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

Hengjun Chao; S. Gary Mansfield; Robert C. Bartel; Suja Hiriyanna; Lloyd G. Mitchell; Mariano A. Garcia-Blanco; Christopher E. Walsh

doi:10.1038/nm900

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

Hengjun Chao, S. Gary Mansfield, Robert C. Bartel, Suja Hiriyanna, Lloyd G. Mitchell, Mariano A. Garcia-Blanco, Christopher E. Walsh

Research output: Contribution to journal › Article › peer-review

150 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1015-1019
Number of pages	5
Journal	Nature Medicine
Volume	9
Issue number	8
DOIs	https://doi.org/10.1038/nm900
State	Published - Aug 1 2003
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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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.",

author = "Hengjun Chao and Mansfield, {S. Gary} and Bartel, {Robert C.} and Suja Hiriyanna and Mitchell, {Lloyd G.} and Garcia-Blanco, {Mariano A.} and Walsh, {Christopher E.}",

note = "Funding Information: 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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doi = "10.1038/nm900",

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AU - Chao, Hengjun

AU - Mansfield, S. Gary

AU - Bartel, Robert C.

AU - Hiriyanna, Suja

AU - Mitchell, Lloyd G.

AU - Garcia-Blanco, Mariano A.

AU - Walsh, Christopher E.

N1 - Funding Information: 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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Y1 - 2003/8/1

N2 - 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.

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

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