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: 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
• Journal: PloS one (PLoS One) Vol. 9 Issue 2 Pg. e87923 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 24503862 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Brain-Derived Neurotrophic Factor
• Neuroprotective Agents
• Receptor, trkB

Topics

• Animals
• Antibodies, Monoclonal (chemistry, pharmacology)
• Brain-Derived Neurotrophic Factor (metabolism)
• Cell Death (drug effects)
• Cell Line
• Cells, Cultured
• Corpus Striatum (cytology, drug effects)
• Disease Models, Animal
• Drug Evaluation, Preclinical
• Humans
• Huntington Disease (drug therapy, metabolism)
• Mice, Transgenic
• Neurons (drug effects, metabolism)
• Neuroprotective Agents (chemistry, pharmacology)
• Rats
• Receptor, trkB (agonists, metabolism)
• Signal Transduction (drug effects)