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


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.

SUBMITTER: Wang J 

PROVIDER: S-EPMC2835072 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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

Wang Jun J   Mansfield S Gary SG   Cote Colette A CA   Jiang Ping Du PD   Weng Ke K   Amar Marcelo J A MJ   Brewer Bryan H BH   Remaley Alan T AT   McGarrity Gerard J GJ   Garcia-Blanco Mariano A MA   Puttaraju M M  

Molecular therapy : the journal of the American Society of Gene Therapy 20081209 2


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 transcript  ...[more]

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