Trans-splicing into highly abundant albumin transcripts for production of therapeutic proteins in vivo

Jun Wang, Gary S. Mansfield, Colette A. Cote, Ping Du Jiang, Ke Weng, Marcelo J A Amar, Bryan H. Brewer, Alan T. Remaley, Gerard J. McGarrity, Mariano Garcia-Blanco, M. Puttaraju

12 Scopus citations

Abstract

Spliceosome-mediated RNA trans-splicing has emerged as an exciting mode of RNA therapy. Here we describe a novel trans-splicing strategy, which targets highly abundant pre-mRNAs, to produce therapeutic proteins in vivo. First, we used a pre-trans-splicing molecule (PTM) that mediated trans-splicing of human apolipoprotein A-I (hapoA-I) into the highly abundant mouse albumin exon 1. Hydrodynamic tail vein injection of the hapoA-I PTM plasmid in mice followed by analysis of the chimeric transcripts and protein, confirmed accurate and efficient trans-splicing into albumin pre-mRNA and production of hapoA-I protein. The versatility of this approach was demonstrated by producing functional human papillomavirus type-16 E7 (HPV16-E7) single-chain antibody in C57BL/6 mice and functional factor VIII (FVIII) and phenotypic correction in hemophilia A mice. Altogether, these studies demonstrate that trans-splicing to highly abundant albumin transcripts can be used as a general platform to produce therapeutic proteins in vivo.

Original languageEnglish (US)
Pages (from-to)343-351
Number of pages9
JournalMolecular Therapy
Volume17
Issue number2
DOIs
StatePublished - 2009
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Genetics
  • Drug Discovery
  • Pharmacology
  • Medicine(all)

Cite this

Wang, J., Mansfield, G. S., Cote, C. A., Jiang, P. D., Weng, K., Amar, M. J. A., Brewer, B. H., Remaley, A. T., McGarrity, G. J., Garcia-Blanco, M., & Puttaraju, M. (2009). Trans-splicing into highly abundant albumin transcripts for production of therapeutic proteins in vivo. Molecular Therapy, 17(2), 343-351. https://doi.org/10.1038/mt.2008.260