Corridon, T. L.; OMoore, J.; Lian, Y.; Laversenne, V.; Noble, B.; Kamath, N. G.; Serack, F. E.; Shaikh, A. B.; Erickson, B.; Braun, C.; Lenz, K.; Howard, M.; Chan, N.; Reidenbach, A. G.; Cabin, D. E.; Vallabh, S. M.; Grindeland, A.; Oberbeck, N.; Zhao, H. T.; Minikel, E. V.

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 PrPs 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 chow 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 is more readily quantifiable in colon than in other peripheral organs, and appears to have a shorter half-life in colon than in brain. Our data may inform the design of both preclinical and clinical studies of PrP-lowering drugs.