title: A monoclonal antibody TrkB receptor agonist as a potential therapeutic for Huntington's disease.
abstract: Huntington's disease (HD) is a devastating, genetic neurodegenerative disease caused by a tri-nucleotide expansion in exon 1 of the huntingtin gene. HD is clinically characterized by chorea, emotional and psychiatric disturbances and cognitive deficits with later symptoms including rigidity and dementia. Pathologically, the cortico-striatal pathway is severely dysfunctional as reflected by striatal and cortical atrophy in late-stage disease. Brain-derived neurotrophic factor (BDNF) is a neuroprotective, secreted protein that binds with high affinity to the extracellular domain of the tropomyosin-receptor kinase B (TrkB) receptor promoting neuronal cell survival by activating the receptor and down-stream signaling proteins. Reduced cortical BDNF production and transport to the striatum have been implicated in HD pathogenesis; the ability to enhance TrkB signaling using a BDNF mimetic might be beneficial in disease progression, so we explored this as a therapeutic strategy for HD. Using recombinant and native assay formats, we report here the evaluation of TrkB antibodies and a panel of reported small molecule TrkB agonists, and identify the best candidate, from those tested, for in vivo proof of concept studies in transgenic HD models.
authors: BioFocus, Saffron Walden, United Kingdom.
authors: Daniel
authors: D
authors: Todd
authors: BioFocus, Saffron Walden, United Kingdom.
authors: Ian
authors: I
authors: Gowers
authors: BioFocus, Saffron Walden, United Kingdom.
authors: Simon J
authors: SJ
authors: Dowler
authors: BioFocus, Saffron Walden, United Kingdom.
authors: Michael D
authors: MD
authors: Wall
authors: BioFocus, Saffron Walden, United Kingdom.
authors: George
authors: G
authors: McAllister
authors: BioFocus, Leiden, Netherlands.
authors: David F
authors: DF
authors: Fischer
authors: Galapagos, Leiden, Netherlands.
authors: Sipke
authors: S
authors: Dijkstra
authors: Galapagos, Leiden, Netherlands.
authors: Silvina A
authors: SA
authors: Fratantoni
authors: Galapagos, Leiden, Netherlands.
authors: Rhea
authors: R
authors: van de Bospoort
authors: Galapagos, Leiden, Netherlands.
authors: Jessica
authors: J
authors: Veenman-Koepke
authors: Galapagos, Leiden, Netherlands.
authors: Geraldine
authors: G
authors: Flynn
authors: CHDI Management/CHDI Foundation, Princeton, New Jersey, United States of America ; CHDI Management/CHDI Foundation, Los Angeles, California, United States of America.
authors: Jamshid
authors: J
authors: Arjomand
authors: CHDI Management/CHDI Foundation, Princeton, New Jersey, United States of America ; CHDI Management/CHDI Foundation, Los Angeles, California, United States of America.
authors: Celia
authors: C
authors: Dominguez
authors: CHDI Management/CHDI Foundation, Princeton, New Jersey, United States of America ; CHDI Management/CHDI Foundation, Los Angeles, California, United States of America.
authors: Ignacio
authors: I
authors: Munoz-Sanjuan
authors: CHDI Management/CHDI Foundation, Princeton, New Jersey, United States of America ; CHDI Management/CHDI Foundation, Los Angeles, California, United States of America.
authors: John
authors: J
authors: Wityak
authors: CHDI Management/CHDI Foundation, Princeton, New Jersey, United States of America ; CHDI Management/CHDI Foundation, Los Angeles, California, United States of America.
authors: Jonathan A
authors: JA
authors: Bard
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000494:pharmacology*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy / Q000378:metabolism*; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D020813:Receptor, trkB / Q000819:agonists* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D019208:Brain-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; D020813:Receptor, trkB