Therapeutic Applications
AVI’s core technology is versatile, allowing for the development of a range of therapeutic compounds that target different types of RNA. Unlike most other RNA-based approaches, AVI’s technology has been used to directly target both messenger RNA (mRNA) and precursor messenger RNA (pre-mRNA) to either down-regulate or up-regulate targeted genes or proteins.
Splice Switching Oligomers (SSOs)
When designed to target pre–mRNA, which is not yet mature and needs to be processed and spliced to make mRNA, we refer to our compounds as Splice Switching Oligomers, or SSOs. Each gene in the genome can code information for the expression of multiple proteins via a process called alternative RNA splicing. Our PMO-based SSO technology enables manipulation of the alternative splicing process to direct protein expression and represents a relatively new and dynamic area of RNA–based drug discovery.
SSOs can direct alternative splicing by guiding the pre-mRNA cellular splicing machinery toward one of multiple alternative protein expression outcomes. The direction of alternative splicing via SSO may lead to a preference for a splicing variant naturally seen in nature, or an entirely novel alternative not a part of normal gene expression. In either case, the objective is to produce an important therapeutic outcome. AVI’s current SSO compounds in development include those targeting Duchenne muscular dystrophy.
Exon Skipping With SSOs
Genes stored in human DNA are organized in short DNA stretches, called exons, that code for fragments of the protein regulated by that gene. Exons are separated by long, non–coding pieces of DNA called introns. During processing of pre–mRNA, which is copied from the DNA template, introns are removed and exons are spliced together to create the mature mRNA. The mRNA thus brings the exons together, providing a contiguous set of instructions from which the full protein can be translated.
Our SSOs have the potential to manipulate splicing in a way that is distinct from conventional antisense or siRNA based approaches to modulate the alternative splicing process.
By targeting elements in precursor RNA that are essential for splicing, our SSO compounds force the cellular machinery to skip over targeted exons, creating an altered mRNA template. In a disease situation, SSOs are intended to prevent formation of harmful proteins and help restore beneficial proteins. When the exon contains a disease–causing mutation, for example, the resulting altered protein may have its function restored, partially restored or neutralized by forced skipping of a specific exon. This approach may be used to overcome the consequences of certain disease–causing mutations.
Therapeutic applications of SSOs include:
- Inhibition of mRNA production via a kinetically favored process
- Repair of RNA mutations
- Expression of novel proteins
- Alteration of protein compartmentalization
- Alteration of the profile of protein isoforms
Translation Suppressing Oligomers (TSOs)
When the target is mRNA, which translates genetic information into protein, AVI compounds are called Translation Suppressing Oligomers or TSOs. AVI’s current TSO compounds in development include, for example, those targeting hemorrhagic viruses.
TSOs are PMO based compounds that interfere with gene expression or other mRNA–dependent cellular processes by binding to their specific target sequence in mRNA. TSOs have high mRNA binding and act by a steric–blocking mechanism to inhibit protein translation, instead of by mRNA degradation mediated via RNAse H or RISC. We can use different PMO analogues as TSOs to achieve down regulation of genes or silencing of targeted mRNA sequences.
The primary application of TSOs is to inhibit the translation of either a specific endogenous or viral protein through this binding process, thus inducing a desired therapeutic effect.
This page was last updated on July 8, 2010.
