Sarepta’s pioneering work with phosphorodiamidate morpholino oligomer (PMO) chemistries is the basis of our exon-skipping therapies.
Our next-generation chemistry is called PPMO because it adds a peptide to the PMO structure, with the goal of increasing cell nuclei penetration, and has the potential to expand our therapeutic portfolio.
The origins of inherited neuromuscular and central nervous system diseases can almost always be traced to genetic mutations that interfere with the production of critical proteins.
Genes are segments of DNA, and they’re found in nearly every cell in the body. When the body needs to make a protein, information in the DNA is passed on to a similar molecule known as RNA. Ultimately, a form of RNA called messenger RNA (mRNA) passes the instructions on to a particle in the cell that uses the instructions to assemble the protein. A genetic disorder occurs when a mutation is passed on to the messenger RNA creating an error in the instruction needed to produce a certain protein.
Phosphorodiamidate morpholino oligomers, or PMOs, are synthetic molecules modeled after the natural framework of RNA. While PMOs have the same nucleic acid bases found in RNA, they are bound to six-sided morpholine rings instead of five-sided ribose rings. In addition, the morpholine rings are connected to each other by phosphorodiamidate linkages instead of the phosphodiester linkages found in RNA. This allows PMOs to bind to specific pre-messenger RNA sequences while remaining highly resistant to degradation.
Peptide phosphorodiamidate morpholino oligomers, or PPMOs, are Sarepta’s proprietary next-generation PMO-based therapies in development and are specifically designed to increase tissue penetration compared with PMOs. Nonclinical studies have demonstrated targeted delivery to skeletal, cardiac, and smooth muscles cells, and subsequent increased mRNA modification. The goal of these development programs is to learn whether the addition of the peptide may improve efficacy and reduce dosing, in addition to expanding the range of diseases it may treat.
Many diseases are caused by a genetic mutation in a particular gene. Most commonly, one or more exons (parts of the gene) are missing, causing errors in the instructions for making a specific protein. This results in the body not being able to produce enough—or any—of that protein. The goal of exon skipping, is to act on the RNA to allow the body to make a version of the missing protein to bypass the mutation.
A gene is made up of exons (portions of a gene) that are linked together to provide instructions for making a specific protein.
Each exon connects with its neighboring exons in a specific way. Exon 43, for instance, connects on one side with exon 42 in a specific way and on the other with exon 44, also in a specific way.
If exon 43 is missing, exon 42 cannot connect directly to exon 44 because their connectors don’t fit together, and because they don't fit together the body is unable to read the genetic instructions for making the protein.
By hiding certain exons, we can “skip” their location to link with an exon with the right connector. This would allow for a production of a shortened and potentially functional form of the missing protein.
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 shorter form of the missing protein.