NR AWDU
AU Crozet,C.A.; Perrier,V.; Lin,Y.L.; Mettling,C.; Corbeau,P.; Lehmann,S.
TI Development of a cell therapy strategy for the treatment of prion diseases
QU International Conference - Prion 2006: Strategies, advances and trends towards protection of society - 3.10.-6.10.2006, Torino, Italy, Lingotto Conference Centre - Poster sessions THE-05
PT Konferenz-Poster
AB Once a patient becomes infected with a prion disease, or transmissible spongiform encephalopathy (TSE), the progression of infection is inexorably fatal. Although the potential for late stage therapies using chemical molecules seems limited, cell therapy strategies which have been shown to be effective in other neurodegenerative conditions might ameliorate TSE induced neuropathology. By taking advantage of prion "resistant" polymorphisms Q171R and E219K that naturally exist in sheep and humans, respectively, we have evaluated a cell therapy strategy combined with a gene therapy approach. In order to orchestrate a brain repair with prion resistant cells, our specific objective is to genetically modify embryonic stem cells (ES), by introducing "dominant negative" PrP mutants, before their transplantation in scrapie infected mouse brain. According to a strategy employed by Dr. A. Aguzzi, we have differentiated embryonic stem cells (ES) in vitro. When placed in a "neural" differentiation medium, the ES cells formed embryoid bodies (EBs) enriched in neural precursors that are collected for transplantation. We have then set up optimised conditions for gene delivery in these cells using lentiviral systems. We succeeded to transduce the EBs with the lentivirus carrying the dominant negative PrP mutants. We have previously shown that these lentivirus were able to inhibit prion replication ex vivo. To test the feasibility of this graft approach, C57bl/6 mice have been intra-cerebrally inoculated with the Me7 prion strain and transduced EBs have then been injected into different area of the mice brain using a stereotaxic frame. We are now assessing the effect of the transplantation on the development of a prion disease. Although we do not expect, for this first pilot study, an increase of the incubation period, we hypothesize an inhibition of the prion replication through the dominant negative properties of the mutated PrPs in the grafted area, as well as a brain repair around the transplanted area. Supported by the Neuroprion Network of Excellence LOI STEM-TSE
AD Carole Crozet, S. Lehmann: Biology of spongiform encephalopathies, Institut de génétique humaine, 34396 Montpellier, France, CNRS UPR 1142 Montpellier, France; V. Perrier: Molecular mechanisms in neurodegenerative dementia, U710 INSERM, UM2, Montpellier, France; Y.L. Lin, C. Mettling, P. Corbeau: Lentivirus and gene transfer IGH, CNRS UPR 1142, Montpellier, France
SP englisch
PO Italien