Abstract
The term ‘trans-splicing’ encompasses several platform technologies that combine two RNA or protein molecules to generate a new, chimeric product. RNA trans-splicing reprograms the sequences of endogenous messenger mRNA or pre-mRNA, converting them to a new, desired gene product. Trans-splicing has broad applications, depending on the nature of the sequences that are inserted or trans-spliced to the defined target. Trans-splicing RNA therapy offers significant advantages over conventional gene therapy: expression of the trans-spliced sequence is controlled by the endogenous regulation of the target pre-mRNA; reduction or elimination of undesirable ectopic expression; the ability to use smaller constructs that trans-splice only a portion of the gene to be replaced; and the conversion of dominant-negative mutations to wild-type gene products.
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References
Johnson JM et al. Genome-wide survey of human alternative pre-mRNA splicing with exon junction microarrays. Science 2003; 302: 2141–2144.
Garcia-Blanco MA, Baraniak AP, Lasda EL . Alternative splicing in disease and therapy. Nat Biotechnol 2004; 22: 1–13.
Takahara T et al. Delay in synthesis of the 3′ splice site promotes trans-splicing of the preceding 5′ splice site. Mol Cell 2005; 18: 245–251.
Flouriot G, Brand H, Seraphin B, Gannon F . Natural trans-spliced mRNAs are generated from the human estrogen receptor-alpha (hER alpha) gene. J Biol Chem 2002; 277: 26244–26251.
Finta C, Zaphiropoulos PG . Intergenic mRNA molecules resulting from trans-splicing. J Biol Chem 2002; 277: 5882–5890.
Kikumori T, Cote GJ, Gagel RF . Naturally occurring heterologous trans-splicing of adenovirus RNA with host cellular transcripts during infection. FEBS Lett 2002; 522: 41–46.
Romani A, Guerra E, Trerotola M, Alberti S . Detection and analysis of spliced chimeric mRNAs in sequence databanks. Nucl Acids Res 2003; 31: e17.
Finta C, Warner SC, Zaphiropoulos PG . Intergenic mRNAs. Minor gene products or tools of diversity? Histol Histopathol 2002; 17: 677–682.
Liu X et al. Partial correction of endogenous Delta F508 CFTR in human cystic fibrosis airway epithelia by spliceosome-mediated RNA trans-splicing. Nat Biotechnol 2002; 20: 47–52.
Puttaraju M et al. SMaRT RNA-based therapy for cervical cancer and HPV infections. Mol Ther 2002; 5 (Suppl.) Abstr. 1361.
Mansfield SG et al. 5′ Exon replacement by spliceosome-mediated RNA trans-splicing. RNA 2003; 9: 1290–1297.
Pergolizzi RG et al. In vivo trans-splicing of 5′ and 3′ segments of pre-mRNA directed by corresponding DNA sequences delivered by gene transfer. Mol Ther 2003; 8: 999–1008.
Chao H et al. Phenotype correction of hemophilia A mice by spliceosome-mediated RNA trans-splicing. Nat Med 2003; 9: 1015–1019.
Conlon TJ, Flotte TR . Recombinant adeno-associated virus vectors for gene therapy. Expert Opin Biol Ther 2004; 4: 1093–1101.
Mansfield SG, Chao H, Walsh CE . RNA repair using spliceosome-mediated RNA trans-splicing. Trends Mol Med 2004; 10: 263–268.
Garcia-Blanco MA . Messenger RNA reprogramming by spliceosome-mediated RNA trans-splicing. J Clin Invest 2003; 112: 474–480.
Dallinger G et al. Development of spliceosome-mediated RNA trans-splicing (SMaRT) for the correction of inherited skin diseases. Exp Dermatol 2003; 12: 37–46.
Liu X et al. Spliceosome-mediated RNA trans-splicing with recombinant adeno-associated virus partially restores cystic fibrosis transmembrane conductance regulator function to polarized human cystic fibrosis airway epithelial cells. Hum Gene Ther 2005 (in press).
