Treatment of Adenosine Deaminase Deficiency with Polyethylene Glycol–Modified Adenosine Deaminase

Abstract

We treated two children who had adenosine deaminase deficiency and severe combined immunodeficiency disease by injecting bovine adenosine deaminase modified by conjugation with polyethylene glycol. The modified enzyme was rapidly absorbed after intramuscular injection and had a half-life in plasma of 48 to 72 hours. Weekly doses of approximately 15 U per kilogram of body weight maintained plasma adenosine deaminase activity at two to three times the level of erythrocyte adenosine deaminase activity in normal subjects. The principal biochemical consequences of adenosine deaminase deficiency were almost completely reversed. In erythrocytes, adenosine nucleotides increased and deoxyadenosine nucleotides decreased to less than 0.5 percent of total adenine nucleotides. The activity of S-adenosylhomocysteine hydrolase, which is inactivated by deoxyadenosine, increased to normal in red cells and nucleated marrow cells. Neither toxic effects nor hypersensitivity reactions were observed. In vitro tests of the cellular immune function of each patient showed marked improvement, along with an increase in circulating T lymphocytes. Clinical improvement was indicated by absence of infection and resumption of weight gain. We conclude that from the standpoints of efficacy, convenience, and safety, polyethylene glycol-modified adenosine deaminase is preferable to red-cell transfusion as a treatment for adenosine deaminase deficiency. Patients with other inherited metabolic diseases in which accumulated metabolites equilibrate with plasma could benefit from treatment with the appropriate polyethylene glycol-modified enzyme.

The Use of Enzyme Therapy to Regulate the Metabolic and Phenotypic Consequences of Adenosine Deaminase Deficiency in Mice

“…Whereas PEG-ADA was detectable in the blood of this animal, it was not detected in any of the tissues examined, including the thymus, spleen, liver, kidney, and lung. These data suggested that most if not all of the PEG-ADA in ADAdeficient mice was found in the circulatory system, as has been assumed to be the case in humans (2,28).…”

“…For determination of ADA trough values, heparinized blood samples were collected from the tail vein of mice just prior to the next injection of PEG-ADA, and plasma isolated by low-speed centrifugation. ADA specific activity in plasma was determined using established protocols (28).…”

“…PEG-ADA Is Found Only in the Circulatory System of ADAdeficient Mice-PEG-ADA does not enter erythrocytes or blood lymphocytes of human ADA-deficient patients, however, the distribution of PEG-ADA in other tissues is not known (2,28). ADA-deficient mice provided the opportunity to examine the levels of PEG-ADA present in various non-hematopoietic tissues.…”

Persistence and expression of the adenosine deaminase gene for 12 years and immune reaction to gene transfer components: long-term results of the first clinical gene therapy trial

“…Alternative options are haploidentical BMT 3,4 and enzyme replacement with polyethylene glycol-conjugated bovine ADA (PEG-ADA). 5 In the mid 1980s gene transfer was proposed as a therapy for ADA deficiency. The simple regulation of the ADA gene 6 and the expected selective advantage of gene-corrected cells suggested ADA deficiency as an ideal initial candidate disease to test gene therapy.…”

Cerebral Lymphoma in an Adenosine Deaminase–Deficient Patient With Severe Combined Immunodeficiency Receiving Polyethylene Glycol–Conjugated Adenosine Deaminase

“…Polyethylene glycol-conjugated bovine ADA (PEG-ADA) is a replacement therapy for ADA deficiency. 3,4 PEG prolongs the half-life of the ADA enzyme by reducing its catabolism. By greatly reducing the levels of toxic metabolites, PEG-ADA therapy has been successful in preventing infections, although restoration of immune function is only partial.…”