Transmission of Cervid prions to Humanized Mice Demonstrates the Zoonotic Potential of CWD

Hannaoui, Samia; Zemlyankina, Irina; Chang, Sheng Chun; Arifin, Maria Immaculata; Béringue, Vincent; McKenzie, Debbie; Schätzl, Hermann; Gilch, Sabine

doi:10.1101/2022.04.19.488833

Cited by 4 publications

(3 citation statements)

References 60 publications

(107 reference statements)

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“…When divided by prion strain, kuru emerges as the major research interest of first wave, with more recent studies focused on transmission of bovine spongiform encephalopathy (BSE) and chronic wasting disease (CWD) (Fig 2B). Notably, considering that more than 99% of prion disease cases diagnosed today are sporadic or genetic, a minority of experimental primate inoculations have used a prion subtype currently affecting human patients; the kuru and BSE/vCJD epidemics are no longer major public health threats, and despite conflicting results regarding zoonotic potential assessed in animal models, CWD is not known to have transmitted to humans [22][23][24][25][26].…”

Section: Resultsmentioning

confidence: 99%

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

2022

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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.

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Section: Resultsmentioning

confidence: 99%

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

2022

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“…CWD transmission studies in transgenic mouse models expressing PrPs from various species including ovine, bovine, and human showed low or absent ability of CWD prions to cross relevant species barriers (Tamgüney et al 2009b;Wilson et al 2012;Kurt et al 2015;Wadsworth et al 2022). Interestingly, a more recent study found atypical disease and fecal prion shedding in transgenic mice expressing human PrP when infected with deer prions, indicating zoonotic potential of CWD (Hannaoui et al 2022). In addition, transmission of CWD into non-human primates via the oral route (Marsh et al 2005;Race et al 2009Race et al , 2018 and efficient in vitro conversion of human PrP by CWD prions (Barria et al 2011;Wang et al 2021) should also not be ignored.…”

Section: Prion Diseases Of Different Speciesmentioning

confidence: 99%

Vaccines for prion diseases: a realistic goal?

Napper

Schätzl

2023

Cell Tissue Res

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Prion diseases are fatal infectious neurodegenerative disorders and prototypic conformational diseases, caused by the conformational conversion of the normal cellular prion protein (PrPC) into the pathological PrPSc isoform. Examples are scrapie in sheep and goat, bovine spongiform encephalopathy (BSE) in cattle, chronic wasting disease (CWD) in cervids, and Creutzfeldt–Jacob disease (CJD) in humans. There are no therapies available, and animal prion diseases like BSE and CWD can negatively affect the economy, ecology, animal health, and possibly human health. BSE is a confirmed threat to human health, and mounting evidence supports the zoonotic potential of CWD. CWD is continuously expanding in North America in numbers and distribution and was recently identified in Scandinavian countries. CWD is the only prion disease occurring both in wild and farmed animals, which, together with extensive shedding of infectivity into the environment, impedes containment strategies. There is currently a strong push to develop vaccines against CWD, including ones that can be used in wildlife. The immune system does not develop a bona fide immune response against prion infection, as PrPC and PrPSc share an identical protein primary structure, and prions seem not to represent a trigger for immune responses. This asks for alternative vaccine strategies, which focus on PrPC-directed self-antibodies or exposure of disease-specific structures and epitopes. Several groups have established a proof-of-concept that such vaccine candidates can induce some levels of protective immunity in cervid and rodent models without inducing unwanted side effects. This review will highlight the most recent developments and discuss progress and challenges remaining.

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“…More studies are needed for other emerging strains like small ruminant atypical scrapie and cervid chronic wasting disease prions [237,238]. In fact, chronic wasting disease prions have proved to have certain zoonotic potential [239].…”

Section: Transgenic Mouse Models For the Study Of Prion Diseasesmentioning

confidence: 99%

Transgenic Mouse Models for the Study of Neurodegenerative Diseases

Marín-Moreno¹,

Canoyra²,

Fernández‐Borges³

et al. 2023

Front. Biosci. (Landmark Ed)

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Neurodegenerative diseases (NDs) are some of the most important health challenges modern medicine and advanced societies face. Indeed, the number of patients affected by one of these illnesses will increase in the following years at the same rate that human life expectancy allows us to live longer. Despite many years of research, NDs remain invariably fatal. A complete understanding of the exact mechanisms leading to neuronal death, which will ideally allow preclinical detection and the development of effective treatments, has not yet been achieved. However, a great deal of information about ND pathology and the search for possible therapies has been acquired using animal models and more precisely transgenic mouse models. In this review, the main contributions of these powerful research tools in NDs as well as their advantages and caveats are discussed.

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Transmission of Cervid prions to Humanized Mice Demonstrates the Zoonotic Potential of CWD

Cited by 4 publications

References 60 publications

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

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

Vaccines for prion diseases: a realistic goal?

Transgenic Mouse Models for the Study of Neurodegenerative Diseases

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