Expression of therapeutic proteins after delivery of chemically modified mRNA in mice

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Abstract
Messenger RNA has received little attention as a potential therapeutic agent. Kormann et al. show that intramuscular injection of chemically modified erythropoietin mRNA substantially increases the hematocrit in mice and demonstrate the curative potential of pulmonary mRNA delivery in a mouse model of congenital surfactant protein B deficiency. Current viral vectors for gene therapy1,2,3 are associated with serious safety concerns, including leukemogenesis4, and nonviral vectors are limited by low gene transfer efficiency5. 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.