title: Lentivector-mediated SMN replacement in a mouse model of spinal muscular atrophy.
abstract: Spinal muscular atrophy (SMA) is a frequent recessive autosomal disorder. It is caused by mutations or deletion of the telomeric copy of the survival motor neuron (SMN) gene, leading to depletion in SMN protein levels. The treatment rationale for SMA is to halt or delay the degeneration of motor neurons, but to date there are no effective drug treatments for this disease. We have previously demonstrated that pseudotyping of the nonprimate equine infectious anemia virus (using the lentivector gene transfer system) with the glycoprotein of the Evelyn-Rokitnicki-Abelseth strain of the rabies virus confers retrograde axonal transport on these vectors. Here, we report that lentivector expressing human SMN was successfully used to restore SMN protein levels in SMA type 1 fibroblasts. Multiple single injections of a lentiviral vector expressing SMN in various muscles of SMA mice restored SMN to motor neurons, reduced motor neuron death, and increased the life expectancy by an average of 3 and 5 days (20% and 38%) compared with LacZ and untreated animals, respectively. Further extension of survival by SMN expression constructs will likely require a knowledge of when and/or where high levels of SMN are needed.
authors.affiliation: Oxford BioMedicaLtd., Medwar Centre, Robert Robinson Avenue, The Oxford Science Park, Oxford OX4 4GA, UK. m.azzouz@oxfordbiomedica.co.uk
authors.forename: Mimoun
authors.initials: M
authors.lastname: Azzouz
authors.forename: Thanh
authors.initials: T
authors.lastname: Le
authors.forename: G Scott
authors.initials: GS
authors.lastname: Ralph
authors.forename: Lucy
authors.initials: L
authors.lastname: Walmsley
authors.forename: Umrao R
authors.initials: UR
authors.lastname: Monani
authors.forename: Debbie C P
authors.initials: DC
authors.lastname: Lee
authors.forename: Fraser
authors.initials: F
authors.lastname: Wilkes
authors.forename: Kyriacos A
authors.initials: KA
authors.lastname: Mitrophanous
authors.forename: Susan M
authors.initials: SM
authors.lastname: Kingsman
authors.forename: Arthur H M
authors.initials: AH
authors.lastname: Burghes
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Mazarakis
mesh_terms: D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D007150:Immunohistochemistry; D007763:Lac Operon; D016086:Lentivirus / Q000235:genetics*; D051379:Mice; D008856:Microscopy, Fluorescence; D009046:Motor Neurons / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics*; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; D013997:Time Factors
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins