Binding of bovine T194A PrP<sup>C</sup>by PrP<sup>Sc</sup>-specific antibodies

Madampage, Claudia; Määttänen, Pekka; Marciniuk, Kristen; Brownlie, Robert; Andrievskaia, Olga; Potter, Andrew; Cashman, Neil R.; Lee, Jeremy S.; Napper, Scott

doi:10.4161/pri.25148

Cited by 14 publications

(9 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The ability of the antibodies generated in response to the vaccine to discriminate subtle structural differences between mutant and wild-type proteins, 25 suggests that care may be necessary in applying this vaccination approach to disease susceptible individuals. While tga20 mice expressing wild-type PrP do not show any clinical signs of disease, would mice overexpressing a disease-specific mutant respond differently?…”

Section: Discussionmentioning

confidence: 99%

“…Using a single molecule binding technique and immunoprecipitations, we recently discovered that PrP Sc -specific antibodies generated against the expanded YYR epitope (SN6b) bind to the bovine equivalent of human T183A prion protein associated with a rare form of early onset familial dementia. 25 Thus, the PrP Sc -specific polyclonal antibodies generated in response to the vaccine can recognize subtle conformational differences and may interact with partially folded PrP. While such interactions are unlikely to elicit a misfolding event, the process of template-directed misfolding remains poorly understood, and any therapeutic approach that involves binding of PrP and potential perturbation of its structure, should be carefully tested for safety in vivo.…”

mentioning

confidence: 99%

See 1 more Smart Citation

PrP^Sc-specific antibodies do not induce prion disease or misfolding of PrP^Cin highly susceptible Tga20 mice

Määttänen

Taschuk

Ross

et al. 2013

Prion

Self Cite

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

PrP^Sc-specific antibodies do not induce prion disease or misfolding of PrP^Cin highly susceptible Tga20 mice

Määttänen

Taschuk

Ross

et al. 2013

Prion

Self Cite

View full text Add to dashboard Cite

“…The approach to target the PrP Sc template and at the same time avoid the recognition of abundantly expressed PrP c , guided the development of the vaccine based on the PrP Sc dominant epitope YYR [ 40 ]. The follow up studies were focused to (i) exclude the concern that such anti-PrP Sc antibodies might by themselves induce the formation of the PrP Sc template and to (ii) drive the anti-PrP antibody response towards conformations of PrP mutants associated with genetic types of the disease [ 76 ]. The animal studies show that still mucosal vaccination seems to be the most effective, although this approach would be restricted to preventing oral transmission among animals and human populations at risk [ 77 , 78 ].…”

Section: Active and Passive Immunotherapy Approachesmentioning

confidence: 99%

Prion Protein-Specific Antibodies-Development, Modes of Action and Therapeutics Application

Roviš¹,

Legname²

2014

Viruses

View full text Add to dashboard Cite

Prion diseases or Transmissible Spongiform Encephalopathies (TSEs) are lethal neurodegenerative disorders involving the misfolding of the host encoded cellular prion protein, PrPC. This physiological form of the protein is expressed throughout the body, and it reaches the highest levels in the central nervous system where the pathology occurs. The conversion into the pathogenic isoform denoted as prion or PrPSc is the key event in prion disorders. Prominent candidates for the treatment of prion diseases are antibodies and their derivatives. Anti-PrPC antibodies are able to clear PrPSc from cell culture of infected cells. Furthermore, application of anti-PrPC antibodies suppresses prion replication in experimental animal models. Major drawbacks of immunotherapy are immune tolerance, the risks of neurotoxic side effects, limited ability of compounds to cross the blood-brain barrier and their unfavorable pharmacokinetic. The focus of this review is to recapitulate the current understanding of the molecular mechanisms for antibody mediated anti-prion activity. Although relevant for designing immunotherapeutic tools, the characterization of key antibody parameters shaping the molecular mechanism of the PrPC to PrPSc conversion remains elusive. Moreover, this review illustrates the various attempts towards the development of anti-PrP antibody compounds and discusses therapeutic candidates that modulate PrP expression.

show abstract

“…Incubation of the T194A mutant with the ovine DSE antibodies failed to generate protease resistant species indicating the probability of antibodies inducing misfolding is minimal, even with a substrate with greater structural propensity for misfolding. 64 In vivo template directed misfolding While the inability of the DSE-specific antibodies to promote in vitro misfolding of PrP C is reassuring, it is important to appreciate that such experiments do not replicate the in vivo environment. Therefore, we inquired whether DSE-based vaccines were capable of antibody-induced misfolding of PrP C in sheep.…”

Section: Safety Of Induced Immune Responsesmentioning

confidence: 99%

Safety, specificity and immunogenicity of a PrP^Sc-specific prion vaccine based on the YYR disease specific epitope

Taschuk

Marciniuk

Määttänen

et al. 2014

Prion

Self Cite

View full text Add to dashboard Cite

Prions are a novel form of infectivity based on the misfolding of a self-protein (PrP(C)) into a pathological, infectious isomer (PrP(Sc)). The current uncontrolled spread of chronic wasting disease in cervids, coupled with the demonstrated zoonotic nature of select livestock prion diseases, highlights the urgent need for disease management tools. While there is proof-of-principle evidence for a prion vaccine, these efforts are complicated by the challenges and risks associated with induction of immune responses to a self-protein. Our priority is to develop a PrP(Sc)-specific prion vaccine based on epitopes that are uniquely exposed upon misfolding. These disease specific epitopes (DSEs) have the potential to enable specific targeting of the pathological species through immunotherapy. Here we review outcomes of the translation of a prion DSE into a PrP(Sc)-specific vaccine based on the criteria of immunogenicity, safety and specificity.

show abstract

Binding of bovine T194A PrP^Cby PrP^Sc-specific antibodies

Cited by 14 publications

References 48 publications

PrP^Sc-specific antibodies do not induce prion disease or misfolding of PrP^Cin highly susceptible Tga20 mice

PrP^Sc-specific antibodies do not induce prion disease or misfolding of PrP^Cin highly susceptible Tga20 mice

Prion Protein-Specific Antibodies-Development, Modes of Action and Therapeutics Application

Safety, specificity and immunogenicity of a PrP^Sc-specific prion vaccine based on the YYR disease specific epitope

Contact Info

Product

Resources

About

Binding of bovine T194A PrPCby PrPSc-specific antibodies

Cited by 14 publications

References 48 publications

PrPSc-specific antibodies do not induce prion disease or misfolding of PrPCin highly susceptible Tga20 mice

PrPSc-specific antibodies do not induce prion disease or misfolding of PrPCin highly susceptible Tga20 mice

Prion Protein-Specific Antibodies-Development, Modes of Action and Therapeutics Application

Safety, specificity and immunogenicity of a PrPSc-specific prion vaccine based on the YYR disease specific epitope

Contact Info

Product

Resources

About

Binding of bovine T194A PrP^Cby PrP^Sc-specific antibodies

PrP^Sc-specific antibodies do not induce prion disease or misfolding of PrP^Cin highly susceptible Tga20 mice

PrP^Sc-specific antibodies do not induce prion disease or misfolding of PrP^Cin highly susceptible Tga20 mice

Safety, specificity and immunogenicity of a PrP^Sc-specific prion vaccine based on the YYR disease specific epitope