Gene Therapy in the Wiskott-Aldrich Syndrome

Salima Hacein-Bey-Abina is Professor of Immunology at Paris Descartes University. She is Head of the Gene Therapy Unit in the Biotherapy Department at Necker Children’s Hospital (Paris, France) and co-Coordinator of the INSERM/AP-HP Center for Clinical Investigation in Biotherapy within the department headed by M. Cavazzana-Calvo (winner of the Irène-Joliot-Curie award in 2012), also at Necker’s.

S. Hacein-Bey-Abina has Doctorates in Pharmacy and Science from Paris-Sud 11 University. Her gene therapy research within M. Cavazzana-Calvo’s group in the INSERM-Paris Descartes Joint Research Unit No.768 (directed by A. Fischer) led to the development of gene transfer in hematopoietic stem cells designed to treat X-linked severe combined immunodeficiency (SCID-X1) and to the first successful clinical trial in gene therapy, in 2000.

At Necker, she is in charge of developing gene therapy trials: transferring research to the clinical phase, and, for each target disorder, producing genetically-modified cells. She has been recognized by the American Society of Gene Therapy for her research in gene therapy.

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One of the main ideas after years of research on gene therapy is that the achievements that have been done are still not enough. Actually, some genetic disorders still lack a gold-standard treatment.

Professor Salima Hacein-Bey-Abina and her research group have dedicated their lives to the study of severe immunodeficiencies, focusing on its treatment, and they contributed to the development of the first pharmacological option to face the disease that was once considered lethal. The importance of this discovery was recognised by the American Society of Gene & Cell Therapy in 2006, for the outstanding Professor Hacein-Bey-Abina on Gene Therapy for Severe Combined Immunodeficiency X1. However, “bubble baby” syndrome is not her unique interest. The iMed 5.0 Conference Reporters team had the honour of interviewing Professor Salima and the opportunity of attending her scientific lecture about Wiskott-Aldrich syndrome therapy. 

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FRONTAL: Before 2000, using gene therapy on X-linked severe combined deficiency was more of an enthusiastic doctor’s dream than an actual reality. When it came true, did you feel that those clinical trials significantly changed the paradigm towards gene therapy? Was there a shift in the conception of a cure for this disease?

Salima Hacein-Bey-Abina: As you know, things did not happen in one day. We worked a long time before 2000 (seven years) and we tried to set up this protocol by doing many preclinical experiments. The preclinical steps were very long before starting the clinical trials. During all these steps, we started to understand that it was possible, by transferring the good genes into hematopoietic stem cells, to lead to the correction of the phenotype. All these steps paved the way towards this clinical success. When we observed in the first two patients that our idea had worked, it was amazing. We observed normal counts of corrected T-cells and that was very good news. At that moment, probably, for short time, we thought that we had passed to a new time, to a new era in Science. But, once again, we didn’t do this work and get this success alone. Gene therapy history started a few decades ago with genetic progress and also with the first trials performed by Michael Blaise.

F: So it was a very long battle?

SHBA: Exactly. As always in science, there are many steps that are followed by many scientists, and not only by one group of scientists.

F: What do you think should be done to make gene therapy a strong reality and a current practice?

SHBA: In fact, for the time being, you have seen that there are many papers and many trials, which have shown that it is possible to correct mainly heritable diseases and rare diseases, immunodeficiencies in particular. But we hope that, in the future, we can work on more frequent diseases. We started experiments at Necker Hospital with beta thalassemia diseases and we hope those results will be reproducibly efficient – not only in one patient, but also in more beta thalassemia patients, and, after that, in sickle-cell anemia patients. You know that these diseases are very frequent: hemoglobinopathies are the most frequently heritable diseases in the world. All those people who work on gene therapy all over the world will have to work on different diseases to make gene therapy a reality.

F: Will we ever enter a true Personalised Medicine era?

SHBA: That is a good question. Gene therapy, in general, is considered a cellular but not a molecular therapy, and cellular biotherapy is considered a customised Medicine, which is true because each product is dedicated to one patient. Obviously, because we are working with these diseases with autologous cells – bone marrow cells – , we are dealing with Personalised Medicine. The question is – what can we do to generalise this Medicine? I think that we need to work with industrial groups in order to fund this new Medicine because it is very expensive.

 F: The therapy is mainly focused on child therapy, which means the target are, mainly, children. Will it be possible to treat larger groups, such as adults?

SHBA: In fact, it absolutely depends on the disease, because some diseases affect children and others affect adults. For example, another disease which is currently treated also in Europe, is Chronic Granulomatous Disease. There are many adults affected by this disease. This is not a severe combined immunodeficiency, it is an immunodeficiency, but people affected by it live in very bad conditions, with many infections. Those people could be treated by gene transference. Once again, I provide you with the example of hemoglobinopathies – we also have to treat adults with these diseases.

F: In your opinion, what is the main obstacle that we must overcome in gene therapy?

SHBA:  Everywhere in the world, the main obstacle is the manufactory on a large scale of a vector. We must have enough vectors to treat many people, and those are too expensive.

F: This kind of treatment has some side effects, for example, leukemia. What strategies are there to overcome this problem?

SHBA: If scientists work and improve the bad bone of the vectors, and if, besides them, the manufacturer who can produce these vectors also work that way, people like us could treat and perform many other clinical trials to test these vectors, and then move towards the good vectors, the safer vectors.

F: One of our concerns as students is which sources of information we should rely on when we do research on one topic. What are your thoughts on that?

SHBA: You are still students, so you have professors and they should direct you. That depends also on your own interest – if you are interested in Genetics or Immunology, you are going to find your away. But not alone, with your group. That is the key for everything in life.

Interviewers: Joana Dionísio, Gabriela Andrade

Writers: Joana Dionísio