I was hoping someone might be able to answer some questions. On the old web site there was a discussion regarding the skipping of exon 51 and the trials and drug that are currently being tested. Our son has a deletion of exon 48-50. Would this trial for exon 51 help us? I also read that someone else has a deletion of 45 & 46 but stated that the deletion was predicted in frame and therefor exon skipping would not help them; What does this mean? Does anyone know when this exon skipping trial will be available in Canada? My last question.... Is this something I should be excited about, do you think exon skipping will be the answer we are praying for?

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Check this link. http://www.dmd.nl/DMD_deldup.html, 51 skipping should help.

By choosing exon deletion, if the result says in-frame, then thats what is needed, For example, my son has exon 12 deletion. If I choose exon 11 to 12, result comes out as in0frame. So to make hi DMD in-frame, they need to skip 11.
I won't pretend to understand everything, but here is what I know.

Exon skipping does not cure DMD, it only changes to may be BMD. When a mutaion is IN_FRAME, it usually does not cause DMD. Sometimes it causes BMD. Leiden database frame cheker is the way that was recommend to us to figure out which exon needs to be skipped. While it is not a complete cure, it is still very good as it can buy us more time..lot more time for some of the othe methods like stem cell, gene therapy to mature.

Latest resarch section has lots of good inofrmation regarding various options beeing pursued currently. Hope this is hellpful.

God bless!
Yes. Skipping exon 51 for a deletion of exons 48-50 would restore the reading frame, so your son would benefit from the current exon skipping research/trials. So as far as mutations go your son has one that is currently being worked on, so there is alot of hope there for your son. I am unsure about trials in Canada this early on, but I would assume once they have gotten over toxicity studies it will open up in many countries.
This is a difficult question with an easy answer: no one knows what the outcome of exon skipping will be, not even the scientists working on it.
It has the potential to become therapeutic in the sense that transforms Duchenne in Beker muscular dystrophy, so it could slow the progression of the disease.

Assuming that exon skipping works as well as it is hoped, the outcome will be different on a case by case basis. Some kids could become asymptomatic, for others the progression would not be any different from Duchenne, and everything in between.
To get some clues, about which mutations may benefit from exon skipping (at least in theory), try this utility/predictor.
http://www.dmdregistry.org/reports/predictor/
Wow, the website is realy impressive. Thanks , Deb.

Deb Robins said:
To get some clues, about which mutations may benefit from exon skipping (at least in theory), try this utility/predictor.
http://www.dmdregistry.org/reports/predictor/
In the earlier site there was lot of discussion on the actual therapeutic benefits of the dystrophin created by exon skipping. Some comments we about benefits will differ for those who had problems on hinges against other areas in the rod domain. Also I read some where that after the trials it was found that dystrophin produced by exon skipping is molecularly same as the original one

Do we have any further conclusions on the structure of the dystrophin produced. How does exon skipping work for problems with hinge areas as compared to non hinge areas.
Tulika,

I asked the same questions about hinges since my son also has a deletion of exon 50. I talked to Steve Wilton and a few other people about this.

It looks like it might not be a problem. If you read the paper published by Prosensa about their proof of principle you notice that one of the patients had a deletion of exon 50. The skipping worked in the sense that a certain % dystrophin was produced. Now it's not clear how functional that protein is... There are documented cases of Becker patients with very mild symptoms that had deletions on hinge 3. The 2 well know cases are: deletion 50-53 elevated CK otherwise asymptomatic (Comi 94) and deletion 45-53 diagnosed at age 60 (Bosone). So it looks like in these 2 cases the protein was functional even though hinge 3 was involved.

I also read a paper about deletions including hinge 3 and heart problems. They looked at 2 groups of Becker patients, one containing deletions of exons including 50, 51 and one group that doesn't include hinge 3. The conclusion of that paper was that there were LESS heart problems for the group that includes deletions of hinge 3. I could email you these papers if you would like to read them.

Now, as they say, the results of exon skipping might differ on a case by case basis.

Nothing can be certain until the clinical trials (skipping 51) are completed.

