title: Cystamine and intrabody co-treatment confers additional benefits in a fly model of Huntington's disease.
abstract: Huntington's disease (HD) is a lethal, neurodegenerative disorder caused by expansion of the polyglutamine repeat in the Huntingtin gene (HTT), leading to mutant protein misfolding, aggregation, and neuronal death. Feeding a Drosophila HD model cystamine, or expressing a transgene encoding the anti-htt intracellular antibody (intrabody) C4-scFv in the nervous system, demonstrated therapeutic potential, but suppression of pathology was incomplete. We hypothesized that a combinatorial approach entailing drug and intrabody administration could enhance rescue of HD pathology in flies and that timing of treatment would affect outcomes. Feeding cystamine to adult HD flies expressing the intrabody resulted in a significant, additional rescue of photoreceptor neurodegeneration, but no additional benefit in longevity. Feeding cystamine during both larval and adult stages produced the converse result: longevity was significantly improved, but increased photoreceptor survival was not. We conclude that cystamine-intrabody combination therapies can be effective, reducing neurodegeneration and prolonging survival, depending on administration protocols.
authors.affiliation: University of Portland, Biology Department, Portland, Oregon 97203, USA.
authors.forename: S F
authors.initials: SF
authors.lastname: Bortvedt
authors.forename: J A
authors.initials: JA
authors.lastname: McLear
authors.forename: A
authors.initials: A
authors.lastname: Messer
authors.forename: A J
authors.initials: AJ
authors.lastname: Ahern-Rindell
authors.forename: W J
authors.initials: WJ
authors.lastname: Wolfgang
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000906:Antibodies / Q000008:administration & dosage* / Q000235:genetics* / Q000378:metabolism; D003538:Cystamine / Q000008:administration & dosage* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000235:genetics* / Q000254:growth & development; D004359:Drug Therapy, Combination; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000178:diet therapy / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008957:Models, Genetic; D009410:Nerve Degeneration / Q000178:diet therapy / Q000473:pathology / Q000517:prevention & control; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology*; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology*; D017956:Photoreceptor Cells, Invertebrate / Q000187:drug effects / Q000473:pathology; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000906:Antibodies; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D003538:Cystamine
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