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Peer-reviewedCC BYPLoS Pathogens

PrP turnover in vivo and the time to effect of prion disease therapeutics

  • Taylor L Corridon1,2
  • Jill O’Moore3,4
  • Alyssa Seerley3,2
  • Daniel A. Sprague1,2
  • Yuan Lian1,5
  • Vanessa Laversenne1,2
  • Briana Noble6,2
  • Nikita G Kamath1,7
  • Fiona E. Serack1,8
  • Abdul Basit Shaikh9,8
  • Brian Erickson10,2
  • Craig R. Braun10,2
11 more authors
  • Kendrick DeSouza-Lenz11,2
  • Michael Howard11,2
  • Nathan Chan11,4
  • Walker S. Jackson12,2
  • Andrew G. Reidenbach1,4
  • Deborah E. Cabin3,13
  • Sonia M. Vallabh14,15,16,1,5
  • Andrea Grindeland Panter3,2
  • Nina Oberbeck17
  • Hien Tran Zhao6
  • Eric Vallabh Minikel14,15,16,1
17 affiliations
  1. 1Program in Brain Health, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
  2. 2Broad Institute of MIT and Harvard
  3. 3Weissman Hood Institute, Great Falls, MT, 59405, USA
  4. 4Weissman Hood Institute
  5. 5Ionis Pharmaceuticals
  6. 6Ionis Pharmaceuticals, Carlsbad, CA, 92010, USA
  7. 7Charles River Laboratories
  8. 8IQ Proteomics
  9. 9Charles River Laboratories, Worcester, MA, 01605, USA
  10. 10IQ Proteomics, Framingham, MA, 01702, USA
  11. 11Comparative Medicine, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
  12. 12Department of Biomedical and Clinical Sciences, Linköping University, Linköping, 581 83, Sweden
  13. 13Gate Bio
  14. 14Department of Neurology, Harvard Medical School, Boston, MA, 02115, USA
  15. 15McCance Center for Brain Health and Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA
  16. 16Prion Alliance, Cambridge, MA, 02139, USA
  17. 17Gate Bio, Brisbane, CA, 94005, USA
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Abstract

PrP lowering is effective against prion disease in animal models and is being tested clinically. Therapies in the current pipeline lower PrP production, leaving pre-existing PrP to be cleared according to its own half-life. We hypothesized that PrP’s half-life may be a rate-limiting factor for the time to effect of PrP-lowering drugs, and one reason why late treatment of prion-infected mice is not as effective as early treatment. Using isotopically labeled diet with targeted mass spectrometry, as well as antisense oligonucleotide treatment followed by timed PrP measurement, we estimate a half-life of 5-6 days for PrP in the brain. PrP turnover is not affected by over-or under-expression. Mouse PrP and human PrP have similar turnover rates measured in wild-type or humanized knock-in mice. CSF PrP appears to mirror brain PrP in real time in rats. PrP in the colon is readily quantifiable and has a half-life just slightly shorter than in brain. An under-expressed pathogenic mutant PrP, corresponding to D178N in humans, exhibits an accelerated turnover rate. Our data may inform the design of both preclinical and clinical studies of PrP-lowering drugs. Author Summary Prion disease is a fatal brain disease caused by misfolding of the prion protein (PrP). Emerging therapies for prion disease seek to reduce the amount of PrP produced in the brain in order to delay onset of disease or slow progression. Mouse studies have shown that if these therapies are initiated too late, their benefit is limited or they may not help at all. Here we measure the half-life of PrP in the mouse brain, and find that it is about 5 days. When drugs are used to lower PrP by cutting up the RNA that encodes PrP, the RNA drops rapidly while the protein lags behind, and does not reach its minimum level until 4 weeks after the drug is dosed. This half-life is about the same regardless of the species of PrP (mouse or human) and whether or not the brain is infected with prions. Cerebrospinal fluid appears to reflect the real-time levels of brain PrP with no appreciable lag. PrP can be measured in colon, which may be useful in animal studies of systemic drugs to lower PrP. PrP turns over more quickly in the presence of a pathogenic genetic variant, the equivalent of the human D178N variant. These findings suggest that clinical trials can monitor PrP in cerebrospinal fluid to look at drug activity, but should plan timepoints far enough post-dose to account for PrP’s rate of turnover, and should focus on patients who will survive long enough to benefit from the drug.

