遗传增强
免疫原性
分子生物学
信使核糖核酸
生物
化学
基因
受体
基因表达
免疫学
免疫系统
生物化学
作者
Michael Kormann,Günther Hasenpusch,Manish Kumar Aneja,Gabriela Nica,Andreas W. Flemmer,Susanne Herber-Jonat,Marceline Huppmann,Lauren Mays,M. Illenyi,Andrea Schams,Matthias Griese,Iris Bittmann,Rupert Handgretinger,Dominik Hartl,Joseph Rosenecker,Carsten Rudolph
摘要
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.
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