Abstract
The development of multicistronic vectors has opened up new opportunities to address the fundamental issues of molecular and cellular biology related to the need for the simultaneous delivery and joint expression of several genes. To date, the examples of the successful use of multicistronic vectors have been described for the development of new methods of treatment of various human diseases, including cardiovascular, oncological, metabolic, autoimmune, and neurodegenerative disorders. The safety and effectiveness of the joint delivery of therapeutic genes in multicistronic vectors based on the internal ribosome entry site (IRES) and self-cleaving 2A peptides have been shown in both in vitro and in vivo experiments as well as in clinical trials. Co-expression of several genes in one vector has also been used to create animal models of various inherited diseases which are caused by mutations in several genes. Multicistronic vectors provide expression of all mutant genes, which allows the most complete mimicking disease pathogenesis. This review comprehensively discusses multicistronic vectors based on IRES nucleotide sequence and self-cleaving 2A peptides, including its features and possible application for the treatment and modeling of various human diseases.
Highlights
Gene therapy was introduced as having significant potential for the treatment of various diseases
To differentiate induced pluripotent stem cells (iPSCs) into insulin-producing cells, iPSCs were co-transduced with multicistronic adenoviral vectors containing the pancreatic and duodenal homeobox-1 (Pdx1), neurogenin 3 (Ngn3), or musculoaponeurotic fibrosarcoma oncogene homolog A (MafA) genes linked through internal ribosome entry site (IRES) to the green fluorescent protein (GFP) reporter gene
IRES-based and 2A peptide-based vectors are promising tools that can be used in combined gene therapy of many rare and/or heterogeneous diseases
Summary
Gene therapy was introduced as having significant potential for the treatment of various diseases. The IRES-dependent initiation of translation in various viruses occurs in different ways Due to their specific structures, some IRESs can functionally replace many protein factors and, it is assumed, can bind and modify the ribosome conformation [45,46], which is why the IRES-dependent initiation of translation does not require a complete (or any) eIF set. The translation of all genes which are located downstream of the IRES occurs independently of each other [49], in contrast to vectors containing 2A peptide sequences [32]. A significant advantage of IRES sequences is the complete separation of proteins, whereas the use of 2A peptides can result in incomplete cleavage of the translated polypeptide (Table 1) [50]. Ribosomal skipping occurs after the synthesis of the first gene is complete, synthesis continues without the dissociation of ribosome
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