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.

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.

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.