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Therapeutic potential of in vivo administered pseudouridine-containing mRNA
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Therapeutic potential of in vivo administered pseudouridine-containing mRNA
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Therapeutic potential of in vivo administered pseudouridine-containing mRNA
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Journal Article
Therapeutic potential of in vivo administered pseudouridine-containing mRNA
2012
Overview
In vitro-transcribed mRNA has great therapeutic potential to transiently express the encoded protein without the adverse effects associated with viral- and DNA-based deliveries or direct protein supplementation. We have demonstrated that HPLC-purified pseudouridine-containing mRNA is non-immunogenic and translates very efficiently in cultured primary cells. We tested Transit-mRNA-complexed erythropoietin (EPO)-encoding mRNA in mice as a model therapeutic. We observed that a single injection of 100 ng (0.005 mg/kg) of mRNA elevated serum EPO levels significantly by 6 h and levels were maintained for 4 days. In comparison, mRNA containing uridine produced 10 to 100-fold lower levels of EPO that returned to baseline after 1 day. EPO translated from pseudouridine-mRNA was functional and caused a significant increase of both reticulocyte counts and hematocrits. Weekly injection of 100 ng of EPO mRNA containing pseudouridine was sufficient to maintain significantly increased hema tocrits without inducing the production of inflammatory cytokines or anti-EPO antibodies. Extending this approach to macaques, we could detect significantly increased serum EPO levels following intraperitoneal or subcutaneous injection of pseudouridine-containing mRNA coding for rhesus EPO. These results demonstrate that HPLC-purified, pseudouridine-containing mRNAs encoding therapeutic proteins have great potential for clinical applications.
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