Svetlana Smirnikhina

Svetlana Smirnikhina
Research Centre of Medical Genetics (RCMG) · Laboratory of Genome Editing

MD, PhD

About

61
Publications
4,548
Reads
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99
Citations
Additional affiliations
September 2007 - October 2018
Research Centre of Medical Genetics (RCMG)
Position
  • Principal Investigator

Publications

Publications (61)
Article
Recombinant adeno‐associated viruses (rAAVs) are promising vectors for the delivery of various genetic constructs into eukaryotic cells. rAAVs have a number of properties that make it possible to successfully use them both in vitro and in vivo. Purification and concentration of rAAV vectors are critical for achieving high viral titer, stability, ef...
Article
Full-text available
The efficient delivery of CRISPR-Cas components is still a key and unsolved problem. CRISPR-Cas delivery in the form of a Cas protein+sgRNA (ribonucleoprotein complex, RNP complex), has proven to be extremely effective, since it allows to increase on-target activity, while reducing nonspecific activity. The key point for in vivo genome editing is t...
Article
Full-text available
The recently discovered CRISPR-Cas9 modification, base editors (BEs), is considered as one of the most promising tools for correcting disease-causing mutations in humans, since it allows point substitutions to be edited without generating double-stranded DNA breaks, and, therefore, with a significant decrease in non-specific activity. Until recentl...
Article
Full-text available
Duchenne muscular dystrophy (DMD) is a relatively widespread genetic disease which develops as a result of a mutation in the gene DMD encoding dystrophin. In this review, animal models of DMD are described. These models are used in preclinical studies to elucidate the pathogenesis of the disease or to develop effective treatments; each animal model...
Article
Dysferlinopathies belong to a phenotypically heterogeneous group of neuromuscular diseases caused by mutations in the DYSF gene, which disrupt the expression of dysferlin protein in human skeletal muscle cells. These pathologies are of an autosomal recessive inheritance pattern, their prevalence is 1: 200000. Dysferlinopathies include diseases such...
Article
Введение. Эффективная точная коррекция мутаций очень важна для внедрения CRISPR-Cas в качестве инструмента для потенциальной генной терапии. Механизм направленной гомологичной репарации (НГР), активируемый после внесения нуклеазой двунитевого разрыва, позволяет корректировать все существующие типы мутаций. Однако НГР не является доминирующим механи...
Article
Full-text available
Gene therapy of genetically determined diseases, including some pathologies of the respiratory system, requires an efficient method for transgene delivery. Recombinant adeno-associated viral (rAAV) vectors are well studied and employed in gene therapy, as they are relatively simple and low immunogenic and able to efficiently transduce eukaryotic ce...
Article
Наследственные кардиомиопатии характеризуются неблагоприятным прогнозом и низкой пятилетней выживаемостью пациентов с выраженной клиникой. При этом лечение, за исключением хирургического, в основном паллиативное, во многих случаях лишь трансплантация сердца может улучшить состояние пациента и прогноз. Часть наследственных кардиомиопатий ассоциирова...
Article
Full-text available
The prospects for the human embryos genome editing cause intense debates both in the scientific community and in general public. While the main attention of scientists is focused on the safety, effectiveness and clinical feasibility of the inherited genome editing, the public pays attention to the bioethical aspects of the issue - the prospects of...
Article
Full-text available
Skin fibroblasts obtained from a 28-year-old man with clinically manifested and genetically proven (F508del/W1282X) cystic fibrosis were successfully transformed into induced pluripotent stem cells (iPSCs) by using non-viral, non-integrating, self-replicating RNA reprogramming vector that contains five reprogramming factors: OCT4, KLF4, SOX2, GLIS1...
Article
Full-text available
Cystic fibrosis is one of the most common inherited diseases caused by mutations in CFTR gene, of which F508del is the most common. Currently, the possibility of cell therapy including genome editing is widely discussed. We generated induced pluripotent stem cells from fibroblasts obtained from a 22-year-old woman with clinically manifested and gen...
Article
Genome editing techniques could be used as gene therapy for hereditary diseases. Clinical trials are already underway for at least seven of them, and several dozen drugs are at the preclinical stage of research.
Article
Full-text available
