A monoclonal antibody TrkB receptor agonist as a potential therapeutic for Huntington's disease.

Daniel Todd, Ian Gowers, Simon J Dowler, Michael D Wall, George McAllister, David F Fischer, Sipke Dijkstra, Silvina A Fratantoni, Rhea van de Bospoort, Jessica Veenman-Koepke, Geraldine Flynn, Jamshid Arjomand, Celia Dominguez, Ignacio Munoz-Sanjuan, John Wityak, Jonathan A Bard

Index: PLoS ONE 9(2) , e87923, (2014)

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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.