June 1, 1990, Human Gene Therapy Subcommittee Minutes 
percentage of success of bone marrow transplantation in patients with ADA in 
comparison to those with SCID. 
Dr. Blaese said that ADA deficiency is a more heterogenous disease with more residual 
immune function than SCID. Thus, NK cells may not be the only factor in eliciting a 
better outcome with engraftment. 
Dr. Parkman then discussed issues involved with the protocol. He said that it was 
important in discussing any human gene therapy protocol to understand the mechanism 
by which the therapy is to work. He said the original proposal was ambiguous in this 
regard and offered two potential hypotheses: 
1. The T cells into which the ADA would be introduced would act to produce 
nucleated cells expected to be more efficient at detoxifying deoxyadenosine 
metabolites than is achievable with either polyethylene glycol (PEG)-ADA or red 
cell ADA; or, 
2. The T cells are more capable of immunologic function due to the fact they now 
have normal intracellular levels of ADA. 
Dr. Parkman said that there was a paucity of data to support either hypothesis. 
However, recent preclinical data has addressed this from Dr. Claudio Bordignon, in 
Milan, Italy. When ADA deficient T cells are put into mice, they appear able to support 
immunoglobulin synthesis and are capable of responding to alloantigens. Without such a 
model, issues of mechanism and persistence of the ADA gene in a T cell population 
would have been unclear. 
Dr. Parkman noted that the investigators have postulated an additive effect of 
extracellular PEG-ADA plus the intracellular ADA in the transduced T cells. Questions 
of what might occur both in the presence and absence of PEG-ADA constitute legitimate 
variables that will need to be answered in the future. This leads to questions about the 
proper patient population for the protocol. 
Dr. Parkman said some of the issues to be considered in patient selection are previous 
irradiation and chemotherapy, and whether the patient is eligible for alternative 
therapies. He said that one very important issue is that the parents and the physician 
have decided not to opt for bone marrow transplantation. He said that inclusion 
criteria should be biologically objective and not subjective. Issues surrounding a parent's 
decision as to what is appropriate therapy is a gray area involving ethical quandaries. 
Dr. Parkman said one of the points that must be taken into account is that the protocol 
must discriminate between patients who, based on their clinical condition, would not be 
candidates for a cytoreduced T cell transplant and patients in a stable condition in which 
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