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

被引：589

作者：

Kormann, Michael S. D. ^{[1
,4
,5
]}

Hasenpusch, Guenther ^{[1
]}

Aneja, Manish K. ^{[1
]}

Nica, Gabriela ^{[1
]}

Flemmer, Andreas W. ^{[2
,3
]}

Herber-Jonat, Susanne ^{[2
,3
]}

Huppmann, Marceline ^{[2
,3
]}

Mays, Lauren E. ^{[4
,5
]}

Illenyi, Marta ^{[1
]}

Schams, Andrea ^{[1
]}

Griese, Matthias ^{[1
]}

Bittmann, Iris ^{[6
]}

Handgretinger, Rupert ^{[4
,5
]}

Hartl, Dominik ^{[4
,5
]}

Rosenecker, Joseph ^{[1
]}

Rudolph, Carsten ^{[1
]}

机构：

[1] Univ Munich, Dept Pediat, Munich, Germany

[2] Univ Munich, Childrens Hosp, Div Neonatol, D-8000 Munich, Germany

[3] Univ Munich, Perinatal Ctr, Munich, Germany

[4] Univ Tubingen, Childrens Hosp, Tubingen, Germany

[5] Univ Tubingen, Interdisciplinary Ctr Infect Dis, Tubingen, Germany

[6] Diakonien Hosp Rotenburg Wumme LTD, Inst Pathol, Rotenburg, Wumme, Germany

来源：

NATURE BIOTECHNOLOGY | 2011年 / 29卷 / 02期

关键词：

SEVERE COMBINED IMMUNODEFICIENCY; HYDROPHOBIC SURFACTANT PROTEINS; NONVIRAL GENE DELIVERY; LUNG-DISEASE; CELLS; ERYTHROPOIETIN; IMPEDANCES; DEFICIENCY; EFFICACY; TOOL;

D O I：

10.1038/nbt.1733

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

Current viral vectors for gene therapy(1-3) are associated with serious safety concerns, including leukemogenesis(4), and nonviral vectors are limited by low gene transfer efficiency(5). 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.

引用

页码：154 / U96

页数：6

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