PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of actamyolLink to Publisher's site
 
Acta Myol. 2009 October; 28(2): 62–65.
PMCID: PMC2858951

The progress reports on the development of therapies of Duchenne muscular dystrophy

Summary

The roots of the progress reports on the development of therapies for Duchenne muscular dystrophy (DMD) that since 2000 have been produced at Breitnau/Germany and distributed to the parents of DMD patients cover over 30 years of continual occupation with this disease. The beginning was marked by the development of an early detection programme for the genetic disposition for DMD in infant boys. The next step was the organisation of workshops on the management of DMD and the writing of progress reports on these and other relevant conferences. Getting acquainted with the ideas of the protagonists in the research field by holding interviews was a decisive prerequisite for this activity. This took place in tandem with the development of a new kind of multiplex “family letters” that attempted to answer frequently asked questions to many DMD families at the same time.

When – with the beginning of the new millennium – the endeavours towards gene therapies for DMD started to boom all over the scientific world, progress reports designed to keep the families informed about research on DMD treatment were added to the family letters. These reports that give an account of the latest state of the research are written in a plain language that can be understood by laypersons. In the meantime the reports have adopted the character of reviews that are updated annually. They are written in English and German and translated into Spanish and many other languages.

Keywords: Duchenne muscular dystrophy, CK screening, multiplex family letters, progress reports, gene therapy, exon skipping

The beginning: a screening test for the early detection of Duchenne muscular dystrophy

I was first acquainted with Duchenne muscular dystrophy (DMD) in 1972 when, during work in the USA for the German pharmaceutical company Merck, I met the Swiss neurologist Hans Zellweger, who was in charge of the Duchenne patients at the University of Iowa. He pointed out to me the possibility of detecting newborn boys who would later develop DMD by determining the activity of the enzyme creatine kinase (CK) in dry blood spots. He went on to explain that this early detection would allow, among other advantages, genetic counselling to prevent the birth of additional affected boys in families where the mother was likely to be a carrier of the Duchenne gene (1). The test would make use of the finding that in affected boys CK entered the blood from the deteriorated muscle cells. I was fascinated by this possibility and regarded this test as so important that I decided to establish a laboratory at my home in Breitnau near Freiburg/Breisgau. Here I developed Zellweger’s preliminary method into a simple routine test where CK activity is determined by a bioluminescence test using the luciferase enzyme of fireflies as the main component. By 1977 I was already able to offer a cheap voluntary screening programme for all of West Germany. More than 500,000 parents have since made use of this test. Among the samples, 150 were found to be positive for DMD (1:3,300) and 35 were found to be positive for the less severe Becker form of the disease (1:14,300).

The entire procedure of the method comprising the collection of the samples, the performance of the improved bioluminescence test and parent notification was first published in 1986 (2). In March 1992, the European Neuromuscular Centre (ENMC) conducted a workshop with the title “Neonatal Screening for Muscular Dystrophy” (3) with representatives of all 7 CK screening programs running at that time.

Workshops to improve and standardise the management of DMD: first progress reports

While trying to promote the CK screening test I realised that – at least in the German Republic of the early 80s – the management of DMD was by no means harmonised among the physicians. Therefore I got involved with advertising workshops designed to discuss the matter between experts in order to come forward with standardised treatment schemes. I organised three such workshops. The first of these was the very first such meeting on this subject held in Germany. It was staged in 1980 in Saig (Black Forest) and directed by the paediatrician Wilhelm Mortier from Wuppertal. The second workshop was held soon after the detection of the Duchenne gene and its product. It was staged in Aix-la-Chapelle (Aachen) and directed by the orthopaedic surgeon Raimund Forst. The third workshop took place relatively recently (1997) in Rotterdam (4). It was chaired by the paediatrician Victor Dubowitz from London.

For all three workshops I produced progress reports. They were translated into many languages and became a kind of “gold standard for care” for many years. This standard for care is now being professionally produced and steadily improved by Kate Bushby within the framework of the European organization “TREAT-NMD” at Newcastle upon Tyne. State-of-the-art information is available on the internet at www.treat-nmd.eu/patients/patient-care/dmd/.

The above-mentioned workshop reports were my first steps, so to speak, of becoming a routine reporter. But at that time, I had also started to write about Duchenne research in a more general way. For instance, as the delegate of the German muscular patients’ association (DGM) to the annual meetings of the European Alliance of Muscular Dystrophy Associations (EAMDA), I wrote summaries of these meetings for the DGM’s quarterly journal “Muskelreport”. Following the identification of the dystrophin gene and protein in 1986/87 I wrote several reports on these sensational findings under the heading of “News from the Duchenne gene”. The reactions of parents to this reporting taught me how important it was to let the families know what the researchers – at that time there were only a few – would do next to find a therapy for their boys. These were the foundations for my research reports which began soon after.

