Alzheimer's disease: development of drugs in silico
Russian mathematicians will accelerate the creation of a cure for Alzheimer's disease
Scientists from The Institute of Systems Biology has developed a mathematical model that allows evaluating the effectiveness of potential drugs for Alzheimer's disease without conducting experiments on volunteers or animals, according to an article published in the journal CPT: Pharmacometrics & Systems Pharmacology (Karelina et al., A translational systems pharmacology model for Aß kinetics in mouse, monkey, and human).
"We have created a structural model calibrated on a large array of data. With the help of it, it is very easy to compare the results of tests of cerebrospinal fluid with real processes in the patient's brain. In fact, now we will be able to assess whether the drug will work or not in advance, knowing its parameters. This will significantly accelerate the development of therapy and improve the accuracy of its selection," says Tatiana Karelina from Institute of Systems Biology in Moscow, whose words are quoted by the press service of the organization.
It is believed that Alzheimer's disease is caused by the accumulation of a pathogenic substance inside neurons, the beta-amyloid protein. It is formed from the "scraps" of the APP protein, which is involved in the repair of damaged neurons and in the formation of connections between them. Violations in the processing of old molecules of this protein lead to the appearance of beta-amyloid plaques and the destruction of nerve cells.
In recent years, scientists have created dozens of prototypes of drugs for Alzheimer's disease that purify cells from beta-amyloid or prevent their formation. All these drugs either did not reach clinical trials due to the most powerful side effects, or failed in them, which led many researchers to believe that Alzheimer's disease may not be related to the APP protein and disorders in its "utilization".
Tatiana Karelina and her colleagues at the institute, as well as Pfizer specialists, decided to approach this problem from the other side by creating a computer model of the formation of beta-amyloid plaques and the development of Alzheimer's disease, which can predict how a particular drug will behave in the patient's body at different stages of the disease.
This model, as scientists say, takes into account the differences in the work of the brain of primates, mice and humans, which is extremely important for understanding how the results of animal experiments and the possible effect of different prototypes of drugs for Alzheimer's disease on human brain cells will correlate.
As the calculations of Russian scientists have shown, previous failures in clinical experiments may be due to the fact that their authors "directly" transferred the results of experiments on mice to humans, adjusted for the difference in weight and metabolic rate. This, as it turned out, was an absolutely incorrect approach.
Mathematical equations derived by scientists have shown that rodents and higher primates not only have a different rate of beta-amyloid production and the activity of some genes associated with Alzheimer's disease, but also the barrier between the brain and the circulatory system is arranged in a completely different way. On the other hand, Karelina and her colleagues did not find a significant difference between a human and a monkey, which makes it possible to use the results of experiments on primates to create a medicine.
According to the researchers, their model even made it possible to predict that the optimal scheme for taking new-generation drugs will consist in the maximum fragmentation of the dose of the substance during the day. According to scientists, their developments have already interested representatives of the pharmaceutical industry and they are negotiating with them on their implementation in the process of developing drugs for Alzheimer's disease.
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22.06.2017