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Therapeutic Trial o...
Therapeutic Trial of anle138b in Mouse Models of Genetic Prion Disease
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- Vallabh, Sonia M. (author)
- Broad Inst & Harvard, MA 02142 USA; Massachusetts Gen Hosp, MA 02114 USA; Massachusetts Gen Hosp, MA 02114 USA; Harvard Med Sch, MA 02115 USA; Pr Alliance, MA 02139 USA
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- Zou, Dan (author)
- Montana Vet Diagnost Lab, MT USA
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- Pitstick, Rose (author)
- McLaughlin Res Inst, MT 59405 USA
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- OMoore, Jill (author)
- McLaughlin Res Inst, MT 59405 USA
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- Peters, Janet (author)
- McLaughlin Res Inst, MT 59405 USA
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- Silvius, Derek (author)
- McLaughlin Res Inst, MT 59405 USA
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- Kriz, Jasna (author)
- Univ Laval, Canada
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- Jackson, Walker (author)
- Linköpings universitet,Avdelningen för neurobiologi,Medicinska fakulteten
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- Carlson, George A. (author)
- Univ Calif San Francisco, CA USA
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- Minikel, Eric Vallabh (author)
- Broad Inst & Harvard, MA 02142 USA; Massachusetts Gen Hosp, MA 02114 USA; Massachusetts Gen Hosp, MA 02114 USA; Harvard Med Sch, MA 02115 USA; Pr Alliance, MA 02139 USA
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- Cabin, Deborah E. (author)
- McLaughlin Res Inst, MT 59405 USA
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(creator_code:org_t)
- AMER SOC MICROBIOLOGY, 2023
- 2023
- English.
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In: Journal of Virology. - : AMER SOC MICROBIOLOGY. - 0022-538X .- 1098-5514. ; 97:2
- Related links:
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Abstract
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- There is an urgent need to develop drugs for prion disease, a currently untreatable neurodegenerative disease. In this effort, there is a debate over which animal models can best support a drug development program. Phenotypic screening has yielded small-molecule inhibitors of prion replication that are effective in vivo against certain prion strains but not others. Here, we sought to test the small molecule anle138b in multiple mouse models of prion disease. In mice inoculated with the RML strain of prions, anle138b doubled survival and durably suppressed astrogliosis measured by live-animal bioluminescence imaging. In knock-in mouse models of the D178N and E200K mutations that cause genetic prion disease, however, we were unable to identify a clear, quantifiable disease endpoint against which to measure therapeutic efficacy. Among untreated animals, the mutations did not impact overall survival, and bioluminescence remained low out to >20 months of age. Vacuolization and PrP deposition were observed in some brain regions in a subset of mutant animals but appeared to be unable to carry the weight of a primary endpoint in a therapeutic study. We conclude that not all animal models of prion disease are suited to well-powered therapeutic efficacy studies, and care should be taken in choosing the models that will support drug development programs.IMPORTANCE There is an urgent need to develop drugs for prion disease, a currently untreatable neurodegenerative disease. In this effort, there is a debate over which animal models can best support a drug development program. While the study of prion disease benefits from excellent animal models because prions naturally afflict many different mammals, different models have different capabilities and limitations. Here, we conducted a therapeutic efficacy study of the drug candidate anle138b in mouse models with two of the most common mutations that cause genetic prion disease. In a more typical model where prions are injected directly into the brain, we found anle138b to be effective. In the genetic models, however, the animals never reached a clear, measurable point of disease onset. We conclude that not all prion disease animal models are ideally suited to drug efficacy studies, and well-defined, quantitative disease metrics should be a priority.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)
Keyword
- drug development; neurodegeneration; prion
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Vallabh, Sonia M ...
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Zou, Dan
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Pitstick, Rose
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OMoore, Jill
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Peters, Janet
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Silvius, Derek
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show more...
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Kriz, Jasna
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Jackson, Walker
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Carlson, George ...
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Minikel, Eric Va ...
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Cabin, Deborah E ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Medical Biotechn ...
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and Medical Biotechn ...
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Journal of Virol ...
- By the university
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Linköping University