June 1, 1990, Human Gene Therapy Subcommittee Minutes 
there would be little argument about use of alternative therapies, and for whom the risks 
of cytoreduction would be significantly less. 
Dr. Parkman said another issue was that of dealing with patients who have low levels of 
immune function versus no immune function. The chances of graft rejection in those 
with no immune function are less than those with low levels. After cytoreduction with 
busulfan, many transplant centers find this will allow patients to be safely transplanted. 
Further, the question of detoxification of adenosine metabolites needs to be addressed. 
Merely increasing the frequency or dosage amount of PEG- ADA could constitute an 
equally effective treatment. 
Dr. Mahoney asked if there is work in progress to study the effect of increased doses of 
PEG-ADA and how important the development of antibodies to PEG- ADA is in treating 
ADA deficiency. Dr. Blaese said he had spoken with Dr. Hirschfield and had been 
informed that in current studies with 14 individuals treated with PEG-ADA, seven had 
developed antibodies to PEG-ADA. Two of these seven have developed neutralizing 
antibody that has interfered with therapy, while the other 5 have definable antibodies 
that bind but do not neutralize the enzymes. The two who developed the neutralizing 
antibodies were taken off therapy, and treated with prednisone and immunoglobulin. 
PEG-ADA was resumed after eight weeks, and the patients have once again responded 
to PEG-ADA therapy. 
Dr. Blaese also commented on the dose escalation question raised by Dr. Parkman. Dr. 
Blaese said that in studies of patients with increased doses (doubling and tripling the 
doses) of PEG-ADA there has been no change in immune response. 
Dr. Parkman then returned to the exclusion criteria. On page 81 of the protocol, the 
term "deficient" was used to define both skin test reactivity and in vivo proliferation. He 
believed that quantitative data was necessary for determining how much reactivity would 
be used as a threshold value for exclusion. He noted all patients would be eligible for 
parts one and two-A. However, patients with pulmonary and hepatic disease with active 
infection would be excluded from Part two-B. 
Dr. Parkman said that another issue related to blood volume needed for the studies, and 
noted that the National Institutes of Health (NIH) Apheresis Protocol was not attached. 
The investigators had said that no more than seven cc's per kilogram per month would 
be drawn, an acceptable level. Dr. Parkman raised questions over the series of tests on 
page 89 of the protocol and wanted to know if these blood drawings were included in the 
seven cc's per Idlogram per month figure, and said that further clarification was needed. 
Dr. Parkman said the issue of changing the method of infusion of autologous peripheral 
blood lymphocytes from intravenous (IV) to intraperitoneal (IP) infusion had been 
Recombinant DNA Research, Volume 14 
[155] 
