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.
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Acknowledgements
We thank J. Huang and X. Zeng for technical assistance, S. Connelly and P. Shirley (GTI/Novartis) for the AdhuF8 mouse plasma and R. Sarkar and H. Kazazian for the F8 E16 knockout mice and advice. H.J.C. is a recipient of a Career Development Award from the National Hemophilia Foundation. National Institutes of Health grant RO1-68215 provided funding for this project.
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S.G.M., R.C.B., S.H. and L.G.M. are employees of Intronn Inc. M.A.G.-B. is a consultant of Intronn Inc.
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Chao, H., Mansfield, S., Bartel, R. et al. Phenotype correction of hemophilia A mice by spliceosome-mediated RNA trans-splicing. Nat Med 9, 1015–1019 (2003). https://doi.org/10.1038/nm900
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DOI: https://doi.org/10.1038/nm900
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