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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10.1038/nm900

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@article{e0c1399a336b4c1daf706fc4e7097465,

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.",

year = "2003",

month = aug,

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doi = "10.1038/nm900",

language = "English (US)",

volume = "9",

pages = "1015--1019",

journal = "Nature Medicine",

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TY - JOUR

T1 - Phenotype correction of hemophilia A mice by spliceosome-mediated RNA trans-splicing

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.

PY - 2003/8/1

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.

UR - https://www.scopus.com/pages/publications/0042388694

UR - https://www.scopus.com/pages/publications/0042388694#tab=citedBy

U2 - 10.1038/nm900

DO - 10.1038/nm900

M3 - Article

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AN - SCOPUS:0042388694

SN - 1078-8956

VL - 9

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EP - 1019

JO - Nature Medicine

JF - Nature Medicine

IS - 8

ER -

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

Abstract

ASJC Scopus subject areas

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