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

Research output: Contribution to journalArticle

12 Citations (Scopus)

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

Trans-Splicing
Albumins
Proteins
RNA Precursors
Therapeutics
Spliceosomes
Single-Chain Antibodies
Human papillomavirus 16
Factor VIII
Hemophilia A
Hydrodynamics
Inbred C57BL Mouse
Tail
Veins
Exons
Plasmids
RNA
Injections

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., ... 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

Trans-splicing into highly abundant albumin transcripts for production of therapeutic proteins in vivo. / Wang, Jun; Mansfield, Gary S.; Cote, Colette A.; Jiang, Ping Du; Weng, Ke; Amar, Marcelo J A; Brewer, Bryan H.; Remaley, Alan T.; McGarrity, Gerard J.; Garcia-Blanco, Mariano; Puttaraju, M.

In: Molecular Therapy, Vol. 17, No. 2, 2009, p. 343-351.

Research output: Contribution to journalArticle

Wang, J, Mansfield, GS, Cote, CA, Jiang, PD, Weng, K, Amar, MJA, Brewer, BH, Remaley, AT, McGarrity, GJ, Garcia-Blanco, M & Puttaraju, M 2009, 'Trans-splicing into highly abundant albumin transcripts for production of therapeutic proteins in vivo', Molecular Therapy, vol. 17, no. 2, pp. 343-351. https://doi.org/10.1038/mt.2008.260
Wang, Jun ; Mansfield, Gary S. ; Cote, Colette A. ; Jiang, Ping Du ; Weng, Ke ; Amar, Marcelo J A ; Brewer, Bryan H. ; Remaley, Alan T. ; McGarrity, Gerard J. ; Garcia-Blanco, Mariano ; Puttaraju, M. / Trans-splicing into highly abundant albumin transcripts for production of therapeutic proteins in vivo. In: Molecular Therapy. 2009 ; Vol. 17, No. 2. pp. 343-351.
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