A Monoclonal Antibody TrkB Receptor Agonist as a Potential Therapeutic for Huntington's Disease

PLoS One. 2014 Feb 4;9(2):e87923. doi: 10.1371/journal.pone.0087923. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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

Grant support

CHDI Foundation is a not-for-profit biomedical research organization exclusively dedicated to discovering and developing therapeutics that slow the progression of Huntington's disease. The research described was conducted by BioFocus (UK and Netherlands) under a fee-for-service agreement from CHDI Foundation. The funder, through CHDI Management, fully participated in study design, data collection and analysis, the decision to publish, and preparation of the manuscript.