View source for Ciliary neurotrophic factor

{{Short description|Protein found in humans}}
{{Infobox_gene}}
'''Ciliary neurotrophic factor''' is a [[protein]] that in humans is encoded by the ''CNTF'' [[gene]].<ref name="pmid1840538">{{cite journal | vauthors = Lam A, Fuller F, Miller J, Kloss J, Manthorpe M, Varon S, Cordell B | title = Sequence and structural organization of the human gene encoding ciliary neurotrophic factor | journal = Gene | volume = 102 | issue = 2 | pages = 271–6 |date=Sep 1991 | pmid = 1840538 | doi =10.1016/0378-1119(91)90089-T  }}</ref><ref name="pmid1714745">{{cite journal | author = Bazan JF | title = Neuropoietic cytokines in the hematopoietic fold | journal = Neuron | volume = 7 | issue = 2 | pages = 197–208 |date=Sep 1991 | pmid = 1714745 | doi =10.1016/0896-6273(91)90258-2  | s2cid = 24161982 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: CNTF ciliary neurotrophic factor| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1270}}</ref>

The protein encoded by this gene is a [[peptide hormone|polypeptide hormone]] and  [[neurotrophic factors|neurotrophic factor]] whose actions have mainly been studied in the nervous system where it promotes [[neurotransmitter]] synthesis and [[neurite]] outgrowth in certain [[neural population]]s including [[astrocyte]]s. It is a hypothalamic [[neuropeptide]] that is a potent survival factor for [[neuron]]s and [[oligodendrocyte]]s and may be relevant in reducing tissue destruction during [[inflammation|inflammatory attacks]]. A [[mutation]] in this gene, which results in aberrant splicing, leads to ciliary neurotrophic factor deficiency, but this phenotype is not [[causality|causally]] related to [[neurological disorder|neurologic disease]]. In addition to the predominant [[cistron|monocistronic]] transcript originating from this locus, the gene is also [[transcription (genetics)|cotranscribed]] with the upstream [[ZFP91]] gene. Cotranscription from the two loci results in a transcript that contains a complete [[coding region]] for the zinc finger protein but lacks a complete coding region for ciliary neurotrophic factor.<ref name="entrez" />

CNTF has also been shown to be expressed by [[cell (biology)|cells]] on the [[bone]] surface, and to reduce the activity of bone-forming cells ([[osteoblast]]s).<ref name="pmid20157807">{{cite journal | doi = 10.1007/s00223-010-9337-4 | vauthors = McGregor NE, Poulton IJ, Walker EC, Pompolo S, Quinn JM, Martin TJ, Sims NA | title = Ciliary neurotrophic factor inhibits bone formation and plays a sex-specific role in bone growth and remodeling | journal = Calcified Tissue International | volume = 86 | issue = 3 | pages = 261–70 |date=Mar 2010 | pmid = 20157807 | s2cid = 23699865 }}</ref>

==Therapeutic applications ==

=== Satiety effects ===

In 2001, it was reported that in a human study examining the usefulness of CNTF for treatment of [[motor neuron disease]], CNTF produced an unexpected and substantial weight loss in the study subjects. Further investigation revealed that CNTF could reduce food intake without causing [[hunger (motivational state)|hunger]] or [[stress (psychological)|stress]], making it a candidate for weight control in [[leptin]]-resistant subjects, as CNTF is believed to operate like leptin, but by a non-leptin pathway.<ref name="pmid11259650">{{cite journal | vauthors = Lambert PD, Anderson KD, Sleeman MW, Wong V, Tan J, Hijarunguru A, Corcoran TL, Murray JD, Thabet KE, Yancopoulos GD, Wiegand SJ | title = Ciliary neurotrophic factor activates leptin-like pathways and reduces body fat, without cachexia or rebound weight gain, even in leptin-resistant obesity | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 98 | issue = 8 | pages = 4652–7 | year = 2001 | pmid = 11259650 | doi = 10.1073/pnas.061034298 | pmc = 31889 | doi-access = free }}</ref>

