LOS ANGELES, Oct. 10, 2005 (PRIMEZONE) -- Alain Fischer, M.D., Ph.D., professor of pediatric immunology at the Hopital Necker, Universite Rene Descartes in Paris, France, and one of the world's foremost authorities on immunodeficiencies in children, was the featured speaker in The Saban Distinguished Lecturer Series at The Saban Research Institute of Chidrens Hospital Los Angeles (Oct. 7) in Los Angeles.
Dr. Fischer's address was entitled, "Severe Combined Immunodeficiencies: From Pathophysiology to Therapy," sponsored by the Gene, Immune and Stem Cell Therapy Program at The Saban Research Institute.
"We were very excited to have Dr. Fischer visit us," said Donald B. Kohn, M.D., director of the Gene, Immune and Stem Cell Therapy Program at Childrens Hospital Los Angeles, professor of pediatrics, molecular microbiology and immunology at the Keck School of Medicine of the University of Southern California and past president of the American Society of Gene Therapy. "He is a world leader on research into understanding the causes of immune deficiency diseases and developing new treatments.
"The Bone Marrow Transplant Program at Childrens Hospital Los Angeles treats many children with these immune diseases," Dr. Kohn said, "and Dr. Fischer's work informs much of what we do."
Researchers at Childrens Hospital Los Angeles performed the world's first successful transfer of a healthy gene into the umbilical cord blood cells of a newborn with severe combined immunodeficiency disorder (SCID), and introduced the first gene therapy trial for children with AIDS. It remains a significant research interest at Childrens Hospital Los Angeles.
Dr. Fischer joined the Hopital Necker-Enfants Malades in 1981 as an assistant professor and started independent basic research in a unit of the "Institut National de la Recherche Medicale" (INSERM) at the "Centre Hospitalo-Universitaire" Necker, where he rapidly became a group leader. Since 1991, he has been the Director of INSERM unit 132/429, whose research theme is "Normal and Pathological Development of the Immune System".
In 1988, he became a professor of pediatric immunology at the Universite Rene Descartes Paris V and, in 1996 he was appointed the division head of the Pediatric Immunology Department at Necker-Enfants Malades, a large referral center for immunodeficiencies.
Since 2002, he has been director of the French program "Research on Rare Diseases."
Dr. Fischer was an advisor for Medical Research at the French Ministry of Research from 2000 to 2002. He has been a member of the Initiative Committee on the Reform of the French Research System since 2004.
Dr. Fischer has received many awards in France and in other countries, including the Louis-Jantet Foundation Prize for Medicine (Geneva) and the A. Philipson Prize (Stockholm). In 2002, he became a member of the French Academy of Science.
In his address, Dr. Fischer described the normal development of the immune system and the problems that can arise and lead to immune deficiency. He discussed the various genes needed for the immune system to develop and how, if those genes are missing, there are blocks to the development of the immune cells.
"If you want to better treat a given disease -- in our context, a primary immunodeficiency -- it's first absolutely crucial to understand as much as we can about the mechanism of the disease," explained Dr. Fischer. "So, for genetic disorders obviously it means to identify the gene -mutations of which caused the disease -- and then to understand what the protein encoded by the gene normally does -- what's its role -- so then we can start to think about potential therapeutics."
"One possibility for some of these diseases is the application of gene therapy," he said, "but this is fully based on our understanding the mechanisms of the disease. Then, of course, one should design the best way to add a normal copy of the gene into the cells which are abnormal. In the case of the diseases we are interested in -- the immune deficiencies -- these are the progenitors in the bone marrow which give rise to different kinds of lymphocytes."
He discussed approaches that have been used to treat these diseases over the years, such as bone marrow transplant, which has restored life to many but not all of these patients. Recent studies show that in some of the children who are 10 or more years post-transplant, the effect is being lost and they are becoming immune deficient again. This late loss of protective immunity may occur because they received the more "grown-up" cells that made T-cells for awhile, but they did not receive sufficient stem cells that can make T-cells for decades.
He also spoke about the tremendous capacity of the immune system to recover, if only a small number of normal stem cells are present. By illustration, he described a patient who had Severe Combined Immune Deficiency (SCID) in the family but was less severe than expected. His group observed that in this "experiment of nature," the patient's own mutation had fixed itself in one rare T-cell progenitor, and that this spontaneously corrected T-cell progenitor gave rise to multiple new T cells that provided some immune function. This demonstrated the power of the immune system to amplify good cells and led to the conceptual basis that underlined the consideration of gene therapy. If one corrected cell can give you a little bit of benefit, then if you can correct more cells with gene therapy you may be able to restore immunity with the patient's own cells.
That led to the trials in which they treated 10 children with X-linked form of SCID. Currently, eight of these children are alive and well. (Two died from complications.) That outcome is better than the current standard treatment using bone marrow from a parent for children who don't have a matched sibling. Despite the complications, it's at least as good as the current approach with bone marrow transplant and by understanding what the problems were, it is potential that the results will be even better in the next generation of studies.
Dr. Fischer is cautiously optimistic about the future of gene therapy. "Of course, one should be always very cautious because one cannot fully predict what can happen. But from studies that have been performed by us and others, we have learned a lot in terms of what we can expect in reconstituting the development of the T-lymphocytes -- the cells that are defective in these severe combined deficiency diseases. Today, with the help of many specialists in the field of vectorology (the way to produce a system to transport therapeutic gene into cells) there have been a number of advances which might be useful to make this technology safer."
Development of the immune system is a complex process and its dysregulation is now recognized in 120 inherited disorders. Dr. Fischer's research has been driven by the clinical investigations of pediatric immunodeficiencies, serving as natural models to delineate their molecular defects and study the lymphoid system in the laboratory.
Founded in 1901, Childrens Hospital Los Angeles has been treating the most seriously ill and injured children in Los Angeles for more than a century, and it is acknowledged throughout the United States and around the world for its leadership in pediatric and adolescent health. Childrens Hospital is one of America's premier teaching hospitals, affiliated with the Keck School of Medicine of the University of Southern California for more than 73 years. It is a national leader in pediatric research.
Today, physician-scientists at Childrens Hospital Los Angeles address the most vexing pediatric medical problems and discover important new therapies for children everywhere, including advances in cancer care, gene transfer, stem cell and organ transplantation and diabetes. The Saban Research Institute is among the largest and most productive pediatric research facilities in the United States, with 100 investigators at work on 251 laboratory studies, clinical trials and community-based research and health services. It is one of the few free-standing research centers in the nation to combine scientific laboratory inquiry with patient clinical care -- dedicated exclusively to children -- and its base of knowledge is widely considered to be among the best in pediatric medicine.
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