World Journal of Personalized Medicine

In the article, the authors proposed the concept of developing and introducing into the clinical practice the technologies of personalized medicine, and first of all, genomic as well as other «omics» technologies. These are the stages from the choice of the problem, which is solved by personalizing the management of patients on the basis of genomic studies to the formation of a model for the introduction of personalized medicine technologies into clinical practice. The role of medical organizations of the Ministry of Health and scientific institutions of the Russian Academy of Sciences in all the proposed stages is presented.

Treatment options are limited for many diseases including diabetes, cancer and neurological and, many patients do not receive adequate therapy. New chemical entities largely developed within the BioPharma industry are not sufficient to satisfy patient’s needs. New gene and modified cell constructs were developed in academia and are expected on the market recently. This review presents describes somatic cells reprogramming technology and its application for the new drug development. We then summarize the progress made in genome editing and its application to cure monogenic hereditary disorders of the endocrine system.

Introduction. Bromdihydrochlorphenylbenzodiazepine is the Russian original tranquilizer which widely using in psychiatry, narcology, neurology and general medicine. Particularly, that drug prescribing for patients with alcohol withdrawal syndrome (AWS). Isoenzyme CYP2C19 takes part in metabolism of the most of benzodiazepines, so the gene CYP2C19 might be included into pharmacogenetics study of bromdihydrochlorphenylbenzodiazepine. There was no study of CYP2C19 polymorphisms as biomarkers of bromdihydrochlorphenylbenzodiazepine’s safety.

Methods. 102 male patients with non-comlicated AWS (F 10.3 by ICD-10) were involved into the study. During 6 days of dynamic observation each participant was prescribed bromdihydrochlorphenylbenzodiazepine (Phenazepam). 5 ml of venous blood was collected from each participant for genotyping. 38 participants were added Pagluferal (contains phenobarbitalum, natrium coffeine-benzoate, bromisoval, papaverine) and/or Carbamazepine. Blood samples were analyzed to detect the CYP2C19*2 (rs4244285), *3 (rs4986893) и *17 (rs12248560) polymorphisms. Safety of therapy was evaluated with UKU Side Effects Rating Scale. Data analysis was performed with SPSS Statistics 21.0.

Results. Carriers of CYP2C19*2 GA+AA genotypes compared to GG homozygous significantly more often had such adverse effects as «Polyuria/polydipsia» in mean grade of penetration (33,3% vs 9%, p=0,016) and “Palpitations/Tachycardia” (16,7% vs 3,8%, p=0,018). Observed relationship between «Polyuria/polydipsia» and CYP2C19*2 GA+AA genotypes was confirmed in the subgroup “Combined pharmacotherapy” (37,5% vs 0%, p=0,006). CYP2C19*17 polymorphism in tendency to significance was associated with less frequent AE «Polyuria/polydipsia» among patients taking bromdihydrochlorphenylbenzodiazepine as monotherapy carriers of allele T had that AE in 16,9%, and CC homozygous in 24,2% (p=0,067).

Conclusion. Significant associations between CYP2C19*2 polymorphism and several AE in patients with alcohol withdrawal syndrome taking bromdihydrochlorphenylbenzodiazepine. Substantial role of CYP2C19*17 as predictor of AE associated with bromdihydrochlorphenylbenzodiazepine was not confirmed. Gene CYP2C19 is the sufficient biomarker of bromdihydrochlorphenylbenzodiazepine’s safety profile and needs further research.

Neonatal diabetes mellitus (NDM) is defined as a heterogeneous group of genetic disorders with onset before 6 months of age. Mutations in KATP channel genes (KCNJ11, ABCC8) and the insulin gene (INS) are the most common causes of NDM. Accurate molecular diagnosis of NDM has significant clinical importance as it may influence diabetes treatment, explain pleiotropic features and define the prognosis in the examined subject as well as in other family members .

In this report we present the results of a genetic examination of 70 patients with NDM, generalized the experience of using sulfonylurea in patients with KCNJ11 and ABCC8 genes mutations for the period from 2009 to 2016. A correlation is shown between the type of mutation, the course of the disease, and the sensitivity of patients to glibenclamide.

Aims. To demonstrate the principles of personalized treatment of diabetes for example the most common MODY subtypes (1-3) identified by NGS

Methods. We study 312 patients aged from 3 months to 25 years (162 boy/150 girls) with suspected MODY. A targeted next-generation sequencing approach (IonTorrent platform) was used for sequencing of monogenic form of diabetes mellitus candidate 28genes (13 MODY genes-candidates and other genes, associated with diabetes mellitus). Clinical and biochemicalphenotypes of the patients were compared with the type of mutations. Previously undescribed nonsynonymous mutations were considered as «probably pathogenic» with the minor allele frequency of <0.1% and «pathogenic» assessment in ANNOVAR database.

Results. We selected group of patients with mutations in the most common genes-candidates (GCK; HNF1A; HNF4A):99GCK gene mutations detectedin the 129 probands (61,1%) and 77 relatives, in HNF1A – 20 mutations in the 19 probands(9,0%) and 14 relatives, in HNF4A – 8 mutations in 9the probands (4,3%) and 3 relatives. The current therapy wasmodificated account the genotype and have been evaluated its effectiveness.

Conclusion. Molecular genetic confirmation of the monogenic nature of metabolic carbohydratedisorders is the basis of personalized therapy of diabetes.