=== Recombinant human CNTF (Axokine) ===
A [[protein production|recombinant]] version of human CNTF (rhCNTF), trade name Axokine, is a modified version with a 15 [[amino acid]] truncation of the [[C-terminus]] and two amino acid substitutions. It is three to five times more potent than CNTF in [[in vitro]] and [[in vivo]] assays and has improved stability properties.<ref name="pmid10818143">{{cite journal | vauthors = Peterson WM, Wang Q, Tzekova R, Wiegand SJ | title = Ciliary neurotrophic factor and stress stimuli activate the Jak-STAT pathway in retinal neurons and glia | journal = J. Neurosci. | volume = 20 | issue = 11 | pages = 4081–90 |date=June 2000 | pmid = 10818143 | pmc = 6772642 | doi = 10.1523/JNEUROSCI.20-11-04081.2000}}</ref>  Like CNTF it is a [[neurotrophic factor]], and may stimulate nerve cells to survive.  It was tested in the 1990s as a treatment for [[amyotrophic lateral sclerosis]]. It did not improve muscle control as much as expected, but trial participants did report a loss of [[appetite]].

Phase III clinical trials for the drug against [[obesity]] were conducted in 2003 by Axokine's maker, [[Regeneron Pharmaceuticals]], demonstrating a small positive effect in some patients, but the drug was not commercialized.  A major problem with the treatment was that in nearly 70% of the subjects tested, antibodies against Axokine were produced after approximately three months of treatment.<ref name="url_Axokine_Press_Release">{{cite web | url = http://www.pharmagon.com/Library/InfoManage/Zoom.asp?InfoID=1813&RedirectPath=Add&FolderID=1561&InfoGroup=Main&InfoType=Article | title = Axokine from Regeneron (REGN): Unexpected Antibodies and Modest Efficacy in Phase III Study | date = 2003-03-31 | work = Press Release | publisher = Regeneron Pharmaceuticals | access-date = 2011-08-20 }}</ref>  In the minority of subjects who did not develop the antibodies, weight loss averaged 12.5 pounds in one year, versus 4.5 pounds for [[placebo]]-treated subjects.  In order to obtain this benefit, subjects needed to receive daily subcutaneous injections of one microgram Axokine per kilogram body weight.

[[Xencor]] patent application raises the disturbing idea that subjects producing antibodies against CNTF analogues may eventually suffer severe [[adverse drug reaction|adverse effect]]s, as these antibodies could potentially interfere with the neuroprotective functions of endogenous CNTF.<ref name="US2005064555">{{ cite patent | country = US | number = 2005064555 | status = application | title = Ciliary neurotrophic factor variants | pubdate = 2005-03-24 | inventor = Marshall S, Barbosa M}}</ref> The application claims methods of designing CNTF analogues with lower [[immunogenicity]] than Axokine based on analysis of affinity of each modified [[epitope]] for each of 52 class II [[major histocompatibility complex|MHC]] alleles, and provides specific examples of such modifications.  No such analogues are currently listed in Xencor's product pipeline.<ref name="urlPipeline | Xencor">{{cite web | url = http://www.xencor.com/products/pipeline/ | title = Product Pipeline | publisher = Xencor | access-date = 2011-08-20 }}</ref>

=== NT-501 ===

NT-501 is a product being developed by Neurotech that consists of encapsulated human cells genetically modified to secrete ciliary neurotrophic factor (CNTF). In a clinical trial, NT-501 demonstrated a statistically significant reduction of photoreceptor degradation in patients with [[retinitis pigmentosa]].<ref name="pmid21087953">{{cite journal | vauthors = Talcott KE, Ratnam K, Sundquist SM, Lucero AS, Lujan BJ, Tao W, Porco TC, Roorda A, Duncan JL | title = Longitudinal study of cone photoreceptors during retinal degeneration and in response to ciliary neurotrophic factor treatment | journal = Invest. Ophthalmol. Vis. Sci. | volume = 52 | issue = 5 | pages = 2219–26 |date=April 2011 | pmid = 21087953 | doi = 10.1167/iovs.10-6479 | pmc=3080173}}</ref><ref name="urlNeurotech’s NT-501 Implant Demonstrates Statistically Significant Photoreceptor Preservation in Patients with Retinal Degenerative Disease | Business Wire">{{cite web | url = http://www.businesswire.com/news/home/20110414005343/en/Neurotech’s-NT-501-Implant-Demonstrates-Statistically-Significant-Photoreceptor | title = Neurotech's NT-501 Implant Demonstrates Statistically Significant Photoreceptor Preservation in Patients with Retinal Degenerative Disease | date = 2011-04-11  | publisher =  Business Wire | access-date = 2011-08-20 }}</ref>

