Objetivo 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. Ámbito científico natural sciencesbiological scienceszoologymammalogyprimatologymedical and health sciencesmedical biotechnologygenetic engineeringgene therapynatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsnatural sciencesbiological sciencesgeneticsmutationmedical and health sciencesbasic medicineneurologyamyotrophic lateral sclerosis Palabras clave amyotrophic lateral sclerosis bidirectional expression lentiviral vector neurodegenerative diseases neuromuscular junction rabies-g retrograde transport spinal muscular atrophy targeting Programa(s) 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) Tema(s) ERC-AG-LS7 - ERC Advanced Grant - Diagnostic tools, therapies and public health Convocatoria de propuestas ERC-2008-AdG Consulte otros proyectos de esta convocatoria Régimen de financiación ERC-AG - ERC Advanced Grant Coordinador IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE Aportación de la UE € 2 000 000,00 Dirección South kensington campus exhibition road SW7 2AZ London Reino Unido Ver en el mapa Región London Inner London — West Westminster Tipo de actividad Higher or Secondary Education Establishments Contacto administrativo Tatjana Palalic (Ms.) Investigador principal Nicholas Mazarakis (Prof.) Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Coste total Sin datos Beneficiarios (1) Ordenar alfabéticamente Ordenar por aportación de la UE Ampliar todo Contraer todo IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE Reino Unido Aportación de la UE € 2 000 000,00 Dirección South kensington campus exhibition road SW7 2AZ London Ver en el mapa Región London Inner London — West Westminster Tipo de actividad Higher or Secondary Education Establishments Contacto administrativo Tatjana Palalic (Ms.) Investigador principal Nicholas Mazarakis (Prof.) Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Coste total Sin datos