By Dr Susan Walsh, Research Officer at the CGD Research Trust
Professor Reinhard Seger works at the University Children’s Hospital of Zurich. He is a leading expert on the treatment of CGD and bone marrow transplantation. He works closely with groups in the UK, rest of Europe and around the world on CGD. I had the great pleasure of meeting him when he came to the UK to attend CGD Research Trust’s Medical and Scientific Panel meeting.
How long have you been working in CGD?
Since 1977 when I saw my first patients with CGD in Zurich. It can be a terrible condition and back then there was very little that could be done except treat infections. We tried various kinds of antibiotics and found some worked and others didn’t. That’s when I started some experimental work.
What did you do?
My first experiments were to find out which antibiotics could get into neutrophils so that they could kill microbes within cells. I tested a range of antimicrobials and saw that some were taken up and concentrated by neutrophils. This led us on the path to choose more carefully those antimicrobials that would be useful for treatment of CGD. Obviously we have come much further than this now and understand much more about which pathogens are dangerous in CGD and how to treat them.
Where did you do your training?
Before I started my clinical training in Switzerland, I worked in London at the School of Tropical Medicine. Really, I discovered the fascinating discipline of immunology there and this made me want to do a Master of Science in Immunology in Birmingham. After having completed my paediatric training in Zurich I took up a consultant position for paediatric infectious diseases and was in charge of the microbiology laboratory. In 1983 I went to Paris to work for one year with Alain Fischer at the Necker Children’s Hospital in immunodeficiency diseases and bone marrow transplantation, BMT. Using this experience I then established the paediatric BMT unit in Zurich.
So you were a pioneer of BMT for CGD?
Well, I did not perform the first BMT for CGD, but pushed the concept hard and showed that it worked for the benefit of patients. The idea of doing a BMT for CGD in the early days was certainly not a recommended procedure and was met with some resistance but when you have very ill patients you have to try and help them. It was in the early 1990s that we did our first procedure. The child had a multi-focal Aspergillus infection that was progressing rapidly. The BMT for this patient was risky because of the acute infection but it was considered better to try and save this person’s life with little chance of success rather than do nothing. The wonderful thing was it worked, and this made me to want to pursue and advance this treatment for other people.
How many people with CGD have you treated by BMT?
We have treated fifteen children and adults in Zurich with BMT. The Newcastle centre with whom we are collaborating has an even bigger experience. Success rates are certainly increasing. Advances are being made in a number of crucial areas. For example in Zurich, we are researching milder methods of chemotherapy treatment for BMT procedures, so that BMT can be offered for sick children and adults with active infections or inflammatory disease at the moment of transplant. These reduced intensity treatments also have the advantage of preserving the patient’s fertility. In addition there is important work going on in Paris and London to reduce graft versus host disease in BMT. Graft versus host disease is caused when the donor’s cells attack the recipient’s body and is due to a specific population of cells known as alloreactive T cells. Both research groups are working out ways to remove these cells from donor’s graft before it is used for transplant so that graft versus host disease will be reduced. Today BMT for CGD is mainly an option for those people who can find suitably matched donors. If depletion of alloreactive T-cells would work out safely, even mismatched BMT might be possible.
You sit on a working party for BMT in Europe. How does this work?
The collaborative group involves clinical experts and scientists from 20-30 BMT centres from around Europe. We are actually devoted to working out procedures for treating rare primary immunodeficiencies and metabolic disorders and we have groups of active centres that are very experienced in treating particular disorders. We discuss the development and implementation of new BMT procedures and increasingly also gene therapy protocols. Because centres are working together we can pool results and get answers more quickly on how successful, or not, new procedures are. We discuss complicated cases and also invite clinical scientists from the USA who are setting up new treatment protocols so we get lots of fresh input. It’s a wonderful instrument for improving BMT for rare disorders.
The community are looking for cures and better treatment. What do you think will be the major advances for CGD for the next five years?
Advances will be made for BMT procedures. I have already mentioned reduced intensity marrow conditioning treatments and steps to prevent graft versus host disease. Advances will hopefully also be made in gene therapy. Gene delivery tools are being developed that increase safety while maintaining efficacy. One of the main problems is ensuring that the patient continues to make phagocytes that have functional oxidase enzyme over a long period of time following gene therapy. There is no growth advantage for gene corrected cells in CGD. This means that the great majority of cells still carry the gene defect and can replace the gene corrected cells with time. This inherent problem of CGD will be difficult to overcome. At present we are only seeing transitory benefits for patients by gene therapy. Even so we have observed that gene therapy treatment can be used to overcome life-threatening infections in a way that can stabilise the patient so that other treatment options can be considered at a later date. For example it can stabilise patients for BMT who would otherwise be too ill to tolerate conditioning. Gene therapy could thus become a new and important part of our armoury in treating CGD.
In the distant future one could imagine that advances will be made such that the corrective gene will be associated with the chromatin, (chromatin is the complex of DNA and protein that makes up chromosomes) in a harmless manner, be protected from becoming silenced and be replicated together with the patient’s DNA and that the gene-corrected cells will persist, so that we can achieve a permanent cure.
One patient has been treated by GT in Zurich. How is he doing and do you have plans for treating more?
One child has been treated by gene therapy in Zurich with long enough follow up. He had severe Aspergillosis and BMT was not suitable because of lack of a donor. Gene therapy was his only chance of survival and he very fortunately overcame the life-threatening aspergillosis. We had to explain to the parents the risks and possible complications. We had to inform them that some children in another trial the one for X-SCID have developed leukaemia, that this could be a long-term risk also for CGD and that a safety-improved version of the present gene therapy reagent would only become available in 2009. The parents took this on-board but they told us that these risks come later, we have a life-threatening situation now, we must act and we have to take the chance of gene therapy helping their child.
