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.
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(2000). Extreme T hrombocytosis in Response to PEG-ADA: Early Therapeutic and Risk Indicator. CLIN PEDIATR
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So, T., Ito, H.-O, Tsujihata, Y., Hirata, M., Ueda, T., Imoto, T.
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Oupicky