"In 1990, National Institutes of Health (NIH) researchers performed the first successful human gene therapy on two girls with ADA SCID. The treatments consisted of removing some of the girls' own T cells, inserting a normal copy of the ADA gene into the cells, expanding the T cells in a culture system and returning them to the girls' bodies through a vein. Repeated treatments led to normalization of T cell numbers. Although the girls have continued to rely on ADA enzyme injections for their primary management, they have developed normal immunity.
Following this pioneering work, scientists at NHGRI and around the world have continued to conduct clinical research with ADA SCID and additional genetic forms of SCID. This work has led to breakthroughs for improving the efficiency of gene transfer as well as insights into the biology of XSCID and ADA SCID. NHGRI researchers are continuing to develop more effective gene therapy treatments, first in experimental animal models and then in very small numbers of humans. One particular discovery made by NHGRI investigators is the observation that in individuals in whom some cells naturally expressed normal levels of γc or ADA, the expressing cells tend to grow better than the defective cells. This discovery showed that gene transfers could be accomplished with relatively few stem cells that would then outgrow the defective cells and give rise to a full complement of corrected T and B cells, restoring the immune system.
Gene therapy trials for SCID were halted worldwide for a number of years when it was reported that children who had been treated for XSCID in a French gene-therapy experiment had developed a type of leukemia. It was soon discovered that the mechanism used to insert the corrective gene had placed it in a region of a receiving cell's chromosome that switched on a cancer-causing gene (oncogene). Today, NHGRI researchers are evaluating insertion profiles of standard and novel gene delivery methods. A goal of this work is to find ways to achieve permanent correction of the DNA in blood-forming stem cells while avoiding the activation of oncogenes.
NHGRI investigators are also studying approaches to improve the effectiveness of bone marrow transplantation for these conditions. A major limitation to bone marrow transplantation is that blood-forming stem cells are not well understood. They are few in number and cannot be purified or expanded outside the body for very long. NHGRI researchers are investigating the roles of genes that control the reproduction and differentiation of blood-forming stem cells in order to significantly increase the supplies of these life-saving cells for clinical use."[12]
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