Analysis of non-human primate models for evaluating prion disease therapeutic efficacy

Abstract

Prion disease is a fatal neurodegenerative disease caused by the conformational corruption of the prion protein (PrP), encoded by the prion protein gene (PRNP). 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. 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. 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. Here we systematically aggregate data from N = 883 prion-inoculated animals spanning six decades of research studies. 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. 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. 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. The models with the shortest and most tightly distributed incubation times are those with smaller brains and weaker homology to humans. 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.

Therapeutic Trial of anle138b in Mouse Models of Genetic Prion Disease

“…Given the difficulty in modeling most neurological diseases in animals, the diversity of models and even species available for prion research by virtue of the panmammalian nature of the disease is an unusual endowment. Although this panoply is united by the core prion disease process, the present study may serve as a cautionary reminder that, as we have argued elsewhere with regard to nonhuman primates ( 55 ), not all prion models are ideally suited to all research purposes. Ultimately, multiple models will be needed to stitch together the complex continuum that bridges fundamental disease biology to therapeutic hypotheses and, ultimately, drug development.…”

Therapeutic trial of anle138b in mouse models of genetic prion disease

“…Given the difficulty of modeling most neurological diseases in animals, the diversity of models and even species available to prion research by virtue of the pan-mammalian nature of the disease is an unusual endowment. Though this panoply is united by the core prion disease process, the present study may serve as a cautionary reminder that, as we have argued elsewhere with regards to non-human primates 31 , not all prion models are ideally suited to all research purposes. Ultimately, multiple models will be needed to stitch together the complex continuum that bridges fundamental disease biology to therapeutic hypotheses and ultimately, drug development.…”

Convergent generation of atypical prions in knockin mouse models of genetic prion disease

“…To this end, the kiBVI D178N and kiBVI E200K lines will be particularly useful for assessing gene editing or PrP C -lowering treatments for spontaneous prion disease, which would be challenging in transgenic models with artificially high PRNP gene dosage. However, as with other animal models of prion disease ( 71 , 72 ), assessing therapeutic efficacy in kiBVI D178N and kiBVI E200K lines will be challenging. In particular, the incomplete penetrance of spontaneous disease by 600 days of age and the variability in age of disease onset create logistical issues when designing therapeutic studies.…”