Antiprion Prophylaxis by Gene Transfer of a Soluble Prion Antagonist

Genoud, Nicolas; Ott, David E.; Braun, Nathalie; Prinz, Marco; Schwarz, Petra; Suter, Ueli; Trono, Didier; Aguzzi, Adriano

doi:10.2353/ajpath.2008.070836

Cited by 15 publications

(19 citation statements)

References 40 publications

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“…Binders that recognize PrP are readily available (Beringue et al, 2003;Curin Serbec et al, 2004;Korth et al, 1999;Paramithiotis et al, 2003;Polymenidou et al, 2008) and strategies to deliver these binders across the BBB are currently being pursued Donofrio et al, 2005;Genoud et al, 2008;Polymenidou et al, 2008;Vetrugno et al, 2005;Wuertzer et al, 2008;Zuber et al, 2008a). These are based on the use of single chain variable fragments or scFv; these are antibody-like fragments comprising a single fusion polypeptide of the variable regions of the Ig light and heavy chains.…”

Section: Immunodetection Of Intracellular Prpmentioning

confidence: 99%

PrP-specific camel antibodies with the ability to immunodetect intracellular prion protein

Tayebi

Taylor

Jones

et al. 2010

Journal of General Virology

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Although there is currently no effective treatment for prion diseases, significant advances have been made in suppressing its progress, using antibodies that block the conversion of PrPC into PrPSc. In order to be effective in treating individuals that have prion diseases, antibodies must be capable of arresting disease in its late stages. This requires the development of antibodies with higher affinity for PrPSc and systems for effective translocation of antibodies across the blood–brain barrier in order to achieve high concentrations of inhibitor at the site of protein replication. An additional advantage is the ability of these antibodies to access the cytosol of affected cells. To this end, we have generated PrP-specific antibodies (known as PrioV) by immunization of camels with murine scrapie material adsorbed to immunomagnetic beads. The PrioV antibodies display a range of specificities with some recognizing the PrP27–30 proteinase K-resistant fragment, others specific for PrPC and a number with dual binding specificity. Independent of their PrP conformation specificity, one of the PrioV antibodies (PrioV3) was shown to bind PrPC in the cytosol of neuroblastoma cells. In marked contrast, conventional anti-PrP antibodies produced in mouse against similar target antigen were unable to cross the neuronal plasma membrane and instead formed a ring around the cells. The PrioV anti-PrP antibodies could prove to be a valuable tool for the neutralization/clearance of PrPSc in intracellular compartments of affected neurons and could potentially have wider applicability for the treatment of so-called protein-misfolding diseases.

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Section: Immunodetection Of Intracellular Prpmentioning

confidence: 99%

PrP-specific camel antibodies with the ability to immunodetect intracellular prion protein

Tayebi

Taylor

Jones

et al. 2010

Journal of General Virology

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“…Moreover, delivery of genes encoding scFv or PrP-Fc fusion protein reduce the PrP Sc burden around the delivery site (14,15). In the present study, i.v.…”

Section: Discussionmentioning

confidence: 77%

“…In the intermediate stage after intracerebral prion inoculation, expression of a PrP-Fc or scFv in brains of mice that have been infected with prions by a using viral vector also inhibits disease progression (14,15). Taken together, these results indicate that immunotherapy is a potential candidate for the treatment of prion diseases, provided the antibodies can be efficiently delivered into the brain parenchyma.…”

mentioning

confidence: 63%

Therapeutic effect of peripheral administration of an anti-prion protein antibody on mice infected with prions

