Ciliary neurotrophic factor
Encyclopedia
Ciliary neurotrophic factor is a protein
that in humans is encoded by the CNTF gene
.
CNTF has also been shown to be expressed by cells on the bone surface, and to reduce the activity of bone forming cells, osteoblasts.
, but by a non-leptin pathway.
. 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
, 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
-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 side effects, as these antibodies could potentially interfere with the neuroprotective functions of endogenous CNTF. 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.
.
with Interleukin-6 receptor
.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the CNTF gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
CNTF has also been shown to be expressed by cells on the bone surface, and to reduce the activity of bone forming cells, osteoblasts.
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 leptinLeptin
Leptin is a 16 kDa protein hormone that plays a key role in regulating energy intake and energy expenditure, including appetite and metabolism. It is one of the most important adipose derived hormones...
, but by a non-leptin pathway.
Axokine
Axokine is a modified version of human Ciliary neurotrophic factor with a 15 amino acid truncation of the C terminus and two amino acid substitutions, which is three to five times more potent than CNTF in in vitro and in vivo assays and has improved stability properties. 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 sclerosisAmyotrophic lateral sclerosis
Amyotrophic lateral sclerosis , also referred to as Lou Gehrig's disease, is a form of motor neuron disease caused by the degeneration of upper and lower neurons, located in the ventral horn of the spinal cord and the cortical neurons that provide their efferent input...
. 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
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
were conducted in 2003 by Axokine's maker, Regeneron
Regeneron
Regeneron is a biotechnology company headquartered in Tarrytown, in New York, USA. The company was founded in 1988. Originally focused on neurotrophic factors and their regenerative capabilities , it branched out into the study of both cytokine and tyrosine kinase receptors - leading to the three...
, 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
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
-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 side effects, 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
Immunogenicity is the ability of a particular substance, such as an antigen or epitope, to provoke an immune response in the body of a human or animal.- Immunogenicity :The ability to induce humoral and/or cell-mediated immune responses....
than Axokine based on analysis of affinity of each modified epitope
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 part of an antibody that recognizes the epitope is called a paratope...
for each of 52 class II MHC
Major histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
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 pigmentosaRetinitis pigmentosa
Retinitis pigmentosa is a group of genetic eye conditions that leads to incurable blindness. In the progression of symptoms for RP, night blindness generally precedes tunnel vision by years or even decades. Many people with RP do not become legally blind until their 40s or 50s and retain some...
.
Interactions
Ciliary neurotrophic factor has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with Interleukin-6 receptor
Interleukin-6 receptor
Interleukin 6 receptor also known as CD126 is a type I cytokine receptor....
.
See also
- Axokine
- Ciliary neurotrophic factor receptorCiliary neurotrophic factor receptorThe ciliary neurotrophic factor receptor also known as CNTFR binds the ciliary neurotrophic factor. This receptor and its cognate ligand support the survival of neurons. This receptor is most closely related to the interleukin-6 receptor. This receptor possesses an unusual attachment to the...
- Interleukin 6Interleukin 6Interleukin-6 is a protein that in humans is encoded by the IL6 gene.IL-6 is an interleukin that acts as both a pro-inflammatory and anti-inflammatory cytokine. It is secreted by T cells and macrophages to stimulate immune response, e.g. during infection and after trauma, especially burns or other...
- George YancopoulosGeorge YancopoulosGeorge D. Yancopoulos, M.D., Ph.D. is an American biomedical scientist who serves as chief scientific officer of Regeneron Pharmaceuticals, Inc.. His work has included study of how nerves regenerate and how muscles connect to nerves...