Prion diseases are infectious, conformational neurodegenerative disorders characterized by the structural modification of the prion protein, PrPC, into a pathological conformer, PrPSc. Currently there is no effective therapy for this group of diseases. The outbreak of bovine spongiform encephalopathy and the resulting emergence of a new human prion disease vCJD, highlight the public health threat from prion diseases. Although the original outbreak of vCJD is waning, there is the possibility of further outbreaks from current asymptomatic carriers of the disease. In the USA an ongoing threat from prion disease is from chronic wasting disease (CWD). High rates of infection among deer and elk populations have been report, with experimental data indicating that this disease is transmissible to primates. In the prior funding of this grant we reported on the first successful in vivo active and passive immunization approaches for prion diseases using wild-type animals. In the last funding cycle we also developed an in vitro tissue culture model of prion disease, and showed that it is a valuable tool to screen for therapeutically active anti-PrP antibodies. Our recent preliminary results indicate that using our novel mucosal immunization approach we are able to completely prevent prion disease among animals with a high anti-PrP titer. We also have shown that anti-PrP antibodies that are active in our tissue culture model of prion infection, can significantly delay prion infection and reduce severity of disease. In our planned studies we will further develop our active and passive immunization approaches, to bring them closer to veterinary and human clinical use for both prion infection prevention and potential treatment of symptomatic disease.
The specific aims of this proposal are to : 1): Development of the optimal oral vaccination method in wild-type mice and transgenic mice expressing elk, sheep or human PrP;2) Characterization of the immune response in successfully vaccinated animals and the development of monoclonal antibodies (Mabs) to mouse and human PrP from these mice. Mabs will be tested for therapeutic efficacy in tissue culture models of scrapie and human sporadic CJD prion infection and 3) Passive immunization studies using existing Mabs and antibodies generated from "successfully" vaccinated mice to determine the mechanisms responsible for therapeutic effects and to investigate if any will be effective in both human and scrapie prion infection in the pre- symptomatic incubation period and in symptomatic disease.

Public Health Relevance

Currently prion diseases are without treatment and are universally fatal. The past outbreak of bovine spongiform encephalopathy with the resulting emergence of variant Creutzfeldt-Jakob disease, as well as the currently epidemic of chronic wasting disease among deer and elk in the USA, which has been shown to be transmissible to primates, all highlights the threat of this group of disorders. This proposal aims to develop both active and passive immunization approaches to both prevent infection and to treat symptomatic disease in animal and human populations, respectively.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS047433-10
Application #
8459517
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Wong, May
Project Start
2004-07-01
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
10
Fiscal Year
2013
Total Cost
$349,614
Indirect Cost
$142,742
Name
New York University
Department
Neurology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Goñi, Fernando; Mathiason, Candace K; Yim, Lucia et al. (2015) Mucosal immunization with an attenuated Salmonella vaccine partially protects white-tailed deer from chronic wasting disease. Vaccine 33:726-33
Rubenstein, Richard; Chiu, Allen; Chang, Binggong et al. (2013) Role of CD40 in prion disease and the immune response to recombinant PrP. J Neuroimmunol 257:21-7
Wisniewski, Thomas; Goni, Fernando (2012) Could immunomodulation be used to prevent prion diseases? Expert Rev Anti Infect Ther 10:307-17
Chung, Erika; Prelli, Frances; Dealler, Stephen et al. (2011) Styryl-based and tricyclic compounds as potential anti-prion agents. PLoS One 6:e24844
Wisniewski, Thomas; Goni, Fernando (2010) Immunomodulation for prion and prion-related diseases. Expert Rev Vaccines 9:1441-52
Chung, Erika; Ji, Yong; Sun, Yanjie et al. (2010) Anti-PrPC monoclonal antibody infusion as a novel treatment for cognitive deficits in an Alzheimer's disease model mouse. BMC Neurosci 11:130
Sadowski, Martin J; Pankiewicz, Joanna; Prelli, Frances et al. (2009) Anti-PrP Mab 6D11 suppresses PrP(Sc) replication in prion infected myeloid precursor line FDC-P1/22L and in the lymphoreticular system in vivo. Neurobiol Dis 34:267-78
Scholtzova, Henrieta; Kascsak, Richard J; Bates, Kristyn A et al. (2009) Induction of toll-like receptor 9 signaling as a method for ameliorating Alzheimer's disease-related pathology. J Neurosci 29:1846-54
Goni, F; Prelli, F; Schreiber, F et al. (2008) High titers of mucosal and systemic anti-PrP antibodies abrogate oral prion infection in mucosal-vaccinated mice. Neuroscience 153:679-86
Spinner, Daryl S; Cho, In Soo; Park, Seung Yong et al. (2008) Accelerated prion disease pathogenesis in Toll-like receptor 4 signaling-mutant mice. J Virol 82:10701-8

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