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Therapeutic applications of group I intron‐based trans‐splicing ribozymes

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Since the breakthrough discovery of catalytic RNAs (ribozymes) in the early 1980s, valuable ribozyme‐based gene therapies have been developed for incurable diseases ranging from genetic disorders to viral infections and cancers. Ribozymes can be engineered and used to downregulate or repair pathogenic genes via RNA cleavage mediated by trans‐cleaving ribozymes or repair and reprograming mediated by trans‐splicing ribozymes, respectively. Uniquely, trans‐splicing ribozymes can edit target RNAs via simultaneous destruction and repair (and/or reprograming) to yield the desired therapeutic RNAs, thus selectively inducing therapeutic gene activity in cells expressing the target RNAs. In contrast to traditional gene therapy approaches, such as simple addition of therapeutic transgenes or inhibition of disease‐causing genes, the selective repair and/or reprograming abilities of trans‐splicing ribozymes in target RNA‐expressing cells facilitates the maintenance of endogenous spatial and temporal gene regulation and reduction of disease‐associated transcript expression. In molecular imaging technologies, trans‐splicing ribozymes can be used to reprogram specific RNAs in living cells and organisms by the 3′‐tagging of reporter RNAs. The past two decades have seen progressive improvements in trans‐splicing ribozymes and the successful application of these elements in gene therapy and molecular imaging approaches for various pathogenic conditions, such as genetic, infectious, and malignant disease. This review provides an overview of the current status of trans‐splicing ribozyme therapeutics, focusing on Tetrahymena group I intron‐based ribozymes, and their future prospects. This article is categorized under: RNA in Disease and Development > RNA in Disease
Modification of a trans‐splicing ribozyme that can enhance ribozyme specificity/efficacy for therapeutic applications. The use of a tissue‐specific promoter or microRNA target site (miR‐T) can facilitate tissue‐specific ribozyme expression in the desired cells or tissues. Ribozyme efficacy and specificity can be increased by adding EGS upstream of IGS and the P10 helix sequence. Ribozyme activity can be controlled exogenously by treatment with a specific ligand after inserting aptamer domains for the ligand into the ribozyme
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Application of the hTERT mRNA‐targeting trans‐splicing ribozyme. This trans‐splicing ribozyme contains HSV‐tk RNA as the 3′‐exon. The ribozyme specifically binds and cleaves the hTERT mRNA target site and replaces the cleaved RNA with the 3′‐exon RNA via a trans‐splicing reaction, resulting in the expression of a hTERT 5′ RNA‐HSV‐tk chimeric mRNA that selectively encodes the HSV‐tk protein in hTERT‐positive cancer cells. Consequently, GCV treatment induces cytotoxicity in only hTERT‐expressing cells. Alternatively, [18F]FHBG is used for hTERT‐expressing cancer cell imaging
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Application of the trans‐splicing ribozyme. (1) RNA repair using a mutated RNA‐targeting ribozyme. The ribozyme, which contains wild‐type RNA as the 3′‐exon, targets and cleaves the upstream sequence of the RNA mutation (blue arrow), and replaces the mutation with wild‐type (wt) RNA via trans‐splicing. (2) RNA reprograming by a viral transcript‐ or tumor‐related gene‐targeting ribozyme. The ribozyme, which contains a therapeutic or imaging reporter gene as the 3′‐exon, targets and cleaves specific RNA (blue arrow), replacing it with therapeutic or imaging reporter RNA by trans‐splicing
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Tetrahymena thermophilia group I intron. (a) Sequence and secondary structure of the group I intron. The red box indicates the internal guide sequence (IGS). Schemes of (b) self‐splicing and (c) trans‐splicing reactions of the group I intron
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