Biochemist Gunter Scheuerbrandt has been following exon skipping for the international Duchenne community for years. Read the latest update from one of this community’s greatest allies.


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Dear Friends and Colleagues:

Today, I am enclosing an interview which I recorded last April with Professor Gertjan van Ommen, the director of the Department of Human Genetics of the University of Leiden in the Netherlands. In this interview, we discussed the history and the future of the exon skipping technique for slowing down the fast muscle degeneration of Duchenne to the slower one of Becker dystrophy. Because of technical difficulties, this interview could not be brought into a final form and be approved by Professor van Ommen until the beginning of this year. Tiberiu in Bucharest, an IT specialist and Duchenne father helped decisively to save this interview.

With my last letter, which you received in May 2011, I sent you another interview which I recorded also last April with Dr. Annemieke Aartsma-Rus of Leiden University about the then actual state of exon skipping. Dr. Aartsma-Rus has updated this interview recently, and this is enclosed here, too, thus the two interviews will give you an up-to-date summary of this most advanced research approach towards a therapy for Duchenne muscular dystrophy.

At the end of 2009 I had sent you my last detailed and updated research report about exon skipping. As you know, the many antisense oligoribonucleotides, AOs, potential skipping drugs, will provide personalized therapies for groups of patients with specific mutations in their dystrophin genes. I am now planning to write a more comprehensive report again about exon skipping but also about all the other “non-skipping” approaches, which would possibly benefit all Duchenne patients independent of their mutation, like upregulation of utrophin, inhibition of myostatin, idebenone, steroid treatments, and other promising methods.

This comprehensive new report will be ready sometime this year 2012, and it will probably be also my last one because I will be 82 in April and thus am now actively looking for someone who would continue what I have been doing since 2000 when I wrote my first report after a Duchenne meeting at the NIH in Bethesda. If there is someone out there whom you know, who knows English and other important languages well, understands the science behind Duchenne and what is being done against it, knows also how to explain it in rather easy language, and is willing to work without being really paid for it, please ask her or him to write to me.

Some of you will know that since 1974 I had a private laboratory where, with some co-workers, I performed a screening program in Germany for the detection of Duchenne (and Becker) dystrophy in infant boys during their first year after birth. After we tested 537,000 boys and found 155 with Duchenne (1:3,600) and 35 with Becker dystrophy (1:15,300) we had to close this program for financial reasons last year at the end of November. I have written a “good bye” summary for the international screening community which I am enclosing here, too.

But now, people realize that exon skipping will probably become a therapy for some Duchenne boys within a few years and that this technique will not regenerate lost muscle fibers, so the AOs, the antisense drugs, will have to be given to the boys soon after birth. Therefore, there is now quite some interest to start new newborn Duchenne screening programs or re-start old ones in countries like Mexico, Taiwan, Australia, Cyprus, Wales (UK), possibly the Netherlands and even the United States. Two pilot programs have been done in the United States, one in the state of Ohio in Columbus and the other in Georgia by the Center of Diseases Control and Prevention, CDC, in Atlanta. The most astonishing news from the Ohio study, which has been published now in Annals of Neurology, is that the base sequences of the entire 79 dystrophin exons can be determined for 150 dollars from the few white blood cells present in a dry blood spot on filter paper. That means, from a high-CK blood spot of a newborn Duchenne boy, the genetic diagnosis can be made from this first drop of blood taken routinely at the time when all other newborn screening tests are being done.

At the end of January, I was for 3 days again in India, in Chennai (former Madras) to explain to the Indian families of the MD association there how exon skipping really works on the molecular level. I also gave a summary of the clinical exon skipping trials completed, running or being prepared. Here is a very short and abbreviated list of these trials:

Four phase-I and phase II trials for the local and systemic skipping of exon 51 were performed by Prosensa in the Netherlands and the American company AVI in the UK between 2006 and 2010, new dystrophin was detected and no toxicity. All other trials are systemic studies, meaning that the potential drug is injected into the blood circulation. For two years now, the systemic phase-II trial of Prosensa is extended as an open study without placebos. GlaxoSmithKline (GSK) performs the decisive („pivotal“) phase-III exon-51 trial in many countries with 180 patients (details see below). A phase-II 51-trial with 54 boys and different dosages has begun in the United States. An open long-term extension exon-51 trial with 220 patients, partly from finished earlier trials, has been started for a two-year treatment. GSK and Prosensa together have started a phase-II trial to skip exon 44. A larger trial to skip exon 44 is being prepared by GSK. Preparations are underway at Prosensa to start the first trials for skipping exons 45 and 53 this year and of exon 52 later. AVI will begin trials for skipping exons 45 and 50.

Concerning GSK’s large phase-III trial for skipping exon 51, 180 patients have to participate for a reliable proof that exon-51 skipping really slows down muscle degeneration and improves muscle function so that the 51-skipping drug can be approved for marketing. But up to today, only 127 boys have been accepted in the study, so 53 more are still needed. If you know families with a Duchenne boy at least 5 years old, still walking independently, receiving steroids for at least 6 months (could be started now), and having a mutation that could be treated by skipping exon 51, please ask them to contact me by e-mail. Also the phase-II exon-51 trial in the United States needs more participants who fulfill the same requirements but don’t need to be on steroids. I enclose a list of the 5 active clinical centers in the US which can now be contacted. In the near future more centers will open in North Carolina, Iowa, Texas, Oregon, Kansas, Minnesota, and Missouri.

At the end of this letter, I would like to invite every family, who wishes to know whether their sick child has a chance to be treated by exon skipping, to let me know by e-mail the exact mutation of their son, preferably by sending a copy of his genetic test results. Then I could tell the family which exon or exons should be skipped if effective skipping drugs become indeed available in the not too distant future.

With kind regards from the very cold and snow-white Black Forest, I am your old friend Gunter.

Guenter Scheuerbrandt, PhD.


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