@article{d32883a105114b039346b40bd41fa126,
title = "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.",
author = "Jun Wang and Mansfield, \{Gary S.\} and Cote, \{Colette A.\} and Jiang, \{Ping Du\} and Ke Weng and Amar, \{Marcelo J.A.\} and Brewer, \{Bryan H.\} and Remaley, \{Alan T.\} and McGarrity, \{Gerard J.\} and Garcia-Blanco, \{Mariano A.\} and M. Puttaraju",
note = "Funding Information: The hemophilia work was supported in part by a Phase II SBIR grant from the National Heart, Lung, and Blood Institute (grant no. R44-HL072687). We thank Laurent Humeau and Peter Donnelly for critical reading of the manuscript; John Stonik, Catherine Knapper, Boris Vaisman for assistance in experimental design and technical help; Lili Portilla for assistance with the CRADA. The apoA-I research was performed under a CRADA between NHLBI{\textquoteright}s Vascular Medicine Branch/ Lipoprotein Metabolism Section and Intronn, Inc. We thank Paul McCray (University of Iowa) for his advice on performing the tail clip assay. J.W., S.G.M., P.D.J., G.J.M., and M.P. are employees of VIRxSYS Corporation (formerly with Intronn, Inc) and C.A.C. and K.W. were former Intronn, Inc employees. Spliceosome-mediated RNA trans-splicing technology was developed by Intronn, Inc., and majority of the work in this article was conducted at Intronn, Inc. In September 2007, VIRxSYS Corporation acquired all of Intronn, Inc., assets including intellectual property. M.A.G.-B is a co-corresponding author in this article and was a co-founder and consultant to Intronn, Inc., and is currently a consultant to VIRxSYS Corporation.",
year = "2009",
doi = "10.1038/mt.2008.260",
language = "English (US)",
volume = "17",
pages = "343--351",
journal = "Molecular Therapy",
issn = "1525-0016",
publisher = "Cell Press",
number = "2",
}