It must be a difficult situation for you to deal with?
Yes it is, but the decision to give gene therapy is not only in our hands. In Switzerland we have an international advisory board of three specialists that assess on a case-by-case basis whether CGD gene therapy can be done. This is an impartial and objective assessment. It has worked well so that Germany is now using the same panel. In the UK you have the Gene Therapy Advisory Committee to carry out this role.
How much research activity is there at the Children’s Hospital in Zurich on CGD?
At the moment we are working on gene therapy for people with CGD who have the p47phox deficiency. The development of a clinical protocol will take several years. This work would open up the second largest CGD patient subgroup that gene therapy could be used for. One problem is that we don’t have a suitable human cell model (p47 deficient cell line) yet to test out the gene therapy reagents (vectors).
Who do you collaborate with?
Key collaborators are Dr Manuel Grez, in Frankfurt and ProfAdrian Thrasher in London who both work on the design of gene therapy tools to treat X-linked CGD. I met Manuel at a conference in the early 1990s and he told me about his work on engineering vectors to treat HIV infections. At that time the genes for CGD were known and isolated and I asked him if it would be possible to use his knowledge in some way to treat CGD. I was invited to go to Frankfurt to discuss CGD from a clinical perspective and possible collaborative work, and then we made the decision to start applying for funds for the work. We have come a long way since then, but working on gene therapy for a disorder such as CGD needs a bigger team than just two persons. Currently there are several teams working together. We call this the CGD Working Group. We look at various aspects of what is involved. For example, you need experts who know in detail about the clinical disorder and the relevant disease mechanisms. You need experts that know how to develop the right gene therapy tools and others who know all about stem cells and bone marrow transplantation techniques. We need experts that can develop models to test the safety and preclinical efficacy of gene therapy reagents and then we need people who have the molecular techniques available to monitor patients once gene therapy has taken place. It is a big commitment and all this needs funding.
How would you describe a typical day?
Well I have the typical office duties – emails and office work. Then I meet with other paediatric immunologists on the ward or in reunions and we discuss what we can do for our patients. I usually see one or two families with CGD every week during a clinic. Many come from outside of Switzerland for a second opinion and have terrible complications. As you know CGD can be a devastating condition. I discuss the range of treatments that are available today. Sometimes our clinical work throws up ethical problems that can’t be dealt with easily and actually need some changes in the way that society views things. This was the case several years ago when I met a young couple that had a son badly affected by CGD and for whom we couldn’t find a suitable bone marrow or cord blood match. The couple decided to opt for prenatal genetic diagnosis, PGD, to screen for an unaffected child who would be able to act as a bone marrow donor for the affected brother. PGD to select for a so called “saviour baby” is not allowed in Switzerland. The couple had to go to Belgium for the procedure, which was successful. In order to highlight their plight the couple got a TV reporter involved who made a film that reflected the human side of their story - why it was important, how difficult a condition CGD is and what suffering can be involved, what were the stark options on offer for parents and that the procedure was not about creating new “designer babies”. The film caused a huge public discussion and media attention (including an article in the Lancet on “Belgian loophole allows Swiss parents a “saviour” baby”). It ended up being translated in different languages and was shown in Austria, France, Germany and Italy. It changed the public’s perception of such procedures and that of our national ethical committee such that the Swiss ethical committee has now invited experts from Belgium to know more about what is involved. I’m pleased to say all has worked out well for the couple and the family in spite of the low chances of success (only 5%!) of this type of PGD. It certainly brought around a change of thinking of the ethical commission and this might help future families. However, the family involved has had enough of the media spot-light and now runs away from reporters!
Is there a CGD specific charity in German speaking countries?
CGD specific charities only exist in the UK and USA. So I recommend English speaking CGD families not only to join the national parent organisations for primary immunodeficiencies, but also to become members of the CGD RT UK charity.
What could CGD RT do to help more people with CGD?
You are very good at informing people about their condition and also provide excellent material for patients and clinicians. I believe that the breakthroughs for CGD will come from stirring interest from basic scientists outside of CGD research. You need to bring mixes of people together with different knowledge bases, CGD experts and basic scientists. Remember I talked about meeting Manuel Grez. He is a basic scientist. That was such a fortuitous meeting. My impression is that few scientists see the full potential of clinical applications of their basic concepts or indeed don’t know the fate of rare patients with conditions such as CGD and how their work could help. Make people understand what it is like to have CGD and how terrible it can be. Motivate young Ph.D. scientists and encourage them.
Thank you so much for taking the time to talk to me and for your commitment to CGD research.
References
Duke, K. Lancet 368; 355-356
‘Saviour sibling case causes controversy in Switzerland’ http://www.phgfoundation.org/news/2608/
IMPORTANT NOTE :
The information contained on this website is intended only as a guideline, not as a substitute for medical advice. Always consult your doctor if you or your child has any CGD symptoms or concerns.
© 2001-2007 The Chronic Granulomatous Disorder (CGD) Research Trust
Registered Charity No. 1003425 email:cgd@cgdrt.co.uk
The CGD Research Trust is a member of the Association of Medical Research Charities (AMRC), the Genetic Interest Group (GiG) and an associate member of the International Patient Organisation of Primary Immunodeficiencies (IPOPI)
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