By Dr Susan Walsh, Research Officer at the CGD Research Trust
Dr Manuel Grez works on the CGD gene therapy project funded by the CGD Research Trust at the Georg-Speyer-Haus Institute in Frankfurt, Germany. He is working closely with Professor Adrian Thrasher of the Institute of Child Health in London on generating second and third generation gene delivery tools, known as vectors, for the treatment of X-CGD. I had the great pleasure of visiting his laboratory and talking with him about the project and at the end of my visit I interviewed him about his work for our website.
You come from Chile originally but how did you come to work in Germany?
I was trained as a chemist in Chile and I then decided to do a Ph.D. in Germany. I actually received a fellowship from the German Government to do this. After finishing my PhD in Marburg I then went on to learn more about biology and chemistry and worked for three years at the Max Planck Institute in Berlin and thereafter for two years at the German Cancer Research Centre in Heidelberg. By that time I was working on regulation of gene expression. I then moved to the USA, to Los Angeles, working on genes involved in the development of cancer.
Back in Germany I joined the Wolfram Ostertag lab in Hamburg where I started to work with retroviruses and stem cells. There is always a woman involved and I had met a German lady and we married and I have settled here with our family ever since. In 1990 I moved to the Georg-Speyer-Haus Institute where I have been since then.
How did you become interested in CGD and gene therapy?
I started working on vectors (modified viruses) for use in stem cell research in the 1980’s. Luckily I visited the USA for a scientific conference and met Professor Reinhard Seger from Switzerland, who is an expert on CGD. We are both German speaking guys and we started talking: ‘What are you doing?’ and so on.
Reinhard said that CGD was a prime candidate for treatment by gene therapy and we should work together. Reinhard actually sent me the gp91phox gene soon after. This was such a fortuitous meeting. We then decided on the approach we would take and we have been working together ever since and we are in contact every week discussing patients and our work. Reinhard was a key player in the development of gene therapy for CGD because of his expertise in CGD.
How did you become a collaborator with Professor Adrian Thrasher at Great Ormond Street Hospital?
Again, we met at a scientific meeting about seven years ago. I was presenting a poster at the American Society for Gene Therapy and we found we had strong common interests. We’ve worked together ever since. He is a major player in gene therapy. He did his Ph.D. on CGD and specifically on p47phox and he has huge clinical experience of CGD and the development of gene therapy for CGD and many immunodeficiency disorders. Our teams are working really well together developing the future generations of tools to treat CGD by gene therapy.
What other genetic disorders are being treated by gene therapy?
There are now several gene therapy trials going on. There are obviously the trials for CGD taking place in Frankfurt, London, Zurich and in the USA and then there are trials running for X-SCID, ADA-SCID, Wiskott Aldrich Syndome (WAS) and beta thalassemia. Soon work will be starting on treating sickle cell anaemia and metachromatic leukodystrophy by gene therapy. It has also been applied to treat some skin diseases.
What have been the main achievements in gene therapy for CGD for the last few years?Our first major step for treating CGD patients was deciding on the design of the gene delivery vector and then there was the production of this clinical grade vector within a commercial company. The first batch produced did not work in pre-clinical tests and we switched to another company who produced the vector successfully. We are going to this company again for production of the second-generation vector. We hope to have this improved second-generation vector in the clinic within the next eighteen months.
The next major step was to get patients to enrol on the trial and to show gene marking of cells and clinical benefit. As you know, gene therapy trials for CGD before 2004 had not shown any clinical benefit and we were extremely excited about the levels of gene marking we saw in our patients. We were even more excited about the clinical improvement of patients and the clearing of residual infections that weren’t being cleared by conventional treatment.
We have treated two adult and one child CGD patients to date. One patient is three years post-GT and he is still in good health. His cells still carry the gene but the number of cells that have functional oxidase activity is now almost undetectable. We are aware that he might be vulnerable to infections in the future and we will be looking for a suitable bone marrow match for him and we hope that we can find a donor quite soon.
A major success was the treatment of a little boy in Zurich in Professor Reinhard Seger’s clinic. He was unable to walk and bedridden. He is now more active, has grown and is a more healthy and happier boy. This is such a beautiful story and shows the real benefits of gene therapy. On the other hand we are now realising that gene therapy has some side effects and that the corrective CGD gene is switched off over time. But we are making real advances in improving the vector design so that it will work better.
As you know one of the GT patients we reported on in our Nature paper died last year. This was very traumatic and sad for everyone involved. We were quite close as I saw him every two months in clinic and I was quite emotionally involved in his treatment but the death of this patient does not imply that our protocol has failed. He lived for two years in good health conditions without life-threatening infections. I think we have to accept that this may happen and we have to work to improve the vector.
When you do think gene therapy will be accepted as routine clinical medicine?
I believe in the next three to five years. There will be lots of trials using gene therapy over the next few years and we will see lots of discussion and progress. There will be successes and there will be failures and as with every medicine there will be side effects but it will be accepted as a routine treatment. It could even become a treatment of choice for some people. Cancer will be a big winner and this field is moving on very quickly. It is will certainly be accepted methodology for diseases that don’t have any other treatment options.
Where do you get your funding from for your work?
The development of gene therapy for CGD is expensive. We get lots of money from the CGD Research Trust, for which we are very grateful, but we also get contributions towards the work from the Else-Kroener-Fresenius-Trust, the German Ministry of Science and Technology and we have had some money from the European Commission for the last two years. It is not just about the money though; it is having the right scientific collaborators and clinicians on board. It is a team-effort but we have to plan ahead to cover the cost of treating larger numbers of patients.
What about the risks involved in gene therapy?
We have to be able to provide benefit to the patient, so how well the treatment works is key. Safety is of course an issue but efficacy is the main issue. This needs to be put in first place. That is what the patient expects from you. If you talk to the patient and explain the possible complications they look at you and understand but they want to know if you can help them – yes or no. They are in a bad situation and they need help urgently.
My motivation is to provide that help but of course I consider safety a very important issue. All medicines have side effects. We just have to make them as safe as possible while ensuring they will provide clinical benefit and we monitor very closely what is happening to the patient’s bone marrow cells and immune system.
Have the German authorities taken on board the needs of German CGD patients?
The German authorities have been very conscious of the risks involved in gene therapy but they have taken an open-minded approach. They are very open to all GT trials. After the death of one of the Frankfurt gene therapy patients they did not close the trials and we will still be able to treat needy patients on a compassionate basis with our current vector until our second -generation vector comes on-line. I believe there is an increasing acceptance by all regulatory authorities that there will be some risks associated with gene therapy.
How many people are in your laboratory?
I have fourteen people working for me and eight of them work on different aspects of the CGD project such as the design of the gene delivery system (vectors), the pre-clinical testing before it can be used in patients, all the work-up for the regulatory authorities and the clinical monitoring of patients after they have had gene therapy. We are also working on treatments for acute myeloid leukaemia.
Is there a CGD specific charity in Germany?
No, not one specifically for CGD. There is a parent led organisation for a number of primary immunodeficiencies. Its main objective is to inform and educate parents about their condition, alternative treatments and to bring money in to support activities so that parents and affected people can come together. They don’t fund research but their main function is support of affected people and their families.
Thank you so much for taking the time to talk to me and for your commitment to CGD research.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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