Development of genome editing methods created new opportunities for the development of etiology-based therapies of hereditary diseases. Here, we demonstrate that CRISPR/Cas9 can correct p.F508del mutation in the CFTR gene in the CFTE29o- cells and induced pluripotent stem cells (iPSCs) derived from patients with cystic fibrosis (CF). We used severa...
Article
CRISPR-Cas system was first mentioned in 1987, and over the years have been studied so active that now it becomes the state-of-the-art tool for genome editing. Its working principle is based on Cas nuclease ability to bind short RNA, which targets it to complementary DNA or RNA sequence for highly precise cleavage. This alone or together with donor...
Article
Full-text available
Skin fibroblasts obtained from a 27-year-old man with clinically manifested and genetically proven (F508del/F508del) cystic fibrosis were successfully transformed into induced pluripotent stem cells (iPSCs) by using Sendai virus-based reprogramming vectors including the four Yamanaka factors, OCT3/4, SOX2, KLF4, and c-MYC. The iPSCs showed a normal...
Article
Хронический миелоидный лейкоз (ХМЛ) - онкогематологическое заболевание. Благодаря разработке таргетных препаратов ингибиторов тирозинкиназ (ИТК) достигнуты большие успехи в лечении ХМЛ, однако около 20-40% пациентов резистентны к терапии. Цель исследования - обнаружение экзомных вариантов, обуславливающих различную эффективность терапии ХМЛ. Нами б...
Article
Full-text available
The majority of CRISPR-Cas9 methods for mutations correction are oriented on gene editing through homologous recombination that is normally restrained by non-homologous end joining (NHEJ). A recently identified protein TIRR can bind a 53BP1 protein, a key effector of NHEJ, and inhibit its recruitment to double-strand break loci. Several studies elu...
Article
Duchenne muscular dystrophy (DMD) is a common genetic disease which develops as a result of a mutation in the gene encoding dystrophin. In this review, the main experimental therapeutic approaches based on gene therapy are described. Independence of the type of mutation in the DMD gene is an advantage of the viral delivery of micro-and minidystroph...
Article
Full-text available
Background Approximately 5–20% of chronic myeloid leukemia (CML) patients demonstrate primary resistance or intolerance to imatinib. None of the existing predictive scores gives a good prognosis of TKI efficacy. Gene polymorphisms, expression and microRNAs are known to be involved in the pathogenesis of TKI resistance in CML. The aim of our study i...
Article
Full-text available
Cardiomyopathy (CMP) is a common group of cardiovascular disorders. Genetic (primary) cardiomyopathies are related to abnormalities in more than 100 genes, including the DES gene encoding desmin protein. Desmin is an essential member of the intermediate filaments, ensuring the structural and functional integrity of myocytes. Mutations in the DES ge...
Article
Full-text available
Despite the recent discover of genome-editing methods, today we can say these approaches have firmly entered our life. Two approaches—knocking out malfunctioning gene allele or correcting the mutation with precise knock-in—can be used in hereditary monogenic diseases treatment. The latter approach is relatively ineffective. Modern data about the wa...
Article
Full-text available
Cystic fibrosis is a severe autosomal recessive disease caused by mutations in the CFTR gene. The most common CFTR mutation occurring in the European population is F508del. Advances in the management of patients with cystic fibrosis aimed at blocking disease progression have considerably improved the prognosis, but gene therapy has turned to be les...
Article
Full-text available
Background. Chronic myeloid leukemia (CML) is a common myeloproliferative disease characterized by pathologic activity of the fusion gene BCR/ABL, which encodes a tyrosine kinase that stimulates uncontrolled cell proliferation and DNA instability. Up to 20% of CML patients demonstrate primary resistance or non-optimal response to targeted tyrosine-...
Article
Full-text available
Chronic myeloid leukemia (CML) is a myeloproliferative disease characterized by the presence of BCR/ABL fusion gene in leukemic cells, which promotes uncontrolled cell proliferation. Up to 20% of CML patients show primary resistance or non-optimal response to tyrosine kinase inhibitor (TKI) therapy. We investigated the association between copy numb...
Data
Differences between groups of patients due to CNVs in GSTT1. (XLSX)
Data
11 genes genotype analysis (CYP1A2, CYP2A6, CYP2C19, CYP2C9, CYP2D6, CYP2E1, CYP3A4, CYP3A5, GSTM1, GSTP1, and GSTT1). (XLSX)
Article
