title: Adeno-associated virus-mediated delivery of a recombinant single-chain antibody against misfolded superoxide dismutase for treatment of amyotrophic lateral sclerosis.
abstract: There is emerging evidence that the misfolding of superoxide dismutase 1 (SOD1) may represent a common pathogenic event in both familial and sporadic amyotrophic lateral sclerosis (ALS). To reduce the burden of misfolded SOD1 species in the nervous system, we have tested a novel therapeutic approach based on adeno-associated virus (AAV)-mediated tonic expression of a DNA construct encoding a secretable single-chain fragment variable (scFv) antibody composed of the variable heavy and light chain regions of a monoclonal antibody (D3H5) binding specifically to misfolded SOD1. A single intrathecal injection of the AAV encoding the single-chain antibody in SOD1(G93A) mice at 45 days of age resulted in sustained expression of single-chain antibodies in the spinal cord, and it delayed disease onset and extension of life span by up to 28%, in direct correlation with scFv titers in the spinal cord. The treatment caused attenuation of neuronal stress signals and reduction in levels of misfolded SOD1 in the spinal cord of SOD1(G93A) mice. From these results, we propose that an immunotherapy based on intrathecal inoculation of AAV encoding a secretable scFv against misfolded SOD1 should be considered as potential treatment for ALS, especially for individuals carrying SOD1 mutations.
authors.affiliation: Research Centre of Institut universitaire en santé mentale de Québec, Québec, Québec, Canada; Department of Psychiatry and Neuroscience, Laval University, Québec, Québec, Canada.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Patel
authors.affiliation: Research Centre of Institut universitaire en santé mentale de Québec, Québec, Québec, Canada; Department of Psychiatry and Neuroscience, Laval University, Québec, Québec, Canada.
authors.forename: Jasna
authors.initials: J
authors.lastname: Kriz
authors.affiliation: Research Centre of Institut universitaire en santé mentale de Québec, Québec, Québec, Canada; Department of Psychiatry and Neuroscience, Laval University, Québec, Québec, Canada.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Gravel
authors.affiliation: Research Centre of Institut universitaire en santé mentale de Québec, Québec, Québec, Canada; Department of Psychiatry and Neuroscience, Laval University, Québec, Québec, Canada.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Soucy
authors.affiliation: Research Centre of Institut universitaire en santé mentale de Québec, Québec, Québec, Canada; Department of Psychiatry and Neuroscience, Laval University, Québec, Québec, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: Bareil
authors.affiliation: Research Centre of Institut universitaire en santé mentale de Québec, Québec, Québec, Canada; Department of Psychiatry and Neuroscience, Laval University, Québec, Québec, Canada.
authors.forename: Claude
authors.initials: C
authors.lastname: Gravel
authors.affiliation: Research Centre of Institut universitaire en santé mentale de Québec, Québec, Québec, Canada; Department of Psychiatry and Neuroscience, Laval University, Québec, Québec, Canada. Electronic address: jean-pierre.julien@fmed.ulaval.ca.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Julien
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000276:immunology / Q000628:therapy*; D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D018450:Disease Progression; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D005911:Gliosis / Q000473:pathology / Q000628:therapy; D057809:HEK293 Cells; D006801:Humans; D007167:Immunotherapy; D007278:Injections, Spinal; D051379:Mice; D017510:Protein Folding; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology; D057127:Single-Chain Antibodies / Q000276:immunology* / Q000494:pharmacology; D013116:Spinal Cord / Q000276:immunology*; D013482:Superoxide Dismutase / Q000276:immunology* / Q000378:metabolism; D000072105:Superoxide Dismutase-1
chemical_list: D011994:Recombinant Proteins; C000606290:SOD1 protein, human; D057127:Single-Chain Antibodies; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1