June 1, 1990, Hunan Gene Therapy Subcomni ttee Minutes 
Dr. Leventhal said Section 10, "Evaluation of Results" needed to be more quantitative in 
assessing what is happening to the immune function in the patients and what is 
happening to the ADA level in their cells. She said that a therapy utilizing a patient's 
own cells was theoretically preferable to transplantation in that another individual is not 
involved. Further, she did not want to see a patients selected who were too sick to 
benefit from the treatment, thereby losing the ability of seeing an effect of the treatment. 
Also, she brought up the question raised earlier by Dr. Parkman as to the amounts of 
blood to be drawn, and she noted that red cell transfusions may present technical 
difficulty in assessing how much change in ADA level is due to the transduced cells and 
how much is due to transfusion. 
Dr. Parkman said he agreed with Dr. Leventhal's concerns and in particular was 
interested in objective criteria for the addition of IL-2 as clearly this would increase risk 
to some degree. Dr. Blaese emphasized that there was no intent to use IL-2 in these 
experiments. Dr. Kelley said that the explanation for the short half-life in the N2/TIL 
experiments was the lack of IL-2. It is not necessary to devise an animal model to 
determine persistence of the inserted genes, but merely to perform animal studies to 
arrive at quantitative data on how often cells would have to be given to a patient in 
order to achieve a level of ADA in the circulation that would be therapeutically 
beneficial. 
Dr. Mclvor said that the subcommittee was going to have to grapple with the issue of 
whether the amount of information provided was sufficient to approve the protocol. He 
had several questions for which he would like to see data. 
Dr. Epstein noted that the reviewers had described the protocol as generally safe and 
that most comments had focused on patient inclusion and exclusion criteria and safety. 
He suggested that the reviewers could sit down over lunch, write down the specific 
questions which need to be answered, and then have the list photocopied and supplied to 
all subcommittee members. 
Dr. Mahoney asked whether there was a correlation between the amounts of intracellular 
ADA activity in transduced lymphocytes and extracellular ADA activity which is tied to 
PEG- ADA therapy, and whether much was known of the trafficking of PEG- AD A. 
Dr. Kelley said the most likely hypothesis for why ADA deficiency leads to SCID is that 
deoxyadenosine accumulates and selectively is converted to deoxy-ATP in immature 
lymphocytes. It inhibits ribonucleotide reductase and prevents replication of T cells. He 
said that if this is true it would not matter whether the ADA were extracellular or 
intracellular, since deoxyadenosine diffuses very rapidly and easily in the presence of 
ADA. The real issue is the functioning of the lymphocytes which contain the ADA. 
Dr. Parkman said the real hypothesis of the experiment is that it is not necessary to 
normalize the entire total body ADA pool. A child can be transplanted with normal 
Recombinant DNA Research, Volume 14 
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