Ohsawa

Song

Suzuki

et al. 2013

Microbiology and Immunology

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It is generally thought that effective treatments for prion diseases need to inhibit prion propagation, protect neuronal tissues and promote functional recovery of degenerated nerve tissues. In addition, such treatments should be effective even when given after clinical onset of the disease and administered via a peripheral route. In this study, the effect of peripheral administration of an anti-PrP antibody on disease progression in prion-infected mice was examined. mAb 31C6 was administered via the tail veins of prion-infected mice at the time of clinical onset (120 days post-inoculation with the Chandler prion strain) and the distribution of this mAb in the brain and its effect on mouse survival assessed. The antibody was distributed to the cerebellums and thalami of the infected mice and more than half these mice survived longer than mice that had been given a negative control mAb. The level of PrP Sc in the mAb 31C6-treated mice was lower than that in mice treated with the negative control mAb and progression of neuropathological lesions in the cerebellum, where the mAb 31C6 was well distributed, appeared to be mitigated. These results suggest that administration of an anti-PrP mAb through a peripheral route is a candidate for the treatment of prion diseases.Key words blood-brain barrier, immunotherapy, prion, scrapie.Prion diseases are fatal neurodegenerative disorders of humans and animals that are strongly associated with conversion of PrP C to PrP Sc . Based on in vitro and in vivo studies, researchers have proposed many inhibitors of PrP Sc formation, including anti-PrP antibodies, as potential therapeutic candidates (1). However, there are still no effective treatments for prion diseases.Anti-PrP antibodies inhibit prion propagation in cells that are persistently infected with these agents (2-7). Researchers have also demonstrated an inhibitory effect of anti-PrP antibodies has in vivo: provided antibodies are administered shortly after prion inoculation, intraperitoneal administration of anti-PrP antibodies prevents prion infection via a peripheral route but is not effective against intracerebral prion inoculation (8). Moreover, active immunization with recombinant PrP, a synthetic PrP peptide or a DNA vaccine following peripheral prion infection reportedly delays onset of the disease in mice and is a prerequisite for obtaining a prophylactic effect (9-12). These results suggest that anti-PrP antibodies can PrP Sc , disease-specific isoform of the prion protein; scFv, single-chain fragment variable antibody.

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“…Transgenic expression of anti-PrP antibodies (22), a fusion protein between PrP C and the Fc portion of immunoglobulin (PrP-Fc) (34), and dominant-negative PrP mutants (40) inhibited prion propagation. In addition, expression of anti-PrP Fab fragments and PrP-Fc in the brain by virus vectors has been reported to antagonize prion propagation in the brain (18,62). Furthermore, intraventricular infusion of an anti-PrP MAb slowed the formation of neuropathological lesions and prolonged the survival of prion-infected mice even when the MAb was administered at clinical onset (53).…”

Section: Discussionmentioning

confidence: 99%

Effect of Transplantation of Bone Marrow-Derived Mesenchymal Stem Cells on Mice Infected with Prions

Song

Ohsawa

Nakamura

et al. 2009

J Virol

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Bone marrow-derived mesenchymal stem cells (MSCs) have been reported to migrate to brain lesions in experimental models of ischemia, tumors, and neurodegenerative diseases and to ameliorate functional deficits. In this study, we attempted to evaluate the therapeutic potential of MSCs for treating prion diseases. Immortalized human MSCs (hMSCs) that express the LacZ gene were transplanted into the unilateral hippocampi or thalami of mice, and their distributions were monitored by the expression of ␤-galactosidase. In mice infected with prions, hMSCs transplanted at 120 days postinoculation (dpi) were detected on the contralateral side at 2 days after transplantation and existed there even at 3 weeks after transplantation. In contrast, few hMSCs were detected on the contralateral side for mock-infected mice. Interestingly, the migration of hMSCs appeared to correlate with the severity of neuropathological lesions, including disease-specific prion protein deposition. The hMSCs also migrated to a prion-specific lesion in the brain, even when intravenously injected. Although the effects were modest, intrahippocampal and intravenous transplantation of hMSCs prolonged the survival of mice infected with prions. A subpopulation of hMSCs in the brains of prion-infected mice produced various trophic factors and differentiated into cells of neuronal and glial lineages. These results suggest that MSCs have promise as a cellular vehicle for the delivery of therapeutic genes to brain lesions associated with prion diseases and, furthermore, that they may help to regenerate neuronal tissues damaged by prion propagation.

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Antiprion Prophylaxis by Gene Transfer of a Soluble Prion Antagonist

Abstract: Prion diseases are untreatable neurodegenerative disorders characterized by accumulation of PrPSc , an aggregated isoform of the normal prion protein PrP C . Here, we delivered the soluble prion antagonist PrP-

Cited by 15 publications

References 40 publications

PrP-specific camel antibodies with the ability to immunodetect intracellular prion protein

PrP-specific camel antibodies with the ability to immunodetect intracellular prion protein

Therapeutic effect of peripheral administration of an anti-prion protein antibody on mice infected with prions

Effect of Transplantation of Bone Marrow-Derived Mesenchymal Stem Cells on Mice Infected with Prions

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