Identification of combinatorial drug regimens for treatment of Huntington's disease using Drosophila.
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.
Agrawal
Namita
N
Department of Developmental and Cell Biology, University of California, Irvine, CA 92697, USA.
Pallos
Judit
J
Slepko
Natalia
N
Apostol
Barbara L
BL
Bodai
Laszlo
L
Chang
Ling-Wen
LW
Chiang
Ann-Shyn
AS
Thompson
Leslie Michels
LM
Marsh
J Lawrence
JL
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
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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