The development of multiplex “family letters” for DMD parents

In the context of my screening programme I had many discussions with DMD families, not only with those whose sons’ conditions had been detected by my test. From these exchanges I learnt that there was a great demand from the families to keep in contact with other families having similar problems. In addition they wanted to be informed about the disease itself, e.g., which doctors were helpful and competent, what was going on in research on DMD, in particular in the search for treatment ecc. And they wanted this conveyed in an understandable manner.

Therefore, I started the production of multiplex letters for affected families. These letters were produced by each participating family sending their actual contributions to me. I then sorted and condensed their questions and concerns in a reasonable sequence, trying to have them answered by myself or by one of the numerous experts that helped me in this task. The resulting “mega”-letter was distributed about three to four times a year to all participants at the same time. The distribution was by normal mail because e-mail did not exist at that time. The number of participating families rapidly increased from about 12 in the beginning (1978) to about 100 by the end (1997), with families from abroad increasingly taking part. Also during this period the emphasis of the contents shifted more and more from tales of the personal fate to medical questions. As I am a biochemist and not a physician, I referred all these questions to an increasing number of experts who were mainly recruited from the scientific council of the DGM.

Dealing with these questions in the family letters that I had to solve in communication with researchers and physicians was another step in my development of becoming a scientific reporter writing progress reports on research on DMD therapy.

The DMD progress reports

In May 2000 I was invited to a conference of the NIH (the US-American National Institute of Health in Bethesda MD, near Washington DC), in order to report on our CK screening programme. At this conference all important research approaches for a therapy for Duchenne muscular dystrophy were presented and discussed by scientists from many countries. I realized that this was an excellent opportunity to write a report for the Duchenne families in Germany, explaining to them in plain language what the researchers were doing in order to help their children. I recorded the presentations on tape, took notes, and talked to most of the participants. Then I had the idea of how best to avoid making mistakes: I asked all speakers to help me prepare my reports by reading my first version of the summary of their results, making any necessary changes and additions and then later by approving the final text. All of them accepted this proposal and most of them were in fact very helpful in this way – and they did it for all 11 reports that I have written in the 10 years since.

During this time I have sought to interview the most important and successful researchers wherever I meet them, even if this is not during a conference. So far I have recorded, transcribed and edited for publication 11 major interviews, and all interviewees have taken the trouble to provide a thorough correction. I feel most confident that they will continue to do this in the future.

These congress reports and interviews are listed in Table Table1.1. The more recent ones (since 2006) can be viewed or downloaded as pdf files under www.duchenne-information.eu in English, German or Spanish. One of them has also been published in Acta Myologica (5). Curiously, I initially compose my all my drafts first in English and then translate them into German. The excellent translations into Spanish are undertaken by Ricardo Rojas, a Mexican patient with Becker dystrophy. Some of the reports were translated into other languages, like French, Italian, Dutch, Polish, Slovakian, Czech, Greek, Japanese, Chinese, and Turkish. The reports are also shown on the internet pages of many muscular dystrophy associations around the world.

Table 1
Progress reports and interviews.

Innovations with the progress report 2009

Until 2008 I wrote my reports mostly with information obtained at the annual meetings of the Duchenne parent groups in the US and the UK, “Parent Project Muscular Dystrophy” and “ActionDuchenne”, respectively, and at the workshops in Monaco organized by the Parent Projects in France and Monaco. In my first report after the NIH meeting in 2000, I reported on about 25 different research approaches. Currently, Duchenne researchers are working on – at the last count – 45 different projects for finding a therapy. Therefore, my last reports have become more independent of the research news presented at the parent project meetings. Although I am still using the recordings from these meetings, I am now also summarising new publications and news from other scientific meetings.

As of 2009 my report has the title “Research Approaches for a Therapy of Duchenne Muscular Dystrophy” and consists of two parts. Part I with the heading “Exon skipping” was published on 30 April (6), Part II with the heading “Gene transfer, stem cells, and pharmacological techniques” will appear by the end of 2009. Each of these two parts is now a basic text, a kind of a review of all the research done on therapy for DMD. Both parts will be updated independently from time to time with the appearance of new results.

Correspondence via e-mail

Anyone wishing to receive the new reports on a regular basis is invited to contact me by e-mail at: gscheuerbrandt@t-online.de.

There are already more than 1,000 entries on my English, German, and Spanish address lists. Most of them are families, but also physicians and researchers and even self-help associations are amongst them. I receive mail from everywhere “from Tierra del Fuego to Siberia”.

