2.4 Rationale for the Current Study 
The proposed protocol represents the initial step in a sequence of 
studies designed to evaluate the potential value of genetically modifying T 
lymphocytes in an attempt to prevent or control HIV infection. This study will 
provide the essential baseline data needed to prospectively evaluate the fate 
of activated CD4 and CD8 cells after reinfusion in HIV infected individuals. In 
addition, in association with other protocols currently in development utilizing 
adoptive transfer of ex vivo expanded and activated cells without gene 
marking, the present study will permit the effects of gene modification of the 
cells to be distinguished from those effects of activated T cell infusions alone. 
By monitoring functional immune status, measures of viral burden, and 
physiological markers of end organ function, we hope to determine whether 
this potential therapeutic approach is feasible and safe. The knowledge 
gained from a careful analysis of CD4 and CD8 cell survival, when correlated 
with quantitative assays of HIV viremia and immune status, has 
immunopathogenic importance that transcends even the arena of gene 
therapy. Indeed, the proposed study may serve to demonstrate whether cell 
survival represents an important surrogate marker for clinical disease that will 
serve as a more sensitive and more precise means of monitoring progression 
of HIV disease. 
3.0 Preclinical and Clinical Studies 
3.1 In Vivo Human Experiments in SCID with Autologous PBLs transduced 
with the ADA gene 
Two patients with severe combined immunodeficiency due to adenosine 
deaminase deficiency have been treated with infusions of autologous' 
lymphocytes transduced with the ADA gene via a retroviral vector (protocol 
#90-C-195). To date, no significant side effects have occurred and 
immunologic benefit has been observed. Specifically, reversal of 
lymphopenia, defective T cell cytolytic activity, skin test anergy, and deficient 
antibody production have been achieved in these patients associated with 
gene/T ceil therapy. Continuous circulation of modified cells during 21 
months of observation has been seen in the first patient enrolled on the 
protocol, including during a 7 month period when this patient received no 
additional infusions of cells. ADA levels in the circulating T cells have 
increased from initially undetectable levels to 10% to 50% of that measured in 
the carrier parents. 
The studies of these children with SCID demonstrate that significant 
reconstitution of T cell function can be achieved in immunodeficient patients 
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