Early in the protein synthesis pathway, DNA is transcribed into an immature form of RNA called precursor messenger RNA (pre-mRNA). Pre-mRNA is spliced—or processed—into messenger RNA (mRNA), which is ultimately translated into a protein.





Alternative splicing often occurs naturally during gene expression, and results in a single gene coding for multiple proteins. RNA therapeutics may use this process to up- or down-regulate the production of proteins, or to alter the function of the protein by changing the splicing.

PMOs can be designed to selectively target elements in the pre-mRNA to redirect the splicing machinery and process an alternate mRNA. The alternate mRNA may be translated into a desired protein. Or it may be made to be nonfunctional to prevent translation of an undesirable protein.

One example of alternative splicing is exon skipping. This may be a useful therapeutic approach for certain inherited disorders, such as Duchenne muscular dystrophy (DMD). The underlying cause of DMD is a mutation, or error, in the gene for dystrophin, an essential protein involved in muscle fiber function.



In this example, the PMO directs the splicing machinery to skip an exon when processing the pre-mRNA. As a result, the alternate mRNA allows for the production of a shortened, functional dystrophin protein.




PMOs can also prevent the cellular machinery from translating mRNA into a protein. PMOs do this by binding to a specific control region in the mRNA and blocking access to the cellular machinery. As a result, the PMO inhibits translation of an undesirable protein.

One therapeutic application for translation suppression with PMOs is inhibiting viral replication. When a virus infects a cell, it inserts its genetic code and forces the cell to replicate the virus. The cell eventually dies and releases the viral copies into the circulation where they infect other cells.


In this example, the PMO binds to specific targets in the viral RNA to block translation of a protein needed to replicate the virus. This approach may stop or slow the viral lifecycle.


PMO-based drug development has the potential to address diseases that otherwise could not be treated with traditional small molecule or biologic drugs. The human genome of about 22,000 genes is the basis for more than 250,000 RNA transcripts and about 150,000 proteins, a universe rich with potential targets for PMO-based therapies.