NR ATNT
AU Crozet,C.A.; Lin,Y.L.; Corinus,A.; Mettling,C.; Mourton-Gilles,C.; Corbeau,P.; Lehmann,S.L.; Perrier,V.
TI Inhibition of PrPsc formation by lentiviral gene transfer of PrP containing dominant negative mutations
QU International Conference - Prion 2005: Between fundamentals and society's needs - 19.10.-21.10.2005, Congress Center Düsseldorf - Poster Session: Human prions, risk of blood products, and therapy HUMAN-17
PT Konferenz-Poster
AB Currently, no treatment is available to cure TSEs. A number of chemical molecules, targeting PrPsc itself or PrPsc replication, were discovered either serendipitously, such as branched polyamines, phtalocyanines and porphyrins derivatives, or by using a more rational approach with the help of structure-based drug design, as for identification of compound 60. These molecules were able to cure scrapie infected cells of their infectivity, however, they were poorly efficient on mice once the clinical symptoms have developed. By taking advantage of prion "resistant" polymorphisms Q171R and E219K that naturally exist in sheep and humans, respectively, we evaluate a lentiviral gene transfer therapeutic approach. Here we show that VSV-G pseudotyped FIV lentiviral vectors carrying the MoPrPQ167R or MoPrPQ218K dominant negative mutants are able to abolish endogenous wt PrPsc replication in chronically prion infected N2a58/22L cells. Injections of virion preparations into mice, using the intracerebral (ic) or intravenous (iv) routes, demonstrate that our lentiviral vectors can transduce cells from brain and spleen tissues. Moreover, when tested in vivo for their therapeutic efficacy, using a rapid -30 days- screening model, lentivirus carrying dominant negative PrP mutant hampered by more than 80 % PrPsc accumulation in the spleen of mice intraperitoneally inoculated with scrapie. Experiments aiming to show a significant prolongation of the incubation period are in progress. Therefore, these results present an advance in the development of gene therapy approaches to combat prion disease.
AD C.A.Crozet, S.Lehmann, "Biology of Transmissible Spongiform Encephalopathies", UPR1142 CNRS, Institute of Human Genetic, Montpellier, France; A.Corinus, V.Perrier, "Molecular Mechanism of Neurodegenerative Dementia", U710 INSERM, Montpellier 2 University, Montpellier, France; Y.L.Lin, C.Mettling, P.Corbeau, "Lentiviral vectorology", Institute of Human Genetic, UPR1142 CNRS, Montpellier, France; C.Mourton-Gilles, BIORAD, UMR 5094 CNRS, Montpellier, France
SP englisch
PO Deutschland