Partner in the Evolution of Genetic Engineering Prof. Levanon and his collaborator, Prof. Shay BenAroya, developed a system that can design a synthetic DNA sequence that, when injected into a cell, triggers the ADAR system to do its job of editing the RNA. “Relying on the previous work of many researchers, we can already inject our system into the liver, heart and brain and trigger ADARs to modify specific genes,” says Prof. Levanon. He adds that although an RNA-editing-based drug is still a long way off, the efforts of scientists and industry around the world are already bearing fruit. Prof. Levanon’s lab, which focuses on the chemistry and protein engineering aspects of RNA editing, has partnered with ADARx Pharmaceuticals, one of three major American RNA-editing pharmaceutical companies to have been created thanks to the important advances in the technology over the past two years. In recent months, this new industry has already raised over $250 million, a sure sign of the confidence in the potential of RNA-editing therapies. Every scientific and technological advance in RNA editing depends on understanding the workings of the body’s own editing system—why it is needed, where it occurs in the genome, and how it adapts to different biological conditions. The evolutionary role of RNA editing is the regulation of our immune system. Because virus attacks are the greatest danger to the cells, the immune system constantly canvasses them to detect viruses and eliminate them. “But, it so happens, the typical structures of viruses are very similar to naturally occurring structures in our genome. So to prevent an immune attack against such a structure, the ADAR system switches one of the RNA nucleotides. This slight modification is enough to prevent the immune system from wrongly identifying the body’s own structure as a virus,” says Prof. Levanon. “A lowfunctioning ADAR system,” as he goes on to explain, “can cause autoimmune diseases, while one that is too high-functioning can weaken our immunity.” Mapping where in the genome RNA editing levels are too low and where they are too high will help researchers address the health consequences of each of these conditions. Furthermore, knowing where the ADAR system tends to naturally occur can help scientists learn how to deliver the RNA-editing technologies to any part of the human body. While working on his doctorate, Prof. Levanon started building a catalog showing each occurrence of RNA editing that he detected; he then completed the map of sites for the entire genome, here at BIU. This catalog and a tool to determine the global editing level of a sample, published in Nucleic Acid Research (2020) and Nature Methods (2019), have since been widely cited. Now, together with Prof. Eli Aizenberg, a theoretical physicist from Tel Aviv University, he is building a catalog comprising exclusively the RNA editing occurrences with the greatest clinical potential. “We saw differences in how this system works under different biological conditions and are studying them together with two research teams from Harvard University, Boston. We have already shown that inhibition of ADAR activity alerts the immune system and causes it to attack tumors more efficiently.” After this discovery was published in Nature (2019), many pharmaceutical companies began developing ADAR-inhibitor drugs, which has made it possible for a greater number of cancer patients to begin benefitting from immunotherapy. 24
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