期刊
CYTOKINE & GROWTH FACTOR REVIEWS
卷 26, 期 5, 页码 507-515出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.cytogfr.2015.07.007
关键词
Ciliary neurotrophic factor; Neurogenesis; Huntington's disease; Amyotrophic lateral sclerosis; Age-related macular degeneration; Obesity
资金
- Canadian Institutes of Health Research (CIHR) [MOP-57832]
- Frederick Banting and Charles Best Canada Graduate Scholarship-Masters (CGS M) CIHR
- Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development [VABX001037]
- MBRF, KCVA Medical Center, Kansas City, MO, USA
Ciliary neurotrophic factor (CNTF) is the most extensively studied member of the cytokine family that signal through intracellular chains of the gp130/LIFR beta receptor. The severe phenotype in patients suffering from mutations inactivating LIFR beta 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 IL6R alpha-LIFR beta-gp130 receptor, CNTFR-specific mutants of CNTF have been developed that bind to the CNTFR alpha-LIFR beta-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 CNTFR alpha to target therapeutically relevant cells that express gp130-LIFR beta and a specific cell surface marker. (C) 2015 Elsevier Ltd. All rights reserved.
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