title: Phenotype correction of hemophilia A mice by spliceosome-mediated RNA trans-splicing.
abstract: Conventional gene therapy of hemophilia A relies on the transfer of factor VIII (FVIII; encoded by the F8 gene) cDNA. We carried out spliceosome-mediated RNA trans-splicing (SMaRT) to repair mutant FVIII mRNA. A pre-trans-splicing molecule (PTM) corrected endogenous FVIII mRNA in F8 knockout mice with the hemophilia A phenotype, producing sufficient functional FVIII to correct the hemophilia A phenotype. This is the first description of phenotypic correction of a genetic defect by RNA repair in a knockout animal model. Our results indicate the feasibility of using SMaRT to repair RNA for the treatment of genetic diseases.
authors.affiliation: Department of Medicine, Mt. Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: Hengjun
authors.initials: H
authors.lastname: Chao
authors.forename: S Gary
authors.initials: SG
authors.lastname: Mansfield
authors.forename: Robert C
authors.initials: RC
authors.lastname: Bartel
authors.forename: Suja
authors.initials: S
authors.lastname: Hiriyanna
authors.forename: Lloyd G
authors.initials: LG
authors.lastname: Mitchell
authors.forename: Mariano A
authors.initials: MA
authors.lastname: Garcia-Blanco
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Walsh
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000502:physiology; D002460:Cell Line; D004195:Disease Models, Animal; D005169:Factor VIII / Q000235:genetics* / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D006467:Hemophilia A / Q000235:genetics* / Q000628:therapy; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D012313:RNA / Q000235:genetics / Q000378:metabolism; D012326:RNA Splicing; D017381:Spliceosomes / Q000378:metabolism*
chemical_list: D012313:RNA; D005169:Factor VIII