Severe combined immunodeficiency syndrome SCIDS

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). 

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. 

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. 

Currently, there is stUl a gap for the potential of gene therapy to be fulfilled. Gene therapy clinical trials have been conducted for diseases such as severe combined immunodeficiency disease (SCID, bubble baby syndrome), sickle cell anemia, cystic fibrosis, familial hypercholesterolemia, and Gaucher disease. 

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

Infants with severe combined immunodeficiency disease (SCID, bubble boy syndrome) have a gene defect that leads to a complete lack of white blood cells. Without treatment, these infants die from complications of infectious diseases during the first few years of life. The only treatment currently approved for this condition is a bone marrow transplant. 

ADCC) [12]. The low molecular weight pyran copolymer (MVE-2, Mw 15,000) does stimulate natural killer (NK) cells [13,14], Thus, at least two cell types, the macrophages and the NK cells, are presumed to play an important role in the antitumor and antiviral activity of MVE-2. The enhancement of the macrophage and the NK cell activity by these immuno-modulators may have the potential to provide tumoricidal effects and protection against viral infections exacerbated during immunosuppression or immunodeficiency in cases such as acquired immunodeficiency syndrome (AIDS) and severe combined immunodeficiency disease (SCID). 

L Severe combined immunodeficiency (SCID) syndromes are excellent models for gene therapy because of the genetic basis of these disorders and significant advances in the technology to transfer therapeutic genes into hematopoietic precursor cells. For all these reasons, which of the following syndromes represents an ideal candidate for gene therapy ... 

A great variety of patients with primary immunodeficiency disorders have now been studied with both bioassay procedures (Bach et al., 1972, 1975 Incefy et al, 1977 Lewis et al, 1978 Iwata et al., 1981). Serum thymic hormone levels are lower than age-matched normal levels for all patients studied with DiGeorge s syndrome, and a high proportion of patients with severe combined immunodeficiency. In patients vdth the complete Di-George s syndrome, thymic hormone levels are always undetectable, whereas in the partial form, FTS-like bioactivity is measurable but lower than normal. In some cases in which thymus grafi ing was utilized as a therapeutic modality, serum FTS-like bioactivity became detectable as early as 1 day after transplantation (Incefy et al., 1977) and eventually returned to normal (Lewis et al, 1978). These results have suggested that the increase in serum thymic hormone levels resulted from production by the transplanted thymus. In patients with SCID, regardless of the bioassay employed, thymic hormone levels were found to be either undetectable or much lower than that of age-matched normal donors. In rare cases serum FTS-like bioactivity... 

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