Recombinant DNA Advisory Committee - 7/31/90 
were received, mainly having to do with making it clear that 
parents are informed accurately about what will be covered in 
later phases of the treatment, particularly if there is movement 
to another treatment or to treatment outside the NIH. He said 
the investigators had agreed to take account of these suggestions 
and to revise the consent and assent forms in response to these 
concerns. Dr. Childress thanked the investigators for their 
cooperation in making the protocol and consent forms responsive 
to the concerns of the subcommittee. 
Dr. Mclvor said that the major considerations during discussions 
of this protocol had centered on the mechanism by which the gene 
insertion was to act to lead to alleviate the symptoms, the 
matter of extended survival of lymphocytes containing ADA, and 
intracellular expression of ADA in the lymphoid cells, leading to 
endogenous detoxification of the environment to make the immune 
system function. He emphasized that the anticipated mechanism of 
action involves the intracellular expression of ADA in 
lymphocytes, leading to their increased survival. 
Dr. Parkman said that there were three hypotheses which were 
discussed: 
1. Introduction of the normal gene would allow the cells 
to function better immunologically, regardless of 
survival; 
2. Introduction of the gene would allow the cells to live 
longer without changing total body tissues or changing 
the intrinsic capacity of the cell to mediate any 
degree of function; and 
3. This nucleated cell, by having ADA contained within it, 
would do a more efficient job of reducing total body 
burden of deoxyadenosine. Since the toxic effects of 
the lack of ADA occur very early in thymic development, 
reducing total body burden would allow normal 
differentiation to occur more rapidly. 
Dr. Parkman said it was important to realize that what was shown 
in the Milan data in a murine model had verified the results of 
previous in vitro studies performed by the NIH investigators. 
They demonstrated that insertion of the gene allowed the cells to 
live longer. 
Therefore, a major consideration arises. In order for this 
protocol to be successful, one has to assume that a patient who 
does not respond well to PEG-ADA still possesses a small number 
of cells capable of protective immunity. Normally these cells 
would die off rapidly, but by the use of gene therapy, such cells 
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