1 .3 Enzyme Replacement Therapy for the Treatment of ADA Deficient SCID 
ADA deficiency is an attractive candidate for enzyme replacement therapy because 
deoxyadenosine, the precursor toxic substrate, is freely diffusible and therefore the detoxifying 
ADA enzyme may not have to enter all (or even any) of a patient’s cells to be effective in 
lowering the intracellular deoxyadenosine concentration. ADA deficient children who were 
initially treated with repeated infusions of irradiated RBC from normal donors as a source of 
ADA have had transient clearing of toxic deoxyadenosine metabolites(32-39). While monthly 
transfusions have been clinically helpful for a few, most patients have experienced little or no 
response. This type of enzyme replacement therapy also has the associated increased risks of 
iron overload and transfusion associated infections including CMV, EBV, AIDS, and hepatitis. 
There is no readily available source of large quantities of human ADA protein and, in any event, 
its very short serum half-life makes its use impractical for direct enzyme replacement. In an 
effort to prolong the functional half-life of infused ADA, bovine ADA was covalently attached to 
polyethylene glycol(PEG) (40). PEG functions to prolong survival and reduce immunogenicity 
in vivo -45). PEG-ADA is rapidly absorbed following intramuscular injection and has a 
plasma half-life of 48-72 hours. To date, reports of the treatment of 3 patients with PEG-ADA 
have been published, although 15 patients are currently being treated with this drug in the USA 
and Europe. The initial 2 patients reported by Hershfield et ai. (40) had onset of recurrent 
infection in infancy and each had failed to engraft haploidentical bone marrow transplants. The 
3rd patient reported by Levy et ai. (31) had a later onset form (onset >2 years of age) with 
less severe immunodeficiency disease. Each child was treated with weekly intramuscular 
injections of PEG-ADA (15 U/Kg) to produce peak blood levels 2 to 3 times the normal whole 
blood ADA activity and trough levels of 1 to 1 .5 times the normal blood ADA activity. 
PEG-ADA injections at 15 U/kg reversed the primary biochemical abnormalities resulting 
from ADA deficiency with the level of red cell total dAdo nucleotides (dATP + dADP + dAMP) 
declining to less than 1 % of the pretreatment levels. In addition, PEG-ADA therapy reversed 
the deficiency of S-adenosylhomocysteine hydrolase (AdoHcyase), an enzyme which is 
irreversibly inactivated by dAdo (46-48). 
The correction of these biochemical abnormalities was accompanied by the gradual development 
of increased numbers of T lymphocytes, although absolute T lymphopenia persisted in many 
cases. Function in the form of blastogenic lymphocyte responses to phytohemagglutinin (PHA) 
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Recombinant DNA Research, Volume 14 
