Alnylam Pharmaceuticals, Inc, a leading RNAi therapeutics company, has announced that publication of data demonstrating that an RNAi therapeutic can silence angiopoietin 2 (Ang2), a key mediator in acute lung injury.

In a paper published in Nature Medicine, scientists from Yale University and Alnylam demonstrated inhibition of acute lung injury and cell death in animals with administration of small interfering RNAs (siRNAs), the molecules that mediate RNAi, targeting Ang2.

These in vivo data showed silencing of Ang2 in the lung, and contribute 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.

"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," said Antonin de Fougerolles, PhD, senior director, research at Alnylam and an author of the study. "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 study published in Nature Medicine demonstrated that acute lung injury caused by cell death, high and potentially toxic concentrations of oxygen (hyperoxia) and the resulting excess fluid in the lungs (pulmonary edema), may be controlled by the Ang2 protein. Data showed that local intranasal administration in mice of and siRNA targeting Ang2 resulted in specific inhibition of messenger RNA (mRNA) by more than 60 per cent. A proportionate drop in Ang2 protein levels was also observed. In addition, acute lung injury was reduced to near non-injury levels as measured by statistically significant reductions in lung inflammation and cell death.

Importantly, mRNA levels of other genes were not affected by administration of the siRNA, including VEGF, Bcl-2 and (beta)-actin. The study was performed in the laboratory of Jack Elias, MD, Chair of Internal Medicine at Yale University School of Medicine.

"Through this study, we have learned that Ang2 seems to be a mediator of cell death in the settings of high oxygen concentrations in the lung causing acute lung injury and pulmonary edema," said Dr. Elias. "In applying an RNAi approach, 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."

"We are pleased with the leadership our scientists and collaborators have consistently demonstrated in pointing to the significant potential for RNAi therapeutics," said John Maraganore, PhD, president and CEO of Alnylam. "Our commitment to scientific excellence through publication of RNAi therapeutic data in the world's top journals highlights what we believe are the industry's leading capabilities to translate the discovery of RNAi into a new class of innovative medicines."

Angiopoietins are a type of growth factor that plays a key role in the angiogenic response whereby proteins stimulate the formation and maturation of blood vessels. Vascular endothelial growth factor (VEGF) stimulates growth of new immature leaky blood vessels. Angiopoietins 1 and 4 (Ang1 and Ang4, respectively) enhance angiogenesis by inducing vascular maturation and decreasing vascular permeability. Ang2 destabilizes blood vessels, enhances vascular leak and antagonizes Ang1 and Ang4. Ang2 can induce apoptosis in endothelial cells in the absence of other angiogenic stimuli.