How RNA Therapeutics Work

Using modern methods of chemical synthesis, AVI makes compounds that bind selectively to RNA, the carrier of genetic information from DNA to protein, and prevent production of a particular protein. If this protein is needed for a virus infection or causes a disease, e.g. cancer, the disease may be prevented or treated. AVI BioPharma is an early pioneer of antisense technology, the precursor of the growing field of RNA therapeutics.

RNA–based therapeutic compounds are made up of subunits or monomers, linked together and called oligomers. Each subunit carries a genetic “letter” or base (A, T, G or C) that allows it to pair with its complementary monomer on the RNA target (A pairs with T and G pairs with C). The order or sequence of these “letters” determines the identity of the RNA to which it binds, as well as the precise position in the sequence of the RNA that it seeks out specifically. When the target is mRNA, which translates genetic information into protein, AVI compounds are called Translation Suppressing Oligomers or TSOs. AVI oligomers can also be targeted to a pre–mRNA, which is not yet mature and needs to be processed and spliced to make mRNA. Used in this capacity, AVI compounds are called Splice Switching Oligomers or SSOs because they can determine which — of several choices — mRNA is actually made preferentially.

Genetic letters and base pairing are common to all RNA therapeutics, but chemists can change the chemical character of the therapeutics molecules in subtle but significant ways. For example, the fine structure and charge of the monomers determines the strength of the linkages that hold them to their target, the “backbone” of the oligomers can be altered to achieve different properties, such as resistance to enzymic degradation or bioavailability. The older antisense compounds, and also siRNA, are designed to degrade their target RNA molecules. Instead, AVI oligomers with morpholino backbone act by "steric blocking" — binding to a target sequence within the RNA molecule and simply obstructing other molecules that might otherwise interact with the RNA. Thus, there is no degradation of the drug or its target mRNA.