title: Single chain variable fragment antibodies block aggregation and toxicity induced by familial ALS-linked mutant forms of SOD1.
abstract: Approximately 10% of amyotrophic lateral sclerosis (ALS) cases are familial (known as FALS) with an autosomal dominant inheritance pattern, and ~25% of FALS cases are caused by mutations in Cu/Zn superoxide dismutase (SOD1). There is convincing evidence that mutant SOD1 (mtSOD1) kills motor neurons (MNs) because of a gain-of-function toxicity, most likely related to aggregation of mtSOD1. A number of recent reports have suggested that antibodies can be used to treat mtSOD1-induced FALS. To follow up on the use of antibodies as potential therapeutics, we generated single chain fragments of variable region antibodies (scFvs) against SOD1, and then expressed them as 'intrabodies' within a motor neuron cell line. In the present study, we describe isolation of human scFvs that interfere with mtSOD1 in vitro aggregation and toxicity. These scFvs may have therapeutic potential in sporadic ALS, as well as FALS, given that sporadic ALS may also involve abnormalities in the SOD1 protein or activity.
authors.affiliation: Department of Neurology, University of Chicago Medical Center, 5841 S. Maryland Avenue, MC2030, Chicago, IL 60637, USA.
authors.forename: Ghanashyam D
authors.initials: GD
authors.lastname: Ghadge
authors.forename: John D
authors.initials: JD
authors.lastname: Pavlovic
authors.forename: Sujatha P
authors.initials: SP
authors.lastname: Koduvayur
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kay
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Roos
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D017104:Bacteriophage M13 / Q000235:genetics; D019921:Biotinylation; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D003001:Cloning, Molecular; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007128:Immunoglobulin Fragments / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000187:drug effects* / Q000235:genetics; D000072105:Superoxide Dismutase-1
chemical_list: D007128:Immunoglobulin Fragments; C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1