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

Nat Med. 2003 Aug;9(8):1015-9. doi: 10.1038/nm900. Epub 2003 Jul 6.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Blood Coagulation / physiology
  • Cell Line
  • Disease Models, Animal
  • Factor VIII / genetics*
  • Factor VIII / metabolism
  • Genetic Therapy / methods*
  • Hemophilia A / genetics*
  • Hemophilia A / therapy
  • Humans
  • Mice
  • Mice, Knockout
  • Phenotype*
  • RNA / genetics
  • RNA / metabolism
  • RNA Splicing*
  • Spliceosomes / metabolism*

Substances

  • RNA
  • Factor VIII