title: Genetic medicine at the RNA level: modifications of the genetic repertoire for therapeutic purposes by pre-mRNA trans-splicing.
abstract: Gene therapy is conventionally carried out by transferring genetic material to the target cell where the exogenous gene is expressed using the endogenous transcription and translation machinery in parallel with the target cell genome. This review focuses on a new paradigm of gene therapy, the use of trans-splicing to modify the genetic repertoire at the pre-mRNA level to treat genetic and acquired disorders. Therapeutic trans-splicing can be used to alter coding domains, to create novel fusion proteins, to direct gene products to various cellular compartments, and to overcome some of the limitations to vector-derived gene transfer technology, including gene therapy with large genes or with genes coding for toxic proteins. To demonstrate the potential of therapeutic trans-splicing, eukaryotic cis-splicing and trans-splicing are reviewed, followed by a discussion of strategies of therapeutic pre-mRNA trans-splicing directed by exogenous gene transfer.
authors.affiliation: Department of Genetic Medicine, Weill Medical College of Cornell University, 515 East 71st Street, S-1000 New York, NY 10021, USA.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Pergolizzi
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Crystal
mesh_terms: D000818:Animals; D023201:CD40 Ligand / Q000235:genetics; D003039:Cobra Neurotoxin Proteins / Q000235:genetics; D005091:Exons / Q000235:genetics; D005544:Forecasting; D018014:Gene Transfer Techniques; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000628:therapy*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006467:Hemophilia A / Q000235:genetics / Q000628:therapy; D006801:Humans; D006942:Hypergammaglobulinemia / Q000235:genetics / Q000628:therapy; D007075:Immunoglobulin M / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000628:therapy; D021122:Protein Subunits / Q000235:genetics / Q000627:therapeutic use; D012313:RNA / Q000235:genetics; D012322:RNA Precursors / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism; D012326:RNA Splicing / Q000235:genetics; D022621:Shiga Toxin / Q000235:genetics / Q000627:therapeutic use; D017381:Spliceosomes / Q000502:physiology; D020040:Trans-Splicing / Q000235:genetics
chemical_list: D003039:Cobra Neurotoxin Proteins; D007075:Immunoglobulin M; D021122:Protein Subunits; D012322:RNA Precursors; C039919:RNA, recombinant; C493898:Shiga toxin subunit A; D023201:CD40 Ligand; D012313:RNA; C025154:alpha-cobratoxin; D022621:Shiga Toxin