Ciliary neurotrophic factor is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

that in humans is encoded by the ''CNTF''

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

. The protein encoded by this gene is a polypeptide hormone and

neurotrophic factor Neurotrophic factors (NTFs) are a family of biomolecules – nearly all of which are peptides or small proteins – that support the growth, survival, and differentiation of both developing and mature neurons. Most NTFs exert their tro ...

whose actions have mainly been studied in the nervous system where it promotes neurotransmitter synthesis and

neurite A neurite or neuronal process refers to any projection from the cell body of a neuron. This projection can be either an axon or a dendrite. The term is frequently used when speaking of immature or developing neurons, especially of cells in cultur ...

outgrowth in certain neural populations including

astrocyte Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of e ...

s. It is a hypothalamic

neuropeptide Neuropeptides are chemical messengers made up of small chains of amino acids that are synthesized and released by neurons. Neuropeptides typically bind to G protein-coupled receptors (GPCRs) to modulate neural activity and other tissues like the ...

that is a potent survival factor for

neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. ...

s and

oligodendrocyte Oligodendrocytes (), or oligodendroglia, are a type of neuroglia whose main functions are to provide support and insulation to axons in the central nervous system of jawed vertebrates, equivalent to the function performed by Schwann cells in the ...

s and may be relevant in reducing tissue destruction during inflammatory attacks. A

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA replication, DNA or viral repl ...

in this gene, which results in aberrant splicing, leads to ciliary neurotrophic factor deficiency, but this phenotype is not causally related to

neurologic disease A neurological disorder is any disorder of the nervous system. Structural, biochemical or electrical abnormalities in the brain, spinal cord or other nerves can result in a range of symptoms. Examples of symptoms include paralysis, muscle weak ...

. In addition to the predominant

monocistronic A cistron is an alternative term for "gene". The word cistron is used to emphasize that genes exhibit a specific behavior in a cis-trans test; distinct positions (or loci) within a genome are cistronic. History The words ''cistron'' and ''gene ...

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 A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, ...

surface, and to reduce the activity of bone-forming cells ( osteoblasts).

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 Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most comm ...

, CNTF produced an unexpected and substantial weight loss in the study subjects. Further investigation revealed that CNTF could reduce food intake without causing

hunger In politics, humanitarian aid, and the social sciences, hunger is defined as a condition in which a person does not have the physical or financial capability to eat sufficient food to meet basic Human nutrition, nutritional needs for a sustaine ...

stress Stress may refer to: Science and medicine * Stress (biology), an organism's response to a stressor such as an environmental condition * Stress (linguistics), relative emphasis or prominence given to a syllable in a word, or to a word in a phrase ...

, 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.

Recombinant human CNTF (Axokine)

A recombinant version of human CNTF (rhCNTF), trade name Axokine, is a modified version with a 15

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...

truncation of the C-terminus and two amino acid substitutions. It is three to five times more potent than CNTF in

in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology ...

and

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...

assays and has improved stability properties. Like CNTF it is a

, 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 Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...

were conducted in 2003 by Axokine's maker,

Regeneron Pharmaceuticals Regeneron Pharmaceuticals, Inc. is an American biotechnology company headquartered in Westchester County, New York. The company was founded in 1988. Originally focused on neurotrophic factors and their regenerative capabilities, giving rise to ...

, 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. 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 A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures. In general, placebos can af ...

-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 effect An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a " side effect", when judged to be secondary to a main or therapeutic effect. The term compl ...

s, as these antibodies could potentially interfere with the neuroprotective functions of endogenous CNTF. The application claims methods of designing CNTF analogues with lower

immunogenicity Immunogenicity is the ability of a foreign substance, such as an antigen, to provoke an immune response in the body of a human or other animal. It may be wanted or unwanted: * Wanted immunogenicity typically relates to vaccines, where the injectio ...

than Axokine based on analysis of affinity of each modified

epitope An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The epitope is the specific piece of the antigen to which an antibody binds. The p ...

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.

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 Retinitis pigmentosa (RP) is a genetic disorder of the eyes that causes loss of vision. Symptoms include trouble seeing at night and decreasing peripheral vision (side and upper or lower visual field). As peripheral vision worsens, people may ...

Interactions

Human ciliary neurotrophic factor has been shown to

interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...

with the Interleukin 6 receptor.

References

External links

* * {{Neurotrophinergics Neurotrophic factors Peptide hormones Proteins Developmental neuroscience