Challenge: Silencing RNAs (siRNAs) are small nucleic acids that can inhibit virtually any gene. Because most diseases could benefit from shutting-down the action of a specific protein encoded by its gene, it is suggested that siRNAs could be used to treat virtually any diseases. However, naked siRNA is unstable in the bloodstream and cannot efficiently cross cell membranes. So far, the inability to efficiently deliver siRNAs into the tissues and organs where they are needed has largely prevented siRNA to reach their full potential as novel therapeutics.

Solution: Recent pieces of evidence demonstrated that vesicles released by cells called exosomes can transfer RNA into the cytoplasm of target cells. The research team aimed to re-appropriate the endogenous ability of exosomes to deliver RNA to allow efficient delivery of RNA therapeutics. To do so, the team integrated siRNA sequences into a specific RNA backbone (pre-miR-451) causing significant enrichment of siRNA in exosomes. To validate siRNA-enriched exosomes as therapeutics, the team tested the ability of different siRNAs to integrate in the pre-miR-451 backbone and then assessed if the generated exosomes could deliver their siRNA cargo and turn off specific gene expression in different organs in mice.

Achievements/Impact: The team has shown that in exosomes, siRNA targeting SOD1, GFP or the Tet repressor can be enriched 10 to 10,000-fold compared to control. The researchers also identified variants of the pre-miR-451 backbone that will enable freedom to operate. They further showed that exosomes distributed broadly to liver, spleen, kidney, lungs and to the intestine, where they inhibited protein expression (40-60% in liver, kidney and intestines). The team has filed patents and is currently setting a new company (Hitchhike Therapeutics Inc.) to commercialize the technology. The project also generated interest from CQDM’s pharma members: while one of them exercised its option to license the technology, another one recently signed a contract to use the technology against a particular cellular target.