I answer all e-mails as best I can, even those with difficult questions. As a biochemist I am not allowed, and do not want to give, medical advice. But by providing information on and explanations of many non-medical matters, I can effectively help the families, especially those in the less developed countries who know so little about their sons’ diseases, and whose doctors, too, are often unable to help.

Exon-51-skipping: is it the method to a first successful gene therapy in DMD?

“How to explain exon-51 skipping to Duchenne families” was the subject of my presentation when I was awarded the Gaetano-Conte-Price 2009 in Cyprus. Exon skipping is the very promising gene therapy technique in which one or more exons – the active regions of the gene – are being skipped in order to bypass the mutation that prevents the production of the dystrophin protein in the muscle cells. As previously mentioned, my latest progress report on all aspects of exon skipping has already appeared (6). Therefore details of this method are not presented here.

I chose the skipping of exon 51 as an example for explaining this technique because skipping of this exon would provide a genetic therapy for 13% of all Duchenne patients, the largest group that would benefit from a particular exon. For this reason exon-51 skipping is already being clinically tested on Duchenne boys in the UK and the Netherlands. Many parents and even older Duchenne boys who regularly read my progress reports have meanwhile learned so much biochemistry that they understand perfectly how exon skipping works.

Only the skipping of exons 51, 50 and 44 is at present being developed through all stages of clinical trials up to marketing approval by the regulatory agencies FDA and EMEA in the US and Europe, respectively. The antisense oligos produced as drugs for skipping these three exons will probably be available in 5-8 years. But they can only be used to treat 23.2% of all Duchenne boys, i.e. those who have the “correct” mutations (7). And only about half of them, i.e., just about 10% of all Duchenne patients, will still have enough muscle left to benefit from this exon-skipping therapy. Thus, 90% of all patients will still need a therapy involving skipping of other exons or else non-exon-skipping drugs. At the present speed of research it will take many more years and very much more money to develop these other techniques. For many boys, these “beyond-51 drugs” will come too late.

Conclusion

These not-so-happy aspects make me doubt whether at my age of almost 80 years I will have sufficient productive time left to fulfil the main aim of my life’s work: to continue writing my research reports until all our boys can be treated so that they can lead a long and almost normal life.

Acknowledgments

The progress reports are produced for the European network TREAT-NMD and the American and British parent associations “Parent Project Muscular Dystrophy” and “ActionDuchenne”, respectively. I thank these organisations for their financial support. TREAT-NMD pays also Ricardo Rojas for his translations into Spanish. In addition I work closely with the German parent project “Aktion Benni & Co”. Finally I would like to thank all contributing physicians and researchers whose help was, and still is, very important for making my reports so helpful for the affected families and their sick children. My special thanks go to the Gaetano-Conte-Academy for awarding me its 2009 prize for social research, and to Reinhardt Rüdel, Ulm, and Jane Miller, London, for their support.

Next reports:

Next reports:

October 2009: Research approaches, Part I, 1st update.

January/February 2010: NIH/TREAT-NMD meeting in Brussels (16-19 November 2009): Bringing down the barriers.

March/April 2010: Research approaches, Part II: Gene transfer, stem cells, pharmacological methods.

References

1. Zellweger H, Antonik A. Newborn screening for Duchenne muscular dystrophy. Pediatrics 1975;55:30-4. [PubMed]
2. Scheuerbrandt G, Lundin A, Lövgren T, et al. Screening for Duchenne muscular dystrophy: an improved screening test for creatine kinase and its application in an infant screening program. Muscle Nerve 1986;9:11-23. [PubMed]
3. Van Ommen GJB, Scheuerbrandt G. Workshop report: neonatal screening for muscular dystrophy. Neuromuscul Disord 1993;3:231-9. [PubMed]
4. Scheuerbrandt G. First meeting of the Duchenne Parent Project in Europe: treatment of Duchenne muscular dystrophy. 7-8 November 1997, Rotterdam, the Netherlands. Neuromuscul Disord 1998;8:213-9. [PubMed]
5. Scheuerbrandt G. Parent Project Muscular Dystrophy annual conference. Cincinnati, Ohio - 13-16 July 2006. Acta Myologica 2006;25:77-97. [PubMed]
6. Scheuerbrandt G. Research approaches for a therapy of Duchenne muscular dystrophy, Part I: Exon skipping. April 2009, www.duchenne-information.eu
7. Aartsma-Rus A, Fokkema I, Verschuuren J, et al. Theoretic applicability of antisense-mediated exon skipping for Duchenne muscular dystrophy mutations. Human Mutation 2009;30:293-9. [PubMed]

Articles from Acta Myologica are provided here courtesy of Pacini Editore