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. 

Challenges Remain

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

Multi-Exon Skips

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.

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Comment by Sharon Hesterlee on July 22, 2014 at 8:02pm

Hi Kimmy:  Neither Prosensa nor Sarepta are working on an exon 43 skip.  If you want to email me privately and tell me what your son's deletion is, I would be happy to look at the options.  Sharon@parentprojectmd.org.


Comment by kimmy watters on July 22, 2014 at 6:03pm

 hi sharon i have question  exon skipping   43  are the drug company  began  trails  in  jan 2015

Comment by Sharon Hesterlee on July 22, 2014 at 10:16am

David:  Prosensa is using the mouse to work out the details for a multi-exon skip that has never been demonstrated before (for these particular exons).  They are also continuing to move forward several clinical trials for single exon skips in parallel.  But for any drug to be tested in humans it must first go through extensive preclinical testing--what you are seeing is forward progress as the company works to develop the next generation of drugs while the current drugs go through the approval process.

Comment by Sharon Hesterlee on July 22, 2014 at 10:11am

Hi Rupjani:

Exon-skipping is certainly not the only game in town and it's not our major focus as an organization.  We deliberately have a very diversified portfolio when it comes to therapy development because you really never know which therapeutics will pan out and which will not...also, not every approach will be right for everyone with Duchenne and our goal is to support ALL of those with Duchenne.  Unfortunately you are correct that exon-skipping probably won't work for your son's deletion, but there are any number of other therapeutics that are not mutation-specific in development now, including halofuginone, which is in phase II.  Both Pfizer and Bristol Myers Squibb are planning to start trials in Duchenne with anti-myostatin drugs (which build muscle--the idea is that you build it faster than you lose it) and plans for gene therapy with a minidystrophin gene are moving ahead as well on multiple fronts.  Also, both Catabasis and Reveragen have drugs that may be able to take the place of steroids without the side effects, and steroids are actually pretty effective if you can separate the benefits from the weight gain etc.  Obviously steroids aren't the answer over the long term, by any means, but in the short term they are as good as any fancier drug that has been tested so far.  So I think you're son will have options and we are funding almost all of these other strategies. 


Comment by Rupjani B on July 22, 2014 at 7:19am

Hi Sharon!

Thanks for this post. My son has a long chain deletion, exon 1 to 41. Three years back when my son was diagnosed I was told that my son was not eligible for exon skipping since he doesn't have exon 1. Since then my only hope is UTROPHIN and other non mutation specific approaches like HALO 100 . Can you please tell me are these exon skipping approaches for my son? PPMD'S main focus is exon skipping, I can understand that. But at the same time am I to believe this that PPMD is not for my son. I'm sorry to write this since I've gathered a lots of info from your connect conference. It is my opinion that if you did this for UTROPHIN what you are doing for exon skipping we have a drug in our hand. Last three years I waited and waited to hear any trial news for BYGLICAN . Only Summit are committed and moving forward in ph2 clinical trial. 

Comment by David on July 21, 2014 at 11:23am
I hate to express disappointment on such a positive post overall. Really great how PPMD seeds the research.

But to learn Prosensa going BACK TO MDX MOUSE AGAIN creates an anger in me I cannot contain.

The worst deja vu ever. You don't have to explain it to me Sharon I know 'that's the way it is'. I just have a hard time understanding how so many brilliant minds can't find a way to stop repeating the same damn studies that prof wilton did years ago!

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