Ciliary neurotrophic factor explained

Ciliary neurotrophic factor is a protein that in humans is encoded by the CNTF gene.^{[1] [2] [3]}

The protein encoded by this gene is a polypeptide hormone and neurotrophic factor whose actions have mainly been studied in the nervous system where it promotes neurotransmitter synthesis and neurite outgrowth in certain neural populations including astrocytes. It is a hypothalamic neuropeptide that is a potent survival factor for neurons and oligodendrocytes and may be relevant in reducing tissue destruction during inflammatory attacks. A mutation in this gene, which results in aberrant splicing, leads to ciliary neurotrophic factor deficiency, but this phenotype is not causally related to neurologic disease. In addition to the predominant monocistronic transcript originating from this locus, the gene is also 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.

CNTF has also been shown to be expressed by cells on the bone surface, and to reduce the activity of bone-forming cells (osteoblasts).^[4]

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 or 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.^[5]

Recombinant human CNTF (Axokine)

A 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.^[6] 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.^[7] 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 effects, as these antibodies could potentially interfere with the neuroprotective functions of endogenous CNTF.^[8] 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 MHC alleles, and provides specific examples of such modifications. No such analogues are currently listed in Xencor's product pipeline.^[9]

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.^{[10] [11]}

Interactions

Human ciliary neurotrophic factor has been shown to interact with the Interleukin 6 receptor.^{[12] [13]}

See also

• Ciliary neurotrophic factor receptor
• Interleukin 6
• George Yancopoulos

Further reading

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

Notes and References

1. Lam A, Fuller F, Miller J, Kloss J, Manthorpe M, Varon S, Cordell B . Sequence and structural organization of the human gene encoding ciliary neurotrophic factor . Gene . 102 . 2 . 271–6 . Sep 1991 . 1840538 . 10.1016/0378-1119(91)90089-T .
2. Bazan JF . Neuropoietic cytokines in the hematopoietic fold . Neuron . 7 . 2 . 197–208 . Sep 1991 . 1714745 . 10.1016/0896-6273(91)90258-2 . 24161982 .
3. Web site: Entrez Gene: CNTF ciliary neurotrophic factor.
4. 10.1007/s00223-010-9337-4 . McGregor NE, Poulton IJ, Walker EC, Pompolo S, Quinn JM, Martin TJ, Sims NA . Ciliary neurotrophic factor inhibits bone formation and plays a sex-specific role in bone growth and remodeling . Calcified Tissue International . 86 . 3 . 261–70 . Mar 2010 . 20157807 . 23699865 .
5. Lambert PD, Anderson KD, Sleeman MW, Wong V, Tan J, Hijarunguru A, Corcoran TL, Murray JD, Thabet KE, Yancopoulos GD, Wiegand SJ . Ciliary neurotrophic factor activates leptin-like pathways and reduces body fat, without cachexia or rebound weight gain, even in leptin-resistant obesity . Proc. Natl. Acad. Sci. U.S.A. . 98 . 8 . 4652–7 . 2001 . 11259650 . 10.1073/pnas.061034298 . 31889 . free .
6. Peterson WM, Wang Q, Tzekova R, Wiegand SJ . Ciliary neurotrophic factor and stress stimuli activate the Jak-STAT pathway in retinal neurons and glia . J. Neurosci. . 20 . 11 . 4081–90 . June 2000 . 10818143 . 6772642 . 10.1523/JNEUROSCI.20-11-04081.2000.
7. Web site: Axokine from Regeneron (REGN): Unexpected Antibodies and Modest Efficacy in Phase III Study . 2003-03-31 . Press Release . Regeneron Pharmaceuticals . 2011-08-20 .
8. US . 2005064555 . application . Ciliary neurotrophic factor variants . 2005-03-24 . Marshall S, Barbosa M.
9. Web site: Product Pipeline . Xencor . 2011-08-20 .
10. Talcott KE, Ratnam K, Sundquist SM, Lucero AS, Lujan BJ, Tao W, Porco TC, Roorda A, Duncan JL . Longitudinal study of cone photoreceptors during retinal degeneration and in response to ciliary neurotrophic factor treatment . Invest. Ophthalmol. Vis. Sci. . 52 . 5 . 2219–26 . April 2011 . 21087953 . 10.1167/iovs.10-6479 . 3080173.
11. Web site: Neurotech's NT-501 Implant Demonstrates Statistically Significant Photoreceptor Preservation in Patients with Retinal Degenerative Disease . 2011-04-11 . Business Wire . 2011-08-20 .
12. Schuster B, Kovaleva M, Sun Y, Regenhard P, Matthews V, Grötzinger J, Rose-John S, Kallen KJ . Signaling of human ciliary neurotrophic factor (CNTF) revisited. The interleukin-6 receptor can serve as an alpha-receptor for CTNF . J. Biol. Chem. . 278 . 11 . 9528–35 . March 2003 . 12643274 . 10.1074/jbc.M210044200. free .
13. Schooltink H, Stoyan T, Roeb E, Heinrich PC, Rose-John S . Ciliary neurotrophic factor induces acute-phase protein expression in hepatocytes . FEBS Lett. . 314 . 3 . 280–4 . December 1992 . 1281789 . 10.1016/0014-5793(92)81489-9. 39538295 . free .