Recombinant DNA Advisoiy Committee - 2/10-11/92 
TRANSDUCED WITH A HUMAN ADA GENE 
Status Report 
Dr. Blaese presented an update on the current status of the ADA deficiency treatment 
protocol and reviewed the background of the protocol. He explained that adenosine 
deaminase (ADA) is the enzyme that deaminates adenosine into inosine and 
deoxyadenosine; and that in the absence of this enzyme, there is an accumulation of 
phosphorylated derivatives which are toxic to lymphocytes. The capacity for immune 
function by lymphocytes is intact in this disease. Therefore, the treatment strategy for 
ADA-deficiency traditionally has been to lower the level of toxic substrates and products in 
order that the immune system can be reconstituted. 
Dr. Blaese said that the treatment of choice for ADA deficiency was bone marrow 
transplantation (BMT) using a matched sibling donor. With current technology, the cure 
rate using this treatment is approximately 90%. However, only about one-quarter of these 
patients will have a matched sibling donor. There has been a search for alternative 
treatments for patients without a matched donor. Different transplantation strategies have 
included using parents or matched, unrelated donors; but the survival rate using these 
alternatives is approximately 50%. 
Dr. Blaese noted that enzyme replacement therapy was first initiated almost twenty years 
ago using red cell transfusion therapy where red cells containing adenosine deaminase 
were given to children by exchange transfusion. The enzyme bound to these transfused 
cells had only a minimal effect but led to specific enzyme replacement therapy with 
polyethylene glycol (PEG) conjugated to ADA. This therapy provided a very high 
concentration of ADA in the circulation. Unfortunately, children who have received 
maximum doses of the PEG-ADA enzyme have not experienced complete immune system 
reconstitution. 
Dr. Blaese discussed the strategy behind bone marrow stem cell correction. If the ADA 
gene could be inserted into totipotent bone marrow stem cells, then theoretically all of the 
cells in both the T lymphocyte and B lymphocyte lineages should contain the corrective 
gene. At the time the ADA protocol was submitted, gene insertion into bone marrow 
stem cells has not been proven successful; therefore, the protocol turned to peripheral 
blood T lymphocyte correction as an alternative strategy. 
Dr. Blaese discussed the background of peripheral blood T lymphocyte correction using 
gene therapy. It was found that children who had been cured by matched sibling donor 
BMT were ADA deficient in all cell populations except T lymphocytes. The hypothesis 
evolved that if the patient's own T lymphocytes could be corrected by gene insertion, then 
Recombinant DNA Research, Volume 15 
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