Cel Lentiviral vectors can be targeted to specific cell types by varying the envelope proteins, a process called pseudotyping. The rabies-G pseudotyped lentivectors are useful for distal targeting of neurons because they are retrogradely transported to the nucleus where they integrate and express the transgene, as first demonstrated by us. Motor neuron (MN) diseases are incurable neurodegenerative diseases causing progressive paralysis and premature death. Most amyotrophic lateral sclerosis (ALS) cases are sporadic, but there are rare inherited forms one of which being due to mutations in the superoxide dismutase (SOD1) gene. Spinal muscular atrophy (SMA) is the second commonest genetic disease affecting children and is due to mutations in the survival motor neuron (SMN1) gene. In mouse models for ALS (SOD1 mutant mouse) or SMA (SMNDelta7 mouse) when we delivered in various muscle groups rabies-G pseudotyped lentiviral vectors expressing either vascular endothelial growth factor or short interfering RNA targeted to a mutated SOD1 gene or the normal SMN1 gene we corrected motor defects and extended survival. Despite these successes, experiments with rabies-G pseudotyped vectors in non-human primates have failed to give good efficiency of transduction of MNs so as to translate this approach to the clinic. Also SMN-1 targeted replacement produced only a marginal increase in survival despite sparing MNs. In this grant we propose: 1) To investigate the molecular pathway of retrograde transport of the rabies-G lentiviral vectors. This might allow us to increase the efficacy of gene transfer with these vector systems. 2) To design novel lentiviral vectors with tropism to the neuromuscular junction (NMJ) so as to try to increase the efficiency/specificity of gene transfer to MNs. 3) To utilise the new NMJ-targeted lentiviral vector derived in (2) to simultaneously deliver several neuroprotective proteins to MNs and test its efficacy in animal models of ALS and SMA. Dziedzina nauki nauki przyrodniczenauki biologicznezoologiamammalogiaprymatologiamedycyna i nauki o zdrowiubiotechnologia medycznainżynieria genetycznaterapia genowanauki przyrodniczenauki biologicznebiochemiabiocząsteczkibiałkanauki przyrodniczenauki biologicznegenetykamutacjamedycyna i nauki o zdrowiumedycyna klinicznaneurologiastwardnienie zanikowe boczne Słowa kluczowe amyotrophic lateral sclerosis bidirectional expression lentiviral vector neurodegenerative diseases neuromuscular junction rabies-g retrograde transport spinal muscular atrophy targeting Program(-y) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Temat(-y) ERC-AG-LS7 - ERC Advanced Grant - Diagnostic tools, therapies and public health Zaproszenie do składania wniosków ERC-2008-AdG Zobacz inne projekty w ramach tego zaproszenia System finansowania ERC-AG - ERC Advanced Grant Koordynator IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE Adres South kensington campus exhibition road SW7 2AZ London Zjednoczone Królestwo Zobacz na mapie Region London Inner London — West Westminster Rodzaj działalności Higher or Secondary Education Establishments Kontakt administracyjny Tatjana Palalic (Ms.) Kierownik naukowy Nicholas Mazarakis (Prof.) Linki Kontakt z organizacją Opens in new window Strona internetowa Opens in new window Wkład UE Brak danych Beneficjenci (1) Sortuj alfabetycznie Sortuj według wkładu UE Rozwiń wszystko Zwiń wszystko IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE Zjednoczone Królestwo Wkład UE € 2 000 000,00 Adres South kensington campus exhibition road SW7 2AZ London Zobacz na mapie Region London Inner London — West Westminster Rodzaj działalności Higher or Secondary Education Establishments Kontakt administracyjny Tatjana Palalic (Ms.) Kierownik naukowy Nicholas Mazarakis (Prof.) Linki Kontakt z organizacją Opens in new window Strona internetowa Opens in new window Środki z innych źródeł Brak danych