==Interactions==
Human ciliary neurotrophic factor has been shown to [[Protein-protein interaction|interact]] with the [[Interleukin 6 receptor]].<ref name="pmid12643274">{{cite journal | vauthors = Schuster B, Kovaleva M, Sun Y, Regenhard P, Matthews V, Grötzinger J, Rose-John S, Kallen KJ | title = Signaling of human ciliary neurotrophic factor (CNTF) revisited. The interleukin-6 receptor can serve as an alpha-receptor for CTNF | journal = J. Biol. Chem. | volume = 278 | issue = 11 | pages = 9528–35 |date=March 2003 | pmid = 12643274 | doi = 10.1074/jbc.M210044200| doi-access =free  }}</ref><ref name="pmid1281789">{{cite journal | vauthors = Schooltink H, Stoyan T, Roeb E, Heinrich PC, Rose-John S | title = Ciliary neurotrophic factor induces acute-phase protein expression in hepatocytes | journal = FEBS Lett. | volume = 314 | issue = 3 | pages = 280–4 |date=December 1992 | pmid = 1281789 | doi = 10.1016/0014-5793(92)81489-9| s2cid = 39538295 | doi-access = free | bibcode = 1992FEBSL.314..280S }}</ref>

==See also==
* [[Ciliary neurotrophic factor receptor]]
* [[Interleukin 6]]
* [[George Yancopoulos]]

