title: Expression of therapeutic proteins after delivery of chemically modified mRNA in mice.
abstract: Current viral vectors for gene therapy are associated with serious safety concerns, including leukemogenesis, and nonviral vectors are limited by low gene transfer efficiency. Here we investigate the therapeutic utility of chemically modified mRNA as an alternative to DNA-based gene therapy. A combination of nucleotide modifications abrogates mRNA interaction with Toll-like receptor (TLR)3, TLR7, TLR8 and retinoid-inducible gene I (RIG-I), resulting in low immunogenicity and higher stability in mice. A single intramuscular injection of modified murine erythropoietin mRNA raises the average hematocrit in mice from 51.5% to 64.2% after 28 days. In a mouse model of a lethal congenital lung disease caused by a lack of surfactant protein B (SP-B), twice weekly local application of an aerosol of modified SP-B mRNA to the lung restored 71% of the wild-type SP-B expression, and treated mice survived until the predetermined end of the study after 28 days.
authors.affiliation: Department of Pediatrics, Ludwig Maximilian's University Munich, Munich, Germany. michael.kormann@med.uni-tuebingen.de
authors.forename: Michael S D
authors.initials: MS
authors.lastname: Kormann
authors.forename: Günther
authors.initials: G
authors.lastname: Hasenpusch
authors.forename: Manish K
authors.initials: MK
authors.lastname: Aneja
authors.forename: Gabriela
authors.initials: G
authors.lastname: Nica
authors.forename: Andreas W
authors.initials: AW
authors.lastname: Flemmer
authors.forename: Susanne
authors.initials: S
authors.lastname: Herber-Jonat
authors.forename: Marceline
authors.initials: M
authors.lastname: Huppmann
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Mays
authors.forename: Marta
authors.initials: M
authors.lastname: Illenyi
authors.forename: Andrea
authors.initials: A
authors.lastname: Schams
authors.forename: Matthias
authors.initials: M
authors.lastname: Griese
authors.forename: Iris
authors.initials: I
authors.lastname: Bittmann
authors.forename: Rupert
authors.initials: R
authors.lastname: Handgretinger
authors.forename: Dominik
authors.initials: D
authors.lastname: Hartl
authors.forename: Joseph
authors.initials: J
authors.lastname: Rosenecker
authors.forename: Carsten
authors.initials: C
authors.lastname: Rudolph
mesh_terms: D000818:Animals; D004921:Erythropoietin / Q000096:biosynthesis* / Q000235:genetics; D018014:Gene Transfer Techniques; D006651:Histocytochemistry; D053208:Kaplan-Meier Estimate; D008168:Lung / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011510:Proteolipids / Q000096:biosynthesis* / Q000235:genetics; D020871:RNA Stability; D012333:RNA, Messenger / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics
chemical_list: D011510:Proteolipids; D012333:RNA, Messenger; D004921:Erythropoietin