I'm often asked by parents to explain exon skipping. In fact, at last month's 20th Annual Connect Conference, after we announced a grant awarded to Dr. Judith van Deutekom, parents wanted to know what it is we are actually funding. You may know that PPMD has a decade-long history of supporting this technology, but what exactly is it? Let me explain...
“Exon-skipping” is a newer technology that has shown promising results in clinical studies for Duchenne. Exon-skipping aims to restore some level of the dystrophin protein to the muscle cells, despite the presence of a mutation that normally prevents the protein from being made. This makes it different from many drug candidates that have the goal of reducing the damage, such as inflammation, that occurs due to the loss of dystrophin.
How Does It Work?
Most genes hold instructions for how to make important building blocks of the body, such as a protein. The dystrophin gene has instructions for making the dystrophin protein. Inside the muscle, each cell makes a copy or “message” of the dystrophin gene in preparation for reading the genetic instructions to make a protein—if you think of this copy as a pearl necklace with spacers between each pearl then you have the general idea. Normally the spacers are removed and the pearls are fitted together precisely before the message is used to make dystrophin; sometimes, however, a missing piece of the gene causes the pearls, or exons, to be mis-aligned when the cell tries to reassemble them. This is actually the most common cause of Duchenne. The goal of exon-skipping is to use little pieces of DNA called “oligos” to coax the muscle cells to sacrifice an additional pearl in the necklace in addition to the spacers so that the remaining pearls will fit together precisely. The result is a shorter, but still functional, dystrophin protein.
The technology is showing great promise in trials such as Sarepta’s phase IIb study of eteplirsen, which recently reported data from a group of boys who have received an exon 51 skipping drug for three years and appear to be progressing significantly more slowly than they might without treatment. Prosensa’s drisapersen may also show benefit when the data from GSK’s phase III study are analyzed differently.
Because this technique is designed to treat specific mutations and there are hundreds of mutations that can lead to Duchenne, developers of exon-skipping have started by testing drugs that could potentially treat the most number of boys at once—this turns out to be a handful of deletions around exon 51. Gradually trials for additional exon skipping drugs that would treat other groups of mutations around exon 44, 45 and 53 have also been started and plans are on the books to start trials to skip exon 50, 52, 55 and 8. Each of these skips could potentially help those with specific deletions around that exon, but that still doesn’t cover all of those who might benefit (to find out what exon someone with a given deletion in the dystrophin gene would need skipped check out the exon-mapping tool on Sarepta’s “Let’s Skip Ahead” website).
More than a decade ago we helped fund the development of exon-skipping in academic laboratories and since have funded, along with the Muscular Dystrophy Association, travel for families participating in the Sarepta phase IIb. Now PPMD is committed to bringing this technology to all of those who might benefit as quickly as possible.
Applying Exon-Skipping to Less Common Deletions & Duplications
In response to our Request for Applications last year focused on applying exon-skipping to less common deletions and duplications, we received several applications and our scientific advisors recommended that we fund a $200,000 project submitted by Judith van Deutekom of Prosensa to develop a method for skipping multiple exons at once. Dr. van Deutekom is focusing on exons 10-30, which would work for those with deletions of any size between exons 10 and 30—mutations that are currently not in the official development pipeline for any of the companies involved in the exon-skipping space. The goal is to use a single drug for these deletions rather than developing new drugs for each exon that might usefully be skipped in this region of the gene. Dr. van Deutekom is also experimenting with a modified chemical backbone for the oligos used in this multi-exon skip that could make them more efficient and reduce potential side effects. This work complements an earlier exploratory project that we funded with Dr. Toshifumi Yokota at the University of Alberta to develop a multi-exon skip for exons 44-55.
Duplications & Point Mutations
In addition to developing multi-exon skips, we are also looking at ways that exon skipping might be used to treat duplications and point mutations and in making the technique more efficient. For example, we recently provided funding to Dr. Eric Hoffman’s group at Reveragen to understand if tiny pieces of genetic message in the cells called “microRNAs” might affect the efficiency of exon-skipping.
Other Approaches in Development
Although exon-skipping holds much promise, please remember that it’s not the only game in town. We are working on expanding the reach of this technology to the broad spectrum of dystrophin mutations, but there are a large number of other approaches in development or testing now that are not mutation-dependent and may prove equally effective. Click here to learn more.
What Can I Do?
If you are interested in helping us expand the reach of exon-skipping, please consider making a donation to PPMD’s research portfolio. We will continue to support not only exon skipping but new treatments and therapies at various stages of development.
It is also more important than ever to register your child with DuchenneConnect. This is your connection to clinical trials that may directly impact your child. If you are already registered with DuchenneConnect, make sure your information is updated.