The need for conditioning cytoreduction/immunosuppression with systemic chemotherapy 
and/or total body irradiation significantly increases the risks of both short and long term 
complications resulting from this treatment.(68) With busulfan/cyclophosphamide, the mos*t 
widely used conditioning regimen, the patients routinely develop leukopenia and 
thrombocytopenia requiring blood and platelet transfusion support until engraftment provides 
sufficient endogenous production. During this period the patients are at significant risk 
hemorrhage and for the acquisition of bacterial, viral, and fungal infections and transfusion 
associated infectious agents. These treated children all develop alopecia and severe mucositis is 
a common problem, even in centers with considerable experience using this conditioning 
regimen. Cyclophosphamide can cause an acute cardiomyopathy which is frequently fatal. The 
first ADA(-)SCID patient we studied (and the donor of the TJF-2 cell line) died of cardiac 
necrosis/failure about 14 days after cyclophosphamide cytoreduction for a haploidentical bone 
marrow transplant. Busulfan is also known to cause cataracts and/or progressive pulmonary 
fibrosis in a small percentage of- patients. Irreversible sterility is an almost universal 
consequence of these conditioning regimens. Other chemotherapeutic agents have a similar 
spectrum of significant acute and long term side effects as does total body irradiation (TBi). 
TBI may adversely affect the development of the CNS in young children. Secondary malignancies 
are also a complication of these treatments and have been seen in SCID transplant recipients 
who have not achieved complete reconstitution. In summary, bone marrow transplantation with 
cytoreduction is a treatment with lethal risk and a significant proportion of patients receiving 
haploidentical grafts have experienced less than complete immunologic reconstitution. 
Not all SCID patients are candidates for bone marrow transplantation. There are children with 
ADA deficiency SCID who are too debilitated to tolerate cytoreductive therapy (18) as well as 
ADA deficient children who have a less severe immunodeficient phenotype for whom the risks 
associated with cytoreductive therapy are felt to be excessive (30,31). The overall treatment- 
related mortality of bone marrow transplantation with cytoreduction may be as high as 10- 
20% depending on the initial condition of the patient. Therefore, additional alternative 
treatments including the development of methods for immune augmentation, enzyme 
replacement by the infusion of ADA and enzyme replacement by insertion of a functioning human 
ADA gene into patient cells have all been vigorously explored. 
Recombinant DNA Research, Volume 14 
[ 211 ] 
