title: Intracerebroventricular delivery of dominant negative prion protein in a mouse model of iatrogenic Creutzfeldt-Jakob disease after dura graft transplantation.
abstract: We have developed a novel procedure in which a small collagen sheet (3 mm x 3 mm) absorbing prion-infected brain homogenates was transplanted onto the brain surface of highly prion-susceptible transgenic mice (Tg(MoPrP)4053/FVB), as an animal model of iatrogenic Creutzfeldt-Jakob disease (iCJD) caused by prion-contaminated cadaveric dura graft transplantation. Using the iCJD model, we further investigated the in vivo efficacy of dominant negative recombinant prion protein with lysine substitution at mouse codon 218 (rPrP-Q218K), which is known to inhibit prion replication in vitro (H. Kishida, Y. Sakasegawa, K. Watanabe, Y. Yamakawa, M. Nishijima, Y. Kuroiwa, N.S. Hachiya, K. Kaneko, Non-glycosylphosphatidylinositol (GPI)-anchored recombinant prion protein with dominant-negative mutation inhibits PrPSc replication in vitro, Amyloid, vol. 11, 2004, pp. 14-20.). Following 7-day intracerebroventricular administration of the rPrP-Q218K via an indwelling catheter connected to the implanted osmotic pump, the median incubation period of Tg(MoPrP)4053/FVB was prolonged considerably from 117 days to 131 days (p=0.016, log-rank test) in the rPrP-Q218K-treated group, even after a lengthy latency period of as long as 30 days by starting the rPrP-Q218K injection. Whether wild-type rPrP, other mutant rPrPs, or the combination of rPrP-Q218K with other anti-prion compounds might extend the survival period in that condition must be further investigated.
authors.affiliation: Department of Neurosurgery, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Tokyo 113-8655, Japan. furuya-nsu@umin.ac.jp
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Furuya
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Kawahara
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Yamakawa
authors.forename: Hitaru
authors.initials: H
authors.lastname: Kishida
authors.forename: Naomi S
authors.initials: NS
authors.lastname: Hachiya
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nishijima
authors.forename: Takaaki
authors.initials: T
authors.lastname: Kirino
authors.forename: Kiyotoshi
authors.initials: K
authors.lastname: Kaneko
mesh_terms: D000818:Animals; D002408:Catheters, Indwelling; D003094:Collagen; D007562:Creutzfeldt-Jakob Syndrome / Q000378:metabolism* / Q000517:prevention & control / Q000635:transmission; D004195:Disease Models, Animal; D004388:Dura Mater / Q000637:transplantation*; D005799:Genes, Dominant; D007049:Iatrogenic Disease; D007260:Infusion Pumps; D007276:Injections, Intraventricular; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009995:Osmosis; D018621:PrPC Proteins / Q000037:antagonists & inhibitors; D011328:Prions / Q000008:administration & dosage* / Q000235:genetics; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics
chemical_list: D018621:PrPC Proteins; D011328:Prions; D011994:Recombinant Proteins; D003094:Collagen