Michael Blaese: Gene Therapy can be a successful Tool It will take Decades of Research
“Gene therapy can be a successful treatment for some patients suffering from ADA-SCID immunodeficiency,” a severe inherited disease of the immune system, concluded Prof. Michael Blaese from the National Institutes of Health (NIH, Bethesda /USA), a scientist with more than five years of experience in this promising new field of medicine. Blaese was a speaker at the 4th Symposium on Gene Therapy (April 19th, 1996) at the Max Delbrück Center for Molecular Medicine (MDC) in Berlin-Buch (Germany). He is one of the pioneers in this field who initiated the first clinical gene therapy trial in September 1990 involving two girls with ADA-deficiency. In the meantime, Blaese told the conference, eleven children with this disease have been enrolled in various gene therapy trials in the United States, Europe and Japan. The ultimate goal is to induce a long lasting effect by genetically altering the precursors of all blood cells, called stem cells, instead of immune cells. A new approach utilizes stem cells taken from the umbilical cord of newborn babies suffering from ADA. Blaese also pointed out more basic research is required for gene therapy.
ADA-deficiency is a rare inherited disease that impairs certain cells of the immune system (T and B cells). Untreated, this disease will lead to the early death of the affected children because their immune system is not able to fight off otherwise harmless infectious diseases such as the common cold or flu. They lack the enzyme ADA (adenosine deaminase) due to a defect in the ADA gene. The enzyme can be substituted by treating these children with an enzyme derived from bovine (PEG-ADA). This drug saves the lives of the affected children, but does not cure the inherited defect. Furthermore, according to Dr. Blaese, complete reconstitution of the children´s impaired immune system has not been regularly achieved. The goal, therefore is, to cure this disease at its root — in the DNA of the affected cell.
More than five years ago, the first gene therapy trials began with two little girls four and nine years of age, who suffer from this inherited defect of the immune system. White blood cells (T cells) of the two patients have been genetically altered by inserting the healthy ADA gene with the help of an inactived retrovirus used as a “gene ferry”. The children received up to 12 infusions of their gene-corrected white blood cells over a period of two years. Additionally, the patients were treated with PEG-ADA to ensure their well-being and to support the function of their immune system. The dose of PEG-ADA has been decreased by more than half in one of the two patients since the beginning of the gene therapy trial. In contrast, ADA-patients who only received PEG-ADA experienced a decline in their immune function when their dose of enzyme was similarly reduced. Blaese pointed out that although the gene treatment of the first two patients ended after two years, the ADA gene expression in the T cells persists today. Both girls, now nine and 14 years of age, regularly attend public schools. According to Dr. Blaese, the first patient benefitted not only from the drug treatment, but also from the gene therapy, whereas, he said, the mechanisms by which gene therapy aided immune reconstitution in the second patient is less clear. Blaese noted that the level of gene corrected T cells is higher in the first patient than in the second patient.
The trials have also shown that the genetically altered T cells have a longer life span in the organism, an effect that was not expected in the beginning of the trials. Moreover, Dr Blaese made clear that he and his colleagues will not stop giving additional PEG-ADA to these patients since they do not want to run the risk that the immune system will be weakened once more. Scientists and physicians need better information about the quality and duration of “this first generation gene therapy trial,” Dr. Blaese noted. According to him, the role of continous treatment with the PEG-ADA drug also needs to be investigated more closely.
Despite these encouraging results with mature white blood cells, whose life-span is limited, the ultimate goal is to induce an ever longer lasting therapeutic effect with gene therapy by altering stem cells. Stem cells are the precursors of all blood cells. They are low in number and difficult to generate. Usually, they are taken either from the bone marrow or from the peripheral blood. Just recently, another source has been utilized for the generation of stem cells, the umbilical cord.
In 1993 Dr. Blaese treated three newborn babies suffering from ADA-disease with their stem cells taken from their own umbilical cord and genetically altered with the ADA gene. He stated that the dose of PEG-ADA these patients receive has been reduced by half. The genetically altered immune cells of these babies still produce ADA in all blood lineages to date. “PEG-ADA is being withdrawn to determine whether the gene-corrected cells will demonstrate the selective growth advantage predicted,” Dr. Blaese told the conference. He feels that correction of genes in the self-renewing stem cells remains the ultimate goal of gene therapy for most haematopoietic diseases.
How safe are retroviral vectors for gene therapy? Dr. Blaese admitted that gene therapists are concerned about the “theoretical potential” of retroviruses to cause mutagenesis even though they are inactivated before being used as gene transporters. “To date, there has been no indication that malignancy associated with this process will be a complication of retroviral gene transfer”, Dr. Blaese pointed out. “Considering the severity of the diseases being treated and the complications associated with the other forms of treatment being tried, retroviral-mediated gene transfer has an excellent safety record,” he said.
A harsh review on gene therapy, published at the end of last year by the NIH, pointed out that gene therapy is still in its infancy. With respect to this report and asked if gene therapy has been applied to patients at too early a stage, Dr. Blaese made clear: “We do not have to change anything. We must alert people that gene therapy needs more basic research. This is not a new policy. This new field has great potential for treating many of the scourges of mankind — but — it will take decades of research before its potential is realized. We need to balance our enthusiasm with the reality of our still limited technology.”
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