↵1Present address: Dana–Farber Cancer Institute, Boston, MA 02215.
↵2Present address: Teva Pharmaceuticals, Netanya 49131, Israel.
↵3To whom correspondence should be addressed. E-mail: firstname.lastname@example.org. Author contributions: D.B.B., D.L., M.G., S.B.P., and K.G. designed research; D.B.B., D.L., M.G., J.C.W., S.B., A.O., and S.J.D. performed research; A.R.R. contributed new reagents/analytic tools; D.B.B., S.J.D., S.B.P., and K.G. analyzed data; and D.B.B., S.J.D., S.B.P., and K.G. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1317164110/-/DCSupplemental.
December 13, 2012
The rise and fall of pentosan polysulfate in prion disease
Friday, October 11, 2013
Quinacrine treatment trial for sporadic Creutzfeldt-Jakob disease
Monday, October 14, 2013
Researchers estimate one in 2,000 people in the UK carry variant CJD proteins