Abstract
This chapter discusses the perspectives about the use of internal ribosome entry site (IRES) and 2A peptides to create multicistronic vectors for gene and gene and cell therapy and the prevention of various human diseases. 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. Self-cleaving 2A peptides are promising candidates for the production of multicistronic vectors due to their small size and self-cleavage ability. In the field of infectious diseases, multicistronic constructs have so far found use only in the production of preventive vaccines and progress in this area is not expected in the near future. Incomplete cleavage of products of 2A-based multicistronic constructs can lead to a decreased yield of the final product and to the disruption of the protein functions.
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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