title: Identification of combinatorial drug regimens for treatment of Huntington's disease using Drosophila.
abstract: We explore the hypothesis that pathology of Huntington's disease involves multiple cellular mechanisms whose contributions to disease are incrementally additive or synergistic. We provide evidence that the photoreceptor neuron degeneration seen in flies expressing mutant human huntingtin correlates with widespread degenerative events in the Drosophila CNS. We use a Drosophila Huntington's disease model to establish dose regimens and protocols to assess the effectiveness of drug combinations used at low threshold concentrations. These proof of principle studies identify at least two potential combinatorial treatment options and illustrate a rapid and cost-effective paradigm for testing and optimizing combinatorial drug therapies while reducing side effects for patients with neurodegenerative disease. The potential for using prescreening in Drosophila to inform combinatorial therapies that are most likely to be effective for testing in mammals is discussed.
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, CA 92697, USA.
authors.forename: Namita
authors.initials: N
authors.lastname: Agrawal
authors.forename: Judit
authors.initials: J
authors.lastname: Pallos
authors.forename: Natalia
authors.initials: N
authors.lastname: Slepko
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Apostol
authors.forename: Laszlo
authors.initials: L
authors.lastname: Bodai
authors.forename: Ling-Wen
authors.initials: LW
authors.lastname: Chang
authors.forename: Ann-Shyn
authors.initials: AS
authors.lastname: Chiang
authors.forename: Leslie Michels
authors.initials: LM
authors.lastname: Thompson
authors.forename: J Lawrence
authors.initials: JL
authors.lastname: Marsh
mesh_terms: D000577:Amides / Q000008:administration & dosage; D000818:Animals; D016227:Benzoquinones; D004195:Disease Models, Animal; D004330:Drosophila; D004359:Drug Therapy, Combination; D005260:Female; D006816:Huntington Disease / Q000188:drug therapy*; D006877:Hydroxamic Acids / Q000008:administration & dosage; D047029:Lactams, Macrocyclic; D009410:Nerve Degeneration / Q000517:prevention & control; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D011725:Pyridines / Q000008:administration & dosage; D011809:Quinones / Q000008:administration & dosage; D000077337:Vorinostat
chemical_list: D000577:Amides; D016227:Benzoquinones; D006877:Hydroxamic Acids; D047029:Lactams, Macrocyclic; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011725:Pyridines; D011809:Quinones; C108830:Y 27632; D000077337:Vorinostat; C001277:geldanamycin
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