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Display items can be reproduced using code available at the following Github repository. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.ĭata Availability: All relevant data are contained within the manuscript and its Supporting Information files. Received: ApAccepted: JPublished: August 22, 2022Ĭopyright: © 2022 Mortberg et al. PLoS Pathog 18(8):Įditor: Ina Maja Vorberg, Deutsches Zentrum fur Neurodegenerative Erkrankungen, GERMANY Finally, we suggest alternative study designs for gathering relevant animal data that may run a lower risk of delaying patient access to promising potential therapies.Ĭitation: Mortberg MA, Minikel EV, Vallabh SM (2022) Analysis of non-human primate models for evaluating prion disease therapeutic efficacy. We further find that the most tractable NHP models are not the most comparable to humans in terms of either brain size or prion protein gene homology, potentially reducing their utility. We find that while there is strong precedent for modeling prion disease in NHPs, a well-powered therapeutic study would be difficult to achieve on a realistic timeline due to the years-long timeframe of such studies and the lack of a well-established, predictable experimental system. We therefore aggregated a comprehensive dataset of prion NHP studies from the literature and analyzed this dataset to determine whether, and under what conditions, this model could realistically be used to assess the efficacy of an experimental therapeutic. Uniquely, prions can be transmitted to and faithfully modeled in many mammals including non-human primates (NHPs), but the possibility of testing new prion disease drugs in prion-infected NHPs has never been formally evaluated. Recent therapeutic advances raise the question of which kinds of animal studies can best support drug development in prion disease. Prion disease is an untreatable, rapidly fatal neurodegenerative disease. Our findings indicate that it would be challenging to conduct efficacy studies in NHPs in a paradigm that honors the potential advantages of NHPs over other available models, on a timeframe that would not risk unduly delaying patient access to promising drug candidates. The models with the shortest and most tightly distributed incubation times are those with smaller brains and weaker homology to humans. We find that while some models may theoretically be able to support therapeutic efficacy studies, pilot studies would be required to confirm incubation time and attack rate before pivotal studies could be designed, cumulatively requiring several years.
We analyze the incubation times observed across diverse models and perform power calculations to assess the practicability of testing prion disease therapeutic efficacy in NHPs. Using this dataset, we assess prion strain, route of administration, endpoint, and passage number to characterize the relationship of tested models to currently prevalent human subtypes of prion disease. Here we systematically aggregate data from N = 883 prion-inoculated animals spanning six decades of research studies. Uniquely, the entire prion disease process can be faithfully modeled through transmission of human prions to non-human primates (NHPs), raising the question of whether NHP models should be used to assess therapeutic efficacy. In light of proposals for clinical testing of such drugs in presymptomatic individuals at risk for genetic prion disease, extensive nonclinical data are likely to be required, with extra attention paid to choice of animal models. While no disease-modifying therapy is currently available, genetic and pharmacological proofs of concept support development of therapies that lower PrP levels in the brain. Prion disease is a fatal neurodegenerative disease caused by the conformational corruption of the prion protein (PrP), encoded by the prion protein gene ( PRNP).