Abstract
The development of antibodies effective in crossing the blood brain barrier (BBB), capable of accessing the cytosol of affected cells and with higher affinity for PrPSc would be of paramount importance in arresting disease progression in its late stage and treating individuals with prion diseases. Antibody-based therapy appears to be the most promising approach following the exciting report from White and colleagues, establishing the “proof-of-principle” for prion-immunotherapy. After passive transfer, anti-prion antibodies were shown to be very effective in curing peripheral but not central rodent prion disease, due to the fact that these anti-prion antibodies are relatively large molecules and cannot therefore cross the BBB. Here, we show that an anti-prion antibody derived from camel immunised with murine scrapie material adsorbed to immunomagnetic beads is able to prevent infection of susceptible N2a cells and cure chronically scrapie-infected neuroblastoma cultures. This antibody was also shown to transmigrate across the BBB and cross the plasma membrane of neurons to target cytosolic PrPC. In contrast, treatment with a conventional anti-prion antibody derived from mouse immunised with recombinant PrP protein was unable to prevent recurrence of PrPSc replication. Furthermore, our camelid antibody did not display any neurotoxic effects following treatment of susceptible N2a cells as evidenced by TUNEL staining. These findings demonstrate the potential use of anti-prion camelid antibodies for the treatment of prion and other related diseases via non-invasive means.
Highlights
Prion diseases known as transmissible spongiform encephalopathies (TSEs) are a group of closely related fatal transmissible neurodegenerative diseases that affect humans and animals [1]
With the exception of an amphotericine analogue that had some effect on disease progression [10], these drugs have been shown to be ineffective in interacting with PrPSc in vivo
And for the first time, we have previously shown that passive transfer of anti-PrP monoclonal antibodies following inoculation of mice with scrapie-infected material via the intraperitoneal route led to inhibition of prion replication in vivo and animals survived throughout their life-span and remained free of detectable prion infection [14]
Summary
Prion diseases known as transmissible spongiform encephalopathies (TSEs) are a group of closely related fatal transmissible neurodegenerative diseases that affect humans and animals [1]. Prion disorders are associated with conversion of the normal cellular prion protein (PrPC) into a disease-associated isoform, PrPSc, that acquires increased b-sheet structure and detergent insolubility [2]. These diseases are characterised by the deposition and aggregation of proteins into highly stable, partially proteinaseresistant plaques and fibrils [3], leading to neuronal cell death and spongiform change of the brain parenchyma [4]. With the exception of an amphotericine analogue that had some effect on disease progression [10], these drugs have been shown to be ineffective in interacting with PrPSc in vivo Their capacity to transmigrate across the BBB has not been established
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