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Cite

BibTeXRIS
BibTeX
@article{corridon2026turnover,
  title = {{PrP turnover in vivo and the time to effect of prion disease therapeutics}},
  author = {Taylor L Corridon and Jill O’Moore and Alyssa Seerley and Daniel A. Sprague and Yuan Lian and Vanessa Laversenne and Briana Noble and Nikita G Kamath and Fiona E. Serack and Abdul Basit Shaikh and Brian Erickson and Craig R. Braun and Kendrick DeSouza-Lenz and Michael Howard and Nathan Chan and Walker S. Jackson and Andrew G. Reidenbach and Deborah E. Cabin and Sonia M. Vallabh and Andrea Grindeland Panter and Nina Oberbeck and Hien Tran Zhao and Eric Vallabh Minikel},
  journal = {PLoS Pathogens},
  year = {2026},
  month = may,
  doi = {10.1371/journal.ppat.1014263},
  url = {https://doi.org/10.1371/journal.ppat.1014263},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - PrP turnover in vivo and the time to effect of prion disease therapeutics
AU  - Taylor L Corridon
AU  - Jill O’Moore
AU  - Alyssa Seerley
AU  - Daniel A. Sprague
AU  - Yuan Lian
AU  - Vanessa Laversenne
AU  - Briana Noble
AU  - Nikita G Kamath
AU  - Fiona E. Serack
AU  - Abdul Basit Shaikh
AU  - Brian Erickson
AU  - Craig R. Braun
AU  - Kendrick DeSouza-Lenz
AU  - Michael Howard
AU  - Nathan Chan
AU  - Walker S. Jackson
AU  - Andrew G. Reidenbach
AU  - Deborah E. Cabin
AU  - Sonia M. Vallabh
AU  - Andrea Grindeland Panter
AU  - Nina Oberbeck
AU  - Hien Tran Zhao
AU  - Eric Vallabh Minikel
PY  - 2026
DA  - 2026/05/26
JO  - PLoS Pathogens
DO  - 10.1371/journal.ppat.1014263
UR  - https://doi.org/10.1371/journal.ppat.1014263
AB  - PrP lowering is effective against prion disease in animal models and is being tested clinically. Therapies in the current pipeline lower PrP production, leaving pre-existing PrP to be cleared according to its own half-life. We hypothesized that PrP’s half-life may be a rate-limiting factor for the time to effect of PrP-lowering drugs, and one reason why late treatment of prion-infected mice is not as effective as early treatment. Using isotopically labeled diet with targeted mass spectrometry, as well as antisense oligonucleotide treatment followed by timed PrP measurement, we estimate a half-life of 5-6 days for PrP in the brain. PrP turnover is not affected by over-or under-expression. Mouse PrP and human PrP have similar turnover rates measured in wild-type or humanized knock-in mice. CSF PrP appears to mirror brain PrP in real time in rats. PrP in the colon is readily quantifiable and has a half-life just slightly shorter than in brain. An under-expressed pathogenic mutant PrP, corresponding to D178N in humans, exhibits an accelerated turnover rate. Our data may inform the design of both preclinical and clinical studies of PrP-lowering drugs. Author Summary Prion disease is a fatal brain disease caused by misfolding of the prion protein (PrP). Emerging therapies for prion disease seek to reduce the amount of PrP produced in the brain in order to delay onset of disease or slow progression. Mouse studies have shown that if these therapies are initiated too late, their benefit is limited or they may not help at all. Here we measure the half-life of PrP in the mouse brain, and find that it is about 5 days. When drugs are used to lower PrP by cutting up the RNA that encodes PrP, the RNA drops rapidly while the protein lags behind, and does not reach its minimum level until 4 weeks after the drug is dosed. This half-life is about the same regardless of the species of PrP (mouse or human) and whether or not the brain is infected with prions. Cerebrospinal fluid appears to reflect the real-time levels of brain PrP with no appreciable lag. PrP can be measured in colon, which may be useful in animal studies of systemic drugs to lower PrP. PrP turns over more quickly in the presence of a pathogenic genetic variant, the equivalent of the human D178N variant. These findings suggest that clinical trials can monitor PrP in cerebrospinal fluid to look at drug activity, but should plan timepoints far enough post-dose to account for PrP’s rate of turnover, and should focus on patients who will survive long enough to benefit from the drug.
SN  - 1553-7366
SN  - 1553-7374
ER  -