Adenosine deaminase enzyme replacement therapy

H3. Hershfield, M. S Chaffee, S., and Sorensen, R. U., Enzyme replacement therapy with polyethylene glycol-adenosine deaminase in adenosine deaminase deficiency Overview and case reports of three patients, including two now receiving gene therapy. Pediatr. Res. 33 (Suppl.), S42-S48 (1993). 

Adenosine deaminase (ADA) deficiency, an autosomal recessive disorder, produces severe combined immunodeficiency (SCID). Lacking both B-cell and T-cell function, children are multiply infected with many organisms Pneumocystis carinii, Candida) and do not survive without treatment. Enzyme replacement therapy and bone marrow transplantation may be used. Experimental gene therapy trials have not yet yielded completely successfiil cures. 

Indications Enzyme replacement therapy for adenosine deaminase (ADA) deficiency in patients with severe combined immunodeficiency disease (SCID) who are not suitable candidates for—or who have failed— bone marrow transplantation... 

Long-term efficacy of enzyme replacement therapy for adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID). Chan, B., Wara, D., Bastian, J., Hershfield, M.S., Bohnsack, J., Azen, C.G., Parkman, R., Weinberg, K., Kohn, D.B. (2005). Clin Immunol, 117 (2) 133-143. 

Severe combined immunodeficiency (SCID) due to adenosine deaminase deficiency (ADA) exhibits autosomal recessive inheritance, and may account for up to 209 of cases (l). Accumulation of intracellular toxic deoxynucleotides and/or S-adenosyl homocysteine particularly in T cells, is considered responsible for the severe lymphoid depletion and dysfunction observed in affected children (2). Unlike other forms of SCID, this variety is amenable to enzyme replacement therapy using regular fresh irradiated red blood cell transfusions as the source of enzyme. Another form of therapy suggested from in vitro studies, is the use of deoxycytidine which theoretically would act as a competitive substrate for deoxycytidine kinase, the enzyme considered responsible for the intracellular accumulation of deoxy-ATP (dATP). This study reports our experience of various treatments in three ADA deficient children. 

Human amniotic cells were considered as an alternative source of enzyme replacement. They do not express HLA antigens or microglobulin and consequently are not rejected when transplanted (5) They secrete many lysosomal storage enzymes and in addition appear to express significant adenosine deaminase activity. However, very little immune function was restored in S.Y. and none at all in K.A. after enzyme replacement therapy by red cell transfusions, and it was thought unlikely that they would have provided any further benefit. All three children have... 

Adagen mPEG-adenosine deaminase prodrug Enzyme replacement therapy for SCID... 

Adenosine deaminase (ADA) was the first therapeutic enzyme coupled to PEG with the aim of reducing clearance and thereby overcoming the short half-life of ADA. Patients deficient in ADA are unable to regulate purine metabolism. As a result purine metabolites (e.g., adenosine monophosphate) accumulate to cytotoxic levels in B-lymphocytes and lead to severe B-cell depletion that presents clinically as severe combined immunodeficiency syndrome (SCIDS). While intramuscular injection of unmodified ADA provides some relief, antibodies develop rapidly against the protein and prevent it from being useful as replacement therapy. Even in the absence of antibodies, unmodified ADA s plasma half-life is only a few minutes. 

PEG-adenosine deaminase (ADAGEN Enzon) was the first PEGylated protein to enter the market, in 1990 [50]. It is used to treat adenosine deaminase-deficient X-linked severe combined immunodeficiency disease (SCID), commonly known as the bubble boy disease . It is an alternative to bone marrow transplantation and enzyme replacement by gene therapy. Since the introduction of ADAGEN, a large number of PEGylated-protein and -peptide pharmaceuticals have followed (Table 1). 

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