== References ==
{{Reflist}}

==Further reading==
{{refbegin | 2}}
*{{cite journal  | vauthors=Sendtner M, Carroll P, Holtmann B |title=Ciliary neurotrophic factor. |journal=J. Neurobiol. |volume=25 |issue= 11 |pages= 1436–53 |year= 1995 |pmid= 7852996 |doi= 10.1002/neu.480251110 |display-authors=etal|url=https://opus.bibliothek.uni-wuerzburg.de/frontdoor/index/index/docId/3564 }}
*{{cite journal  | vauthors=Sleeman MW, Anderson KD, Lambert PD |title=The ciliary neurotrophic factor and its receptor, CNTFR alpha. |journal=Pharmaceutica Acta Helvetiae |volume=74 |issue= 2–3 |pages= 265–72 |year= 2000 |pmid= 10812968 |doi=10.1016/S0031-6865(99)00050-3  |display-authors=etal}}
*{{cite journal  | vauthors=Schooltink H, Stoyan T, Roeb E |title=Ciliary neurotrophic factor induces acute-phase protein expression in hepatocytes. |journal=FEBS Lett. |volume=314 |issue= 3 |pages= 280–4 |year= 1993 |pmid= 1281789 |doi=10.1016/0014-5793(92)81489-9  |s2cid=39538295 |display-authors=etal|doi-access=free |bibcode=1992FEBSL.314..280S }}
*{{cite journal  | vauthors=Masiakowski P, Liu HX, Radziejewski C |title=Recombinant human and rat ciliary neurotrophic factors. |journal=J. Neurochem. |volume=57 |issue= 3 |pages= 1003–12 |year= 1991 |pmid= 1861138 |doi=10.1111/j.1471-4159.1991.tb08250.x  |s2cid=7965554 |display-authors=etal}}
*{{cite journal  | vauthors=McDonald JR, Ko C, Mismer D |title=Expression and characterization of recombinant human ciliary neurotrophic factor from Escherichia coli. |journal=Biochim. Biophys. Acta |volume=1090 |issue= 1 |pages= 70–80 |year= 1991 |pmid= 1883844 |doi=  10.1016/0167-4781(91)90038-n|display-authors=etal}}
*{{cite journal  | vauthors=Negro A, Tolosano E, Skaper SD |title=Cloning and expression of human ciliary neurotrophic factor. |journal=Eur. J. Biochem. |volume=201 |issue= 1 |pages= 289–94 |year= 1991 |pmid= 1915374 |doi=10.1111/j.1432-1033.1991.tb16286.x  |display-authors=etal}}
*{{cite journal  | vauthors=Lichter P, Tang CJ, Call K |title=High-resolution mapping of human chromosome 11 by in situ hybridization with cosmid clones. |journal=Science |volume=247 |issue= 4938 |pages= 64–9 |year= 1990 |pmid= 2294592 |doi=10.1126/science.2294592  |bibcode=1990Sci...247...64L |display-authors=etal}}
*{{cite journal  | vauthors=Winter CG, Saotome Y, Levison SW, Hirsh D |title=A role for ciliary neurotrophic factor as an inducer of reactive gliosis, the glial response to central nervous system injury. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=92 |issue= 13 |pages= 5865–9 |year= 1995 |pmid= 7597043 |doi=10.1073/pnas.92.13.5865  | pmc=41602  |bibcode=1995PNAS...92.5865W |doi-access=free }}
*{{cite journal  | vauthors=Yokoji H, Ariyama T, Takahashi R |title=cDNA cloning and chromosomal localization of the human ciliary neurotrophic factor gene. |journal=Neurosci. Lett. |volume=185 |issue= 3 |pages= 175–8 |year= 1995 |pmid= 7753485 |doi=10.1016/0304-3940(95)11254-T  |s2cid=26711154 |display-authors=etal}}
*{{cite journal  | vauthors=McDonald NQ, Panayotatos N, Hendrickson WA |title=Crystal structure of dimeric human ciliary neurotrophic factor determined by MAD phasing. |journal=EMBO J. |volume=14 |issue= 12 |pages= 2689–99 |year= 1995 |pmid= 7796798 |doi=  10.1002/j.1460-2075.1995.tb07269.x| pmc=398387  }}
*{{cite journal  | vauthors=Saggio I, Paonessa G, Gloaguen I |title=Nonradioactive receptor binding assay for ciliary neurotrophic factor. |journal=Anal. Biochem. |volume=221 |issue= 2 |pages= 387–91 |year= 1995 |pmid= 7810882 |doi=10.1006/abio.1994.1430  |display-authors=etal}}
*{{cite journal  | vauthors=Takahashi R, Yokoji H, Misawa H |title=A null mutation in the human CNTF gene is not causally related to neurological diseases. |journal=Nat. Genet. |volume=7 |issue= 1 |pages= 79–84 |year= 1994 |pmid= 8075647 |doi= 10.1038/ng0594-79 |display-authors=etal|hdl=2433/160721 |s2cid=5606065 |hdl-access=free }}
*{{cite journal  | vauthors=Giovannini M, Romo AJ, Evans GA |title=Chromosomal localization of the human ciliary neurotrophic factor gene (CNTF) to 11q12 by fluorescence in situ hybridization. |journal=Cytogenet. Cell Genet. |volume=63 |issue= 1 |pages= 62–3 |year= 1993 |pmid= 8449041 |doi=10.1159/000133504  }}
*{{cite journal  | vauthors=Robledo O, Auguste P, Coupey L |title=Binding interactions of leukemia inhibitory factor and ciliary neurotrophic factor with the different subunits of their high affinity receptors. |journal=J. Neurochem. |volume=66 |issue= 4 |pages= 1391–9 |year= 1996 |pmid= 8627290 |doi=10.1046/j.1471-4159.1996.66041391.x  |s2cid=35399535 |display-authors=etal}}
*{{cite journal  | vauthors=Gutman CR, Strittmatter WJ, Weisgraber KH, Matthew WD |title=Apolipoprotein E binds to and potentiates the biological activity of ciliary neurotrophic factor. |journal=J. Neurosci. |volume=17 |issue= 16 |pages= 6114–21 |year= 1997 |pmid= 9236223 |pmc=6568355 |doi=  10.1523/JNEUROSCI.17-16-06114.1997}}
*{{cite journal  | vauthors=Cargill M, Altshuler D, Ireland J |title=Characterization of single-nucleotide polymorphisms in coding regions of human genes. |journal=Nat. Genet. |volume=22 |issue= 3 |pages= 231–8 |year= 1999 |pmid= 10391209 |doi= 10.1038/10290 |s2cid=195213008 |display-authors=etal}}
{{refend}}

==External links==
* {{MeshName|Ciliary+neurotrophic+factor}}
* {{PDBe-KB2|P26441|Ciliary neurotrophic factor}}

{{PDB Gallery|geneid=1270}}
{{Neurotrophic factors}}
{{Interleukins}}
{{Neurotrophinergics}}

[[Category:Neurotrophic factors]]
[[Category:Peptide hormones]]
[[Category:Proteins]]
[[Category:Developmental neuroscience]]