Severe combined immunodeficiency syndrome

Poly(ethylene glycol) (PEG) molecules attached to adenosine deaminase (ADA) have been used in patients exhibiting symptoms of the severe combined immunodeficiency syndrome (SCID) caused by ADA deficiency. The modified enzyme has a plasma half-life of weeks as compared to the unmodified enzyme (minutes) (248). PEG-L-asparaginase has induced remissions in patients with non-Hodgkin s lymphoma (248). However, one disadvantage of PEG-enzyme treatment is its expense, ie, a year s treatment costs about 60,000 (248). 

SC ID Severe combined immunodeficiency syndrome sCRl Soluble type-1 complement receptors... 

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. 

Hufnagel, G., Chapman, N., and Tracy, S. (1995). A non-cardiovirulent strain of coxsackievirus B3 causes myocarditis in mice with severe combined immunodeficiency syndrome. Eur Heart J 16 Suppl O, 18-19. 

The first clinical gene therapy trial began in 1990 for the treatment of adenosine deaminase deficiency. B and T lymphocytes fail to develop in this autosomal recessive disease, resulting in a severe combined immunodeficiency syndrome (SCID) made famous by the bubble boys whose lives were confined to tents in an effort to keep them in a germ-free environment. Only two patients were included in this trial, and although both continued to demonstrate clinical improvement 10 years later, gene therapy did not cure the disease, as investigators had hoped. 

A defect in the adenosine deaminase (ADA) gene causes severe combined immunodeficiency syndrome (SCID). When ADA is defective, deoxyadenosine and dATP accumulate in rapidly dividing cells, such as lymphocytes, and prove toxic to these cells. Cells of the immune system cannot proliferate at a normal rate, and children with SCID usually die at an early age because they cannot combat infections. To survive, they must be confined to a sterile, environmental "bubble." When an appropriate donor is available, bone marrow transplantation can be performed with a reasonable degree of success. 

Pegademase (adenosine deaminase EC 3.5.4.4) is a PEGylated enzyme used for treating patients with adenosine deaminase (ADA) deficiency [76] and suffering from a form of severe combined immunodeficiency syndrome (SCID), a disease that occurs in about 1/50,000 births. SCID patients have a severely crippled immune system and cannot clear or recover from the mildest microbial or viral infections. 

The production and field testing of viral vectors face similar challenges. Trials in France using recombinant lentiviruses for amelioration of severe combined immunodeficiency syndrome (SGID) produced significant side effects in subjects, and one person died. Fear of litigation, often warranted, has made many companies conclude that the cost-benefit ratio is simply too high. 

---