Chronic myeloid leukemia (CML) is characterized by the presence of the chimeric tyrosine kinase BCR-ABL in all leukemic cells. This non-specific enzyme promotes uncontrolled cell proliferation and genome instability. Tyrosine kinase inhibitors (TKI) help most of the people to achieve long standing remission, however up to 20% of patients develop sl...
Article
Full-text available
Genome variability of host genome and cancer cells play critical role in diversity of response to existing therapies and overall success in treating oncological diseases. In chronic myeloid leukemia targeted therapy with tyrosine kinase inhibitors demonstrates high efficacy in most of the patients. However about 15 % of patients demonstrate primary...
Article
Chronic myeloid leukemia (CML) is a myeloproliferative disease well treated by tyrosine kinase inhibitors (TKIs). The aim was to identify genes with a predictive value for relapse-free survival after TKI cessation in CML patients. We performed whole-exome sequencing of DNA from six CML patients in long-lasting deep molecular remission. Patients wer...
Article
Full-text available
The standardized RQ-PCR is recommended for the detection of values of BCR-ABL transcripts and the evaluation of patients response for TKI treatment. We have investigated BCR-ABL/ABL value comparability in CML patients with MMR and CMR by new automated GeneXpert Dx System in comparison with manual standardized RQ-PCR. The analysis performed on 46 pa...
Article
Full-text available
Data that support the evidence of mutagens known to cause epigenetic abnormalities that could potentially result in genomic instability and the development of cancer rather than to modifications in the human genome at the gene and chromosomal levels only. The level of global methylation in human lymphocytes in vitro caused by exposure to two mutage...
Article
Full-text available
We studied the effect of dioxidine on genome-wide methylation in short-term cultures of peripheral blood lymphocytes derived from healthy donors. Methylation was evaluated in lymphocytes before culturing, after 25 h in culture, and 1 h after addition of dioxidine in two concentrations (0.1 and 0.01 mg/ml). The total time in culture was 25 h. The le...
Article
Full-text available
We compared two methods of transfection (lipofection and electroporation) with plasmid containing VEGF121 gene in four cultures of mesenchymal stem cells from the human adipose tissue. The efficacy of transfection after 1 day, the dynamics of plasmid elimination after 3, 6, 9 days, and expression of the target gene were evaluated. Transfection by b...
Article
Full-text available
Dynamics of VEGF gene expression in transfected multipotent stromal cells from adipose tissue was examined using electroporation and lipofection. Differences in the potency and dynamics of plasmid elimination (up to day 9) between cell cultures were observed. All cultures were divided into fast and slow plasmid-eliminating ones. Interculture differ...
Article
Full-text available
Adipose tissue (AT) is an easily available source of mesenchymal-like stem cells (MSCs) that are appropriate for applications in regenerative medicine. There is conflicting evidence on the morphology of AT-derived stem cells (ADSCs). Here, we described the morphology and proliferation activity of human ADSCs. The cells were plated at a density of 1...
Article
Full-text available
The review considers the methods most commonly used to detect DNA methylation, their advantages, potential limitations, and selection for various purposes. A detailed protocol is described for bisulfite treatment, which is used as a preliminary step in the majority of DNA methylation assays.
Article
Full-text available
The article provides analysis of common methods for DNA methylation detection. Advantages and limitations of methods used for different purposes are compared. Clue step for most common methods is bisulfite treatment of DNA samples and its protocol is described in details. Recommendations are formulated for each method best in solving specific probl...
Article
Beta-adrenoblockers (BAB) are highly-effective pharmaceuticals used broadly in treatment of cardial diseases. Response to BABs is known to display interindividual variability; pre-treatment analysis of allelic gene variants responsible for BAB pharmacokinetics, allows dose correction according to the genetic features of an individual patient. Pharm...

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Projects

Projects (2)
Project
Our goal is to increase the efficacy and specifity of CRISPR-Cas9 in genome editing by using homology-directed repair. We propose that the best way for improve genome editing tools is to combine existing mechanisms. In this project we are using different methods: knockdown/activation several crucial HDR-factors, fusion Cas9-proteins, small molecules and also cell-cecle synchronisation.
Project
Correcting mutations in CFTR and DES