Creation and Research of Cell Models of Hereditary Neurodegenerative Diseases Using Directed Genome Editing

Abstract

Neurodegenerative diseases make up a large part of overall morbidity around the world. In particular, an increase in the average age of the population in most developed countries leads to a drastic increase in the proportion of patients with diagnoses such as Alzheimer's disease and Parkinson's disease. The existing methods of treatment are predominantly symptomatic and, in some cases can have a pronounced clinical effect, however, they cannot prevent the continuing death of neurons or reverse neurodegenerative process. To a large extent, these problems are associated with an insufficient understanding of the molecular genetic mechanisms that underlie pathogenesis, as well as with the lack of models that allow qualitative and quantitative data on the processes occurring in the neurons of patients to be obtained. The development of technologies of induced pluripotency, directed differentiation of pluripotent cells, and gene editing using programmed nucleases, makes it possible to significantly expand the arsenal of available research tools, especially in the search for new targets for drug and gene therapy.

CRISPR/Cas: History and Perspectives

“…Yana Fedorova from the same laboratory described a compact Cas9 orthologue with all the same functional features but reduced in size, making it easier to deliver to cells (Fedorova et al, 2020). Suren Zakiyan's Epigenetics of Development Laboratory from the Institute of Cytology and Genetics in Novosibirsk is successfully working on the creation of cellular models of various human neurodegenerative diseases (Medvedev et al, 2021), muscular dystrophies (Medvedev et al, 2021), including Huntington's disease (Morozova et al, 2018;Malankhanova et al, 2020), amyotrophic lateral sclerosis (Ustyantseva et al, 2019), and spinal muscular atrophy (Valetdinova et al, 2017) using CRISPR/Cas9 system. Maxim Karagyaur from the Laboratory of Biochemistry and Molecular Medicine at the Faculty of Fundamental Medicine, Moscow State University has been using the CRISPR/Cas technology to knockout genes of interest, to regulate gene expression at the epigenetic level, to model single-nucleotide polymorphisms to create cellular and tissue models to study tissue development and regeneration (Karagyaur et al, 2018;Rysenkova et al, 2018;Tyurin-Kuzmin et al, 2018;Dyikanov et al, 2019;Slobodkina et al, 2020;Rusanov et al, 2020).…”