Antibodies instead of protein
Neurodegenerative diseases have been suggested to be treated with antibodies
Researchers from Russia, Britain and the USA have found a replacement for the brain-derived neurotrophic factor (BDNF) – a protein that supports the growth of neurons and an increase in the number of their processes. Drugs for the treatment of neurodegenerative diseases based on BDNF have proved ineffective in clinical trials, but it turned out that antibodies against tyrosine kinase receptor B (TrkB) are able to mimic the action of brain neurotrophic factor and perform well as a medicine. The results of the study are presented in an article published by the journal Proceedings of the National Academy of Sciences (PNAS).
Neurotropic factors – BDNF, NGF (nerve growth factor) and a number of others have a significant impact on the formation of the nervous system, and then on its development and maintenance. They are relatively small molecules of proteins, and nerve cells carry receptors for these proteins. Neurotropic factors and BDNF, in particular, stimulate the growth of axons and dendrites of neuronal processes that transmit and receive electrical and chemical signals. They also support the viability of nerve cells (as well as the surrounding glial cells). Because of these properties, neurotropic factors have long been considered as candidates for the role of drugs against neurodegenerative diseases – Parkinson's disease, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, retinal degeneration and some others.
Although animal trials of BDNF were successful, and in pilot studies on a small number of patients, this substance helped patients with amyotrophic lateral sclerosis, larger-scale clinical trials showed that it did not increase patient survival and did not improve the functioning of such important internal organs as the lungs, and this was a prerequisite for the successful completion of this series of tests. In addition, the use of BDNF as a medicine has a number of inconveniences. The molecules of this substance are positively charged, but, nevertheless, they do not dissolve well in water (namely, it forms the basis of the cerebrospinal fluid, where the drug was injected in clinical trials). In addition, BDNF decomposes rapidly in the human body, which means that it would have to be administered for medicinal purposes quite often.
The authors of the new article have tried to solve all these problems. The effect of BDNF on nerve cells is provided by receptors for this substance, therefore, it is necessary to use a molecule capable of activating such a receptor. The number of proteins that "perceive" the neurotrophic factor of the brain includes the tyrosine kinase receptor TrkB. It is an enzyme that attaches phosphate groups to the amino acid tyrosine. Scientists began using computer modeling to select antibodies to TrkB.
These proteins of the immune system recognize a molecule or part of it by conformation (i.e. shape) and charge. Accordingly, an antibody was required that "recognizes" the place of interaction of BDNF with TrkB. The researchers found several suitable antibodies and from them "collected" one that reacted only to tyrosine kinase receptor B, but not to other close tyrosine kinases – in order to avoid "false positives". The effect of this potential replacement of BDNF, which is still called ZEB85, was tested on a culture of nerve cells producing the neurotransmitter gamma-aminobutyric acid and grown from human embryonic stem cells.
Experiments with neuron culture have shown that ZEB85 antibody activates tyrosine kinase receptor B as strongly and triggers a chain of the same signaling reactions (leading to elongation and branching of nerve cell processes) as BDNF. This suggests that ZEB85 can become a replacement for the neurotrophic factor of the brain as a drug to maintain and improve the viability of neurons. However, to prove this, it is necessary to test an experimental antibody both on animals and – if preclinical studies are successful – on the appropriate patients.
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