Ofelia
(Hum.Mol.Genet., 2008) Cell-penetrating peptide-conjugated antisense oligonucleotides restore systemic muscle and cardiac dystrophin expression and function

HaiFang Yin1, Hong M Moulton2, Yiqi Seow1, Corinne Boyd1, Jordan Boutilier2, Patrick Iverson2 and Matthew JA Wood1 - USA and UK

Antisense oligonucleotides (AOs) have the potential to induce functional dystrophin protein expression via exon skipping by restoring in-frame transcripts in the majority of patients suffering from Duchenne muscular dystrophy (DMD). AOs of morpholino phosphoroamidate (PMO) and 2'-O-methyl phosphorothioate RNA (2'Ome RNA) chemistry have been shown to restore dystrophin expression in skeletal muscle but not in heart, following high dose systemic delivery in murine models of muscular dystrophy (mdx). Exploiting the cell transduction properties of two basic arginine-rich cell penetrating peptides, we demonstrate widespread systemic correction of dystrophin expression in body-wide muscles and cardiac tissue in adult dystrophic mdx mice, with a single low dose injection of peptide-conjugated PMO AO. This approach was sufficient to restore uniform, high level dystrophin protein expression in peripheral muscle and cardiac tissue, with robust sarcolemmal relocalization of the dystrophin-associated protein complex and functional improvement in muscle. Peptide-conjugated AOs therefore have significant potential for systemic correction of the DMD phenotype.
I was looking up at that Lieden database and found some thing strange.

On page http://www.dmd.nl/DMD_deldup_Leiden.html#break under the heading 'Extent of deletions' it says that deletion of exon 50 and 51, has 2 cases of DMD.

We have been all the while told that skip exon 51 will bring in frame who have deletion of exon 50. How come then 2 occurrences of deletion of 50 and 51 are actually DMD patients?

Also I am not clear on what does "Localization deletion breakpoints (5' end / 3' end)" mean. Can someone explain this too?
Effective rescue of dystrophin improves cardiac function in dystrophin-deficient mice by a modified morpholino oligomer
(PNAS, 2008)

Bo Wu, Hong M. Moulton, Patrick L. Iversen, Jiangang Jiang, Juan Li, Jianbin Li, Christopher F. Spurney, Arpana Sali, Alfredo D. Guerron, Kanneboyina Nagaraju, Timothy Doran, Peijuan Lu, Xiao Xiao, and Qi Long Lu -USA

Antisense oligonucleotide-mediated exon skipping is able to correct out-of-frame mutations in Duchenne muscular dystrophy and restore truncated yet functional dystrophins. However, its application is limited by low potency and inefficiency in systemic delivery, especially failure to restore dystrophin in heart. Here, we conjugate a phosphorodiamidate morpholino oligomer with a designed cell-penetrating peptide (PPMO) targeting a mutated dystrophin exon. Systemic delivery of the novel PPMO restores dystrophin to almost normal levels in the cardiac and skeletal muscles in dystrophic mdx mouse. This leads to increase in muscle strength and prevents cardiac pump failure induced by dobutamine stress in vivo. Muscle pathology and function continue to improve during the 12-week course of biweekly treatment, with significant reduction in levels of serum creatine kinase. The high degree of potency of the oligomer in targeting all muscles and the lack of detectable toxicity and immune response support the feasibility of testing the novel oligomer in treating Duchenne muscular dystrophy
This paper can be found here:

http://www.pnas.org/content/early/2008/09/18/0805676105.abstract

One can download the full text. Results look great in mice.


Tina said:
Effective rescue of dystrophin improves cardiac function in dystrophin-deficient mice by a modified morpholino oligomer
(PNAS, 2008)

Bo Wu, Hong M. Moulton, Patrick L. Iversen, Jiangang Jiang, Juan Li, Jianbin Li, Christopher F. Spurney, Arpana Sali, Alfredo D. Guerron, Kanneboyina Nagaraju, Timothy Doran, Peijuan Lu, Xiao Xiao, and Qi Long Lu -USA

Antisense oligonucleotide-mediated exon skipping is able to correct out-of-frame mutations in Duchenne muscular dystrophy and restore truncated yet functional dystrophins. However, its application is limited by low potency and inefficiency in systemic delivery, especially failure to restore dystrophin in heart. Here, we conjugate a phosphorodiamidate morpholino oligomer with a designed cell-penetrating peptide (PPMO) targeting a mutated dystrophin exon. Systemic delivery of the novel PPMO restores dystrophin to almost normal levels in the cardiac and skeletal muscles in dystrophic mdx mouse. This leads to increase in muscle strength and prevents cardiac pump failure induced by dobutamine stress in vivo. Muscle pathology and function continue to improve during the 12-week course of biweekly treatment, with significant reduction in levels of serum creatine kinase. The high degree of potency of the oligomer in targeting all muscles and the lack of detectable toxicity and immune response support the feasibility of testing the novel oligomer in treating Duchenne muscular dystrophy

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