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

Abstract

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.

Prion Protein as a Toxic Acceptor of Amyloid-β Oligomers

“…Overall, these studies suggest that anti-PrP antibodies have a relatively low acute neurotoxicity at likely therapeutic concentrations for prion infection (65)(66)(67).…”

Administration of FK506 from Late Stage of Disease Prolongs Survival of Human Prion-Inoculated Mice

“…In recent decades, the main strategy for developing drugs against prion diseases focused on reducing abnormal PrP accumulation using either small compounds, antibodies against PrP, or siRNA to stop PrP expression. These treatments showed certain effects on prion-inoculated mice [40][41][42]. These findings indicate that the conversion of PrP has an important role in the initial pathogenesis, and that anti-PrP compounds prolong the incubation time of the disease.…”