Researchers demonstrate utility of transcript replacement therapy
Munich/Tuebingen – German researchers have overcome current limitations of using mRNAs as agents for gene therapy, that include as limited stability and strong immunogenicity due to activation of the innate immune system through its Toll-like receptors TLR3, TLR7, TLR8 or RIG-I (retinoid-inducible gene I). In Nature Biotechnology (9th January), the team headed by Carsten Rudolph (LMU Munich), CEO of Seefeld-based spin-off Ethris GmbH, report that replacement of only 25% of uridine and cytidine with 2-thiouridine and 5-methyl-cytidine synergistically decreased mRNA binding to pattern recognition receptors. The modifications substantially decreased activation of the innate immune system in vitro and in vivo and concomitantly increased the stability of the mRNA. The novel approach allows to circumvent the current safety concerns associated with DNA based gene therapy, including leukemogenesis, or of nonviral vectors such as low gene transfer efficiency. As they demonstrated, a single intramuscular injection of modified murine erythropoietin mRNA raised 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 with an aerosol of modified SP-B mRNA to the lung, restored 71% of the wild-type SP-B expression, with treated mice surviving until the predetermined end of the study after 28 days. Ethris was founded in 2009 to commercialise the SNIM® RNA-Technologie of non-immunogenic, stable mRNAs.