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.
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.
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: stanley@ind.ucsf.edu.
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
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Researchers estimate one in 2,000 people in the UK carry variant CJD proteins
http://creutzfeldt-jakob-disease.blogspot.com/2013/10/researchers-estimate-one-in-2000-people.html
http://creutzfeldt-jakob-disease.blogspot.com/2013/10/researchers-estimate-one-in-2000-people.html
*Exodus 9:1-7
TSS
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