Liu X et al. Ectopic expression of CFTR in adult airway stem cells inhibits capacity to regenerate and differentiate. Mol Ther 2003; 7 (Suppl.) Abstr. 1196.
Tahara M et al. Trans-splicing repair of CD40 ligand deficiency results in naturally regulated correction of a mouse model of hyper-IgM X-linked immunodeficiency. Nat Med 2004; 10: 835–841.
Shin KS, Sullenger BA, Lee SW . Ribozyme-mediated induction of apoptosis in human cancer cells by targeted repair of mutant p53 RNA. Mol Ther 2004; 10: 365–372.
Ryu KJ, Kim JH, Lee SW . Ribozyme-mediated selective induction of new gene activity in hepatitis C virus internal ribosome entry site-expressing cells by targeted trans-splicing. Mol Ther 2003; 3: 386–395.
Bhaumik S et al. Molecular imaging of gene expression in living subjects by spliceosome-mediated RNA trans-splicing. Proc Natl Acad Sci USA 2004; 101: 8693–8698.
Ryu KJ, Lee SW . Identification of the most accessible sites to ribozymes on the hepatitis C virus internal ribosome entry site. J Biochem Mol Biol 2003; 36: 538–544.
Phylactou LA . Repair of myotonic dystrophy protein kinase (DMPK) transcripts by trans-splicing ribozymes. Methods Mol Biol 2004; 252: 373–383.
Einvik C, Fiskaa T, Lundblad EW, Johansen S . Optimization and application of the group I ribozyme trans-splicing reaction. Methods Mol Biol 2004; 252: 359–371.
Park YH, Jung HS, Kwon BS, Lee SW . Replacement of thymidine phosphorylase RNA with group I intron of Tetrahymena thermophila by targeted trans-splicing. J Microbiol 2003; 41: 340–344.
Garcia-Blanco MA . Mending the message. Nat Biotechnol 2003; 21: 1448–1449.
Kastanos E, Hjiantoniou E, Phylactou LA . Restoration of protein synthesis in pancreatic cancer cells by trans-splicing ribozymes. Biochem Biophys Res Commun 2004; 322: 930–934.
Rogers CS, Vanoye CG, Sullenger BA, George Jr AL . Functional repair of a mutant chloride channel using a trans-splicing ribozyme. J Clin Invest 2002; 110: 1783–1789.
Byun J, Lan N, Long M, Sullenger BA . Efficient and specific repair of sickle beta-globin RNA by trans-splicing ribozymes. RNA 2003; 9: 1254–1263.
Deidda G, Rossi N, Tocchini-Valentini GP . An archaeal endoribonuclease catalyzes cis- and trans-nonspliceosomal splicing in mouse cells. Nat Biotechnol 2003; 21: 1499–1504.
Kinsella TM et al. Retrovirally delivered random cyclic peptide libraries yield inhibitors of interleukin-4 signaling in human B cells. J Biol Chem 2002; 277: 37512–37518.
Li J, Liu PXQ, Wang B, Xiao X . Protein trans-splicing as a novel strategy for Duschenne muscular dystrophy gene therapy with AAV vectors. Mol Ther 2002; 5 (Suppl.) Abstr. 5.
Paulmurugan R, Umezawa Y, Gambhir SS . Noninvasive imaging of protein–protein interactions in living subjects by using reporter protein complementation and reconstitution strategies. Proc Natl Acad Sci USA 2002; 26;99 (24): 15608–15613.
Ayre BG, Kohler U, Turgeon R, Haseloff J . Optimization of trans-splicing ribozyme efficiency and specificity by in vivo genetic selection. Nucl Acids Res 2002; 30: e141.
Hasegawa S, Choi JW, Rao J . Single-cell detection of trans-splicing ribozyme in vivo activity. J Am Chem Soc 2004; 126: 7158–7159.
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Mitchell, L., McGarrity, G. Gene Therapy Progress and Prospects: Reprograming gene expression by trans-splicing. Gene Ther 12, 1477–1485 (2005). https://doi.org/10.1038/sj.gt.3302596
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DOI: https://doi.org/10.1038/sj.gt.3302596
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