(1) Since the present protocol in non-human primates indicates that only a 
small number of cells are expressing the human ADA gene, will the postulated f_n 
vivo growth advantage of ADA(+) cells in ADA-deficient patients be sufficient 
for a clinical Improvement In patients receiving ADA gene therapy? If not. 
how much activity (In how many monkeys) would be necessary to determine that an 
adequate level of ADA expression could be expected in an ADA-deficient patient? 
(2) Will the vector-delivered human ADA gene, which has been shown to be 
expressed at a normal level In mature ADA-deficient T cells, also be expressed 
at a sufficiently high level in stem cells and their progeny so that the 
postulated 1_n vivo growth advantage would be maintained throughout the life 
cycle of the T cell? 
(3) Must the retroviral vector particle preparation used to treat the 
patient's bone marrow cells be totally helper virus free In order to make the 
risk/benefit ratio satisfactory? If not. Is the 0.1% (10 4 ffu/ml) 
contamination with replication-competent virus (which exists In our S3A 
preparation) acceptable or unacceptable? 
Questions 1 and 2 relate to the efficacy of the delivery/expression 
system, while question 3 relates to the safety of the protocol. All three are 
relevant, however, in determining the potential risk/benefit ratio for gene 
therapy in ADA-deficient patients. 
Recombinant DNA Research, Volume 12 
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