somatic gene therapy . description of work of A Fischer (page linked to 'gene therapy adverse events')

The research by the team of Alain Fischer:
Towards gene-transfer-based correction of hereditary immunodeficiencies

 Short biography

Alain FISCHER is born in 1949 and of French nationality. He studied medicine in Paris and specialised in paediatrics. He received his M.D. in 1979 and a Ph.D in immunology during the same year. After a post-doctoral stay at the University College in London, he started independent research in an INSERM unit at the Necker Hospital in Paris. In 1988, Alain FISCHER became a professor in paediatric immunology. Since 1991, he directs the INSERM research unit for "Normal and pathological development of the immune system" and, since 1996, the clinical unit of "Paediatric Immunology and Haematology" at the Hospital Necker des Enfants Malades in Paris. Alain FISCHER has received the Halpern Prize in 1984, the Behring-Metchnikoff Prize in 1992, the Prix du Comité du Rayonnement français in 1994, and the Jung Prize for medicine in 1998.


Diseases of the development of the immune system and gene therapy

The end of the 20th century is marked by an upsurge in genomics - the science that studies genes as a whole. Its application to medicine is a potential source of major advances in the understanding, diagnosis and treatment of diseases. Thus, during the course of the last ten years Alain FISCHER and his co-workers have analysed the mechanisms of hereditary diseases of the immune system.

It was known about fifty years ago that there are patients who suffer from increased susceptibility to some types of bacterial and/or viral infections and that this predisposition is hereditary. A hundred or so distinct syndromes, called immune deficiencies, have now been described (Figure 1). Knowledge of the molecular mechanisms responsible for these diseases is likely to contribute to a better understanding of the mechanisms whereby the cells of the immune system, the lymphocytes and phagocytic cells, develop and function and of how immune responses are controlled. Derangement of these control mechanisms causes what we call autoimmune diseases.

Here are two examples of the results obtained by Alain FISCHER's team:

Figure 1: B lymphocytes produce antibodies able to recognise the antigens expressed by micro-organisms. During the immune response, the B lymphocytes that produce the most efficient antibodies are selected. This process occurs inside the secondary lymphoid organs called lymph nodes. It includes two complex mechanisms that modify the genome of these B lymphocytes: rearrangements of the immunoglobulin genes that allow one and the same variable region (involved in antigen recognition) to be combined with another constant region (M -> G, A or E) having distinct biological properties, and the generation of somatic mutations of the variable part. Abnormalities have been identified in two genes whose products are essential to these functions, namely the CD40 ligand involved in the interaction of T lymphocytes with B lymphocytes that is necessary to start this process, and the RNA-modifying enzyme, called AID, expressed by B lymphocytes.

Figure 2: Some hereditary abnormalities of the immune system cause defective homoeostatic control of these responses and are responsible for severe lymphoproliferative and/or autoimmune diseases. Thus, Alain FISCHER's team has shown that several genetic abnormalities perturb the cytotoxic function of T lymphocytes and natural killer (NK) cells and induce uncontrolled activation of T lymphocytes and, consequently, of macrophages, causing fatal diseases. Similarly, a defect in the programming of the death of T and B lymphocytes, normally induced by the membrane receptor called Fas, causes pathological lymphoproliferation associated with autoimmune effects.

Many hereditary diseases of the immune system are fatal. To some degree, the replacement of the patient's failing immune system by means of an allograft of haematopoietic stem cells may correct these diseases. However, failures are still common. Gene therapy by the insertion of a copy of the normal gene into the patient's haematopoietic cells is an attractive strategy for diseases in which the responsible gene has been identified. Alain FISCHER's team has undertaken the treatment of a severe combined immune deficiency (SCID) characterised by defective development of T and NK lymphocytes, linked to mutations of the gene coding for a membrane receptor called gc, expressed by stem cells (Figure 1). The choice of this disease for gene therapy was governed on the one hand by its severity and on the other hand by the fact that induction of the expression of protein gc by lymphocyte stem cells should allow the generation of a very large number of normal T and NK lymphocytes. The principle of the treatment, illustrated diagrammatically in Figure 2, is based on the ex vivo infection of stem cells obtained from the bone marrow by an inoffensive virus containing the gene coding for protein gc. The cells are then re-injected into the patients. After obtaining conclusive results in their in vitro experiments and in a deficient mouse strain, a clinical trial was undertaken in five patients. The treatment proved to be effective in four of them, allowing the development of a functional immune system able to protect these children from serious infections. Although long-term evaluation is still necessary, this initial success of a gene therapy demonstrates the validity of this approach and opens the logical prospect of its use for the treatment of other serious hereditary diseases of the immune system and then perhaps other haematological diseases. Thus, an understanding of hereditary diseases of the immune system may contribute as much to our knowledge of the anti-infectious defence system as to the treatment of these abnormalities.

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