Biology:Ciliary neurotrophic factor

From HandWiki
Short description: Protein found in humans


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[3]

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

References

  1. ↑ "Sequence and structural organization of the human gene encoding ciliary neurotrophic factor". Gene 102 (2): 271–6. Sep 1991. doi:10.1016/0378-1119(91)90089-T. PMID 1840538. 
  2. ↑ Bazan JF (Sep 1991). "Neuropoietic cytokines in the hematopoietic fold". Neuron 7 (2): 197–208. doi:10.1016/0896-6273(91)90258-2. PMID 1714745. 
  3. ↑ 3.0 3.1 "Entrez Gene: CNTF ciliary neurotrophic factor". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1270. 
  4. ↑ "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. doi:10.1007/s00223-010-9337-4. PMID 20157807. 
  5. ↑ "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. doi:10.1073/pnas.061034298. PMID 11259650. 
  6. ↑ "Ciliary neurotrophic factor and stress stimuli activate the Jak-STAT pathway in retinal neurons and glia". J. Neurosci. 20 (11): 4081–90. June 2000. doi:10.1523/JNEUROSCI.20-11-04081.2000. PMID 10818143. 
  7. ↑ "Axokine from Regeneron (REGN): Unexpected Antibodies and Modest Efficacy in Phase III Study". Press Release. Regeneron Pharmaceuticals. 2003-03-31. http://www.pharmagon.com/Library/InfoManage/Zoom.asp?InfoID=1813&RedirectPath=Add&FolderID=1561&InfoGroup=Main&InfoType=Article. 
  8. ↑ Marshall S, Barbosa M, "Ciliary neurotrophic factor variants", US patent application 2005064555, published 2005-03-24
  9. ↑ "Product Pipeline". Xencor. http://www.xencor.com/products/pipeline/. 
  10. ↑ "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. doi:10.1167/iovs.10-6479. PMID 21087953. 
  11. ↑ "Neurotech's NT-501 Implant Demonstrates Statistically Significant Photoreceptor Preservation in Patients with Retinal Degenerative Disease". Business Wire. 2011-04-11. http://www.businesswire.com/news/home/20110414005343/en/Neurotech’s-NT-501-Implant-Demonstrates-Statistically-Significant-Photoreceptor. 
  12. ↑ "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. doi:10.1074/jbc.M210044200. PMID 12643274. 
  13. ↑ "Ciliary neurotrophic factor induces acute-phase protein expression in hepatocytes". FEBS Lett. 314 (3): 280–4. December 1992. doi:10.1016/0014-5793(92)81489-9. PMID 1281789. 

Further reading

External links



Retrieved from "https://handwiki.org/wiki/index.php?title=Biology:Ciliary_neurotrophic_factor&oldid=3633979"