The Laboratory Work is dedicated to the use of genome engineering technologies to create models of hereditary human diseases. The main focus of their work is the creation and study of hereditary neurodegenerative and cardiovascular diseases cell models on the basis of cultured pluripotent human cells. To create cellular models of diseases, induction of pluripotent state is used to obtain patient-specific lines of induced pluripotent stem cells (iPSC), and further directed differentiation of these cells into relevant cell types (neurons, cardiomyocytes) that can reproduce the pathological phenotype at the cellular and molecular levels. Laboratory research areas also include the application of the latest genome editing methods designed to create iPSC-based isogenic cell models of the diseases using CRISPR / Cas9-mediated homologous recombination (directed insertion of gene mutations) and gene knockout. In addition, CRISPR / Cas9-induced modifications (gene knockout or transcription activation) are used to elucidate the molecular mechanisms underlying pathological processes and to search for potential targets for therapy.
In the world today, there is great progress in the creation and investigation of cellular models of diseases. It has been experimentally proven that these models adequately reproduce many aspects of the pathological phenotype in vitro and can be used to search for new drug compounds and for toxicological research. There has also been a real breakthrough in methods for genome editing such as TALEN and CRISPR / Cas9 (Wright et al., 2014, Doudna & Charpentier, 2014). Many studies have shown that these systems are extremely effective and relatively easy to use tools for directional alteration of nucleotide sequences in vitro and in vivo, as well as to control gene expression. The technology for induced pluripotency (obtaining human and animal iPSCs), as well as genomic engineering, are actively used in leading research universities and institutes around the world. In Russia, only individual laboratories have this technology. In the National Scientific Center, a research team under the supervision of Dr. S.M. Zakian (Institute of Cytology and Genetics SB RAS) is obtaining cellular models of hereditary diseases with the use of the CRISPR / Cas9 system. Large projects creating disease model biobanks are being developed in the EU and the US, based on thousands of lines of patient-specific iPSCs (European Bank for induced pluripotent Stem Cells, StemBANCC, Induced Pluripotent Stem Cell (iPSC) Initiative). In the next decade, these biobanks will serve as the basis for conducting interdisciplinary translational research. The goals of this research are to elucidate the molecular basis of hereditary pathologies, to search for therapy targets and screen potential drug compounds, and for toxicological studies. The application of this approach should shorten the time required for the development of new drugs (now, each drug takes 10-15 years) and lower costs due to the elimination of ineffective and toxic compounds in the early stages of testing. The CRISPR / Cas9 system will be improved over the next decade. One of the main aspects of this improvement will be an increase the efficiency of CRISPR / Cas9-mediated homologous recombination (especially in pluripotent cells) and a decrease off-target activity.Head of the laboratory – Doctor of Biological Sciences, professor Suren Zakiyan