Findings show potential for RNAi therapeutic targeting angiopoietin 2.

Scientists from Alnylam Pharmaceuticals and Yale University found that an RNAi therapeutic can silence angiopoietin 2 (Ang2), a key mediator in acute lung injury. They demonstrated inhibition of acute lung injury and cell death in animals with administration of siRNAs targeting Ang2.

“These results showed that we were able to design and synthesize siRNAs that following pulmonary delivery in vivo effectively silence Ang2, a very important target associated with acute lung injury,” points out Antonin de Fougerolles, Ph.D., senior director, research at Alnylam. “The findings demonstrate a critical role for Ang2 in the pathogenesis of hyperoxic acute lung injury and that silencing the Ang2 gene with RNAi may be therapeutically relevant.”

The data published in Nature Medicine contributes to existing data demonstrating the potential for developing RNAi therapeutics that target diseases associated with the lung, such as respiratory syncytial virus (RSV) infection, influenza, and asthma.

The study demonstrated that acute lung injury caused by cell death, hyperoxia, and the resulting pulmonary edema may be controlled by the Ang2 protein. Data showed that local intranasal administration of an siRNA targeting Ang2 in mice resulted in specific inhibition of mRNA by more than 60%. A proportionate drop in Ang2 protein levels was also observed. In addition, acute lung injury was reduced to near noninjury levels as measured by statistically significant reductions in lung inflammation and cell death. mRNA levels of other genes were not affected by administration of the siRNA, including VEGF, Bcl-2, and B-actin.

“In applying an RNAi approach,” explains Jack Elias, M.D., chair of internal medicine at Yale University School of Medicine, “we were able to observe in mice that silencing of the Ang2 protein resulted in animals that lived longer and had evidence of decreased lung injury compared to animals with the protein intact.”

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