SKIP-NMD

The Drug

Antisense oligonucleotides (AON) are made from chemically altered ribonucleotide subunits (RNA) and are used in RNA-based targeted therapeutics for a range of rare and infectious diseases. There are different types of antisense oligonucleotides and the one used in the SKIP-NMD project is known as a phosphorodiamidate-linked morpholino oligomer (PMO). PMO’s work by binding to messenger RNA (mRNA; which encode for protein) and modulating their processing. i.e. inducing exon skipping.

A more detailed explanation of the process of exon-skipping can be found on the patients tab and the MDEX web site page.

In this instance, the PMO is designed to target the region around exon 53 of the dystrophin messenger RNA, directing it to ‘skip’ (remove from the mRNA) exon 53; hence the term ‘exon-skipping’. 

In a subset of DMD boys, skipping exon 53 will restore dystrophin production, by producing a dystrophin protein which has lost a very small part from its middle, but is likely to be at least partially functional. The mechanism of exon skipping across exon 53 of the DMD gene is shown in the below figure.

skipping exon 53 version3



The diagram shows how skipping a mutation in exon 53 by adding a PMO can restore production of a shorter form of dystrophin. Skipping exon 53 will also restore dystrophin production in DMD boys with mutations in exon 52 and mutations spanning exons 52, 45-52, 47-52, 48-52, 49-52 and 50-52.

The drug to be developed in SKIP-NMD will be termed SRP-4053 and synthesized and tested by Sarepta Therapeutics (Cambridge, MA, USA), a leading biopharmaceutical company in RNA-based therapeutics. The SKIP-NMD grant would not be possible without the involvement of Sarepta, who are not only providing the drug and their expertise in its manufacture and supervision of the clinical trial, but additionally half of the drug production, pre-clinical and clinical trial costs. Prof Muntoni and colleagues have an established collaboration with Sarepta since 2007 in developing exon-skipping therapeutics for DMD patients.

The drug to be developed in SKIP-NMD will be termed SRP-4053 and synthesized and tested by Sarepta Therapeutics (Cambridge, MA, USA), a leading biopharmaceutical company in RNA-based therapeutics. The SKIP-NMD grant would not be possible without the involvement of Sarepta, who are not only providing the drug and their expertise in its manufacture and supervision of the clinical trial, but additionally half of the drug production, pre-clinical and clinical trial costs. Prof Muntoni and colleagues have an established collaboration with Sarepta since 2007 in developing exon-skipping therapeutics for DMD patients.