title: The novel KMO inhibitor CHDI-340246 leads to a restoration of electrophysiological alterations in mouse models of Huntington's disease.
abstract: Dysregulation of the kynurenine (Kyn) pathway has been associated with the progression of Huntington's disease (HD). In particular, elevated levels of the kynurenine metabolites 3-hydroxy kynurenine (3-OH-Kyn) and quinolinic acid (Quin), have been reported in the brains of HD patients as well as in rodent models of HD. The production of these metabolites is controlled by the activity of kynurenine mono-oxygenase (KMO), an enzyme which catalyzes the synthesis of 3-OH-Kyn from Kyn. In order to determine the role of KMO in the phenotype of mouse models of HD, we have developed a potent and selective KMO inhibitor termed CHDI-340246. We show that this compound, when administered orally to transgenic mouse models of HD, potently and dose-dependently modulates the Kyn pathway in peripheral tissues and in the central nervous system. The administration of CHDI-340246 leads to an inhibition of the formation of 3-OH-Kyn and Quin, and to an elevation of Kyn and Kynurenic acid (KynA) levels in brain tissues. We show that administration of CHDI-340246 or of Kyn and of KynA can restore several electrophysiological alterations in mouse models of HD, both acutely and after chronic administration. However, using a comprehensive panel of behavioral tests, we demonstrate that the chronic dosing of a selective KMO inhibitor does not significantly modify behavioral phenotypes or natural progression in mouse models of HD.
authors.affiliation: CHDI Foundation/CHDI Management Inc., Los Angeles, USA.
authors.forename: Vahri
authors.initials: V
authors.lastname: Beaumont
authors.affiliation: CHDI Foundation/CHDI Management Inc., Los Angeles, USA.
authors.forename: Ladislav
authors.initials: L
authors.lastname: Mrzljak
authors.affiliation: Brains Online, San Francisco, USA.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Dijkman
authors.affiliation: Brains Online, San Francisco, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Freije
authors.affiliation: Brains Online, San Francisco, USA.
authors.forename: Mariette
authors.initials: M
authors.lastname: Heins
authors.affiliation: Brains Online, San Francisco, USA.
authors.forename: Arash
authors.initials: A
authors.lastname: Rassoulpour
authors.affiliation: Psychogenics, Montvale, USA.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Tombaugh
authors.affiliation: Psychogenics, Montvale, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Gelman
authors.affiliation: Neuroservice SARL, Aix-en-Provence, France.
authors.forename: Amyaouch
authors.initials: A
authors.lastname: Bradaia
authors.affiliation: Neuroservice SARL, Aix-en-Provence, France.
authors.forename: Esther
authors.initials: E
authors.lastname: Steidl
authors.affiliation: Neuroservice SARL, Aix-en-Provence, France.
authors.forename: Melanie
authors.initials: M
authors.lastname: Gleyzes
authors.affiliation: Charles River Discovery Services, Kuopio, Finland.
authors.forename: Taneli
authors.initials: T
authors.lastname: Heikkinen
authors.affiliation: Charles River Discovery Services, Kuopio, Finland.
authors.forename: Kimmo
authors.initials: K
authors.lastname: Lehtimäki
authors.affiliation: Charles River Discovery Services, Kuopio, Finland.
authors.forename: Jukka
authors.initials: J
authors.lastname: Puoliväli
authors.affiliation: Charles River Discovery Services, Kuopio, Finland.
authors.forename: Outi
authors.initials: O
authors.lastname: Kontkanen
authors.affiliation: CHDI Foundation/CHDI Management Inc., Los Angeles, USA.
authors.forename: Robyn M
authors.initials: RM
authors.lastname: Javier
authors.affiliation: Evotec AG, Hamburg, Germany.
authors.forename: Ioana
authors.initials: I
authors.lastname: Neagoe
authors.affiliation: Evotec AG, Hamburg, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Deisemann
authors.affiliation: Evotec AG, Hamburg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Winkler
authors.affiliation: Evotec AG, Hamburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Ebneth
authors.affiliation: CHDI Foundation/CHDI Management Inc., Los Angeles, USA.
authors.forename: Vinod
authors.initials: V
authors.lastname: Khetarpal
authors.affiliation: CHDI Foundation/CHDI Management Inc., Los Angeles, USA.
authors.forename: Leticia
authors.initials: L
authors.lastname: Toledo-Sherman
authors.affiliation: CHDI Foundation/CHDI Management Inc., Los Angeles, USA.
authors.forename: Celia
authors.initials: C
authors.lastname: Dominguez
authors.affiliation: CHDI Foundation/CHDI Management Inc., Los Angeles, USA.
authors.forename: Larry C
authors.initials: LC
authors.lastname: Park
authors.affiliation: CHDI Foundation/CHDI Management Inc., Los Angeles, USA. Electronic address: Ignacio.munoz@chdifoundation.org.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Munoz-Sanjuan
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D055724:Electrophysiological Phenomena / Q000187:drug effects* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006624:Hippocampus / Q000187:drug effects; D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics; D006816:Huntington Disease / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology*; D066298:In Vitro Techniques; D007736:Kynurenic Acid / Q000378:metabolism; D050601:Kynurenine 3-Monooxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017551:Microdialysis; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D017378:Quinolinic Acid / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014162:Transfection; D018911:Trinucleotide Repeats / Q000235:genetics; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000235:genetics / Q000378:metabolism
chemical_list: C000618327:CHDI-340246; D004791:Enzyme Inhibitors; C086055:HTT protein, human; D000071058:Huntingtin Protein; D011743:Pyrimidines; D016194:Receptors, N-Methyl-D-Aspartate; D064569:alpha7 Nicotinic Acetylcholine Receptor; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D050601:Kynurenine 3-Monooxygenase; D017378:Quinolinic Acid; D007736:Kynurenic Acid
keywords: Huntington's disease; Inhibitor; Kynurenic acid; Kynurenine; Neurodegeneration; Pharmacodynamic; Q175; Quinolinic acid; R6/2