title: Ciliary neurotrophic factor (CNTF): New facets of an old molecule for treating neurodegenerative and metabolic syndrome pathologies.
abstract: Ciliary neurotrophic factor (CNTF) is the most extensively studied member of the cytokine family that signal through intracellular chains of the gp130/LIFRβ receptor. The severe phenotype in patients suffering from mutations inactivating LIFRβ indicates that members of this cytokine family play key, non-redundant roles during development. Accordingly, three decades of research has revealed potent and promising trophic and regulatory activities of CNTF in neurons, oligodendrocytes, muscle cells, bone cells, adipocytes and retinal cells. These findings led to clinical trials to test the therapeutic potential of CNTF and CNTF derivatives for treating neurodegenerative and metabolic diseases. Promising results have encouraged continuation of studies for treating retinal degenerative diseases. Results of some clinical trials showed that side-effects may limit the systemically administrated doses of CNTF. Therefore, therapies being currently tested rely on local delivery of CNTF using encapsulated cytokine-secreting implants. Since the side effects of CNTF might be linked to its ability to activate the alternative IL6Rα-LIFRβ-gp130 receptor, CNTFR-specific mutants of CNTF have been developed that bind to the CNTFRα-LIFRβ-gp130 receptor. These developments may prove to be a breakthrough for therapeutic applications of systemically administered CNTF in pathologies such as multiple sclerosis or Alzheimer's disease. The "designer cytokine approach" offers future opportunities to further enhance specificity by conjugating mutant CNTF with modified soluble CNTFRα to target therapeutically relevant cells that express gp130-LIFRβ and a specific cell surface marker.
authors.affiliation: Département de Pharmacologie, Université de Montréal, 2900 Édouard Montpetit, Montreal, QC H3T 1J4, Canada.
authors.forename: Sarah
authors.initials: S
authors.lastname: Pasquin
authors.affiliation: Renal Division, KCVA Medical Center, 4801 Linwood Blvd, Kansas City, MO 64128, USA.
authors.forename: Mukut
authors.initials: M
authors.lastname: Sharma
authors.affiliation: Département de Pharmacologie, Université de Montréal, 2900 Édouard Montpetit, Montreal, QC H3T 1J4, Canada. Electronic address: jf.gauchat@umontreal.ca.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Gauchat
mesh_terms: D000818:Animals; D020934:Ciliary Neurotrophic Factor / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D053739:Ciliary Neurotrophic Factor Receptor alpha Subunit / Q000235:genetics / Q000276:immunology; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000276:immunology; D006801:Humans; D024821:Metabolic Syndrome / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000276:immunology
chemical_list: C548324:CNTFR protein, human; D020934:Ciliary Neurotrophic Factor; D053739:Ciliary Neurotrophic Factor Receptor alpha Subunit; C508603:IL6R protein, human; C494199:IL6ST protein, human; D019947:Receptors, Interleukin-6; D050822:Cytokine Receptor gp130
keywords: Age-related macular degeneration; Amyotrophic lateral sclerosis; Ciliary neurotrophic factor; Huntington's disease; Neurogenesis; Obesity