Phenotype correction of hemophilia A mice by spliceosome-mediated RNA trans-splicing.

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TitlePhenotype correction of hemophilia A mice by spliceosome-mediated RNA trans-splicing.
Publication TypeJournal Article
Year of Publication2003
AuthorsChao, H, Mansfield, GS, Bartel, RC, Hiriyanna, S, Mitchell, LG, García-Blanco, MA, Walsh, CE
JournalNat Med
Volume9
Issue8
Pagination1015-9
Date Published2003 Aug
ISSN1078-8956
KeywordsAnimals, Blood Coagulation, Cell Line, Disease Models, Animal, Factor VIII, Gene Therapy, Hemophilia A, Humans, Mice, Mice, Knockout, Phenotype, RNA, RNA Splicing, Spliceosomes
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.
DOI10.1038/nm900
Alternate JournalNat. Med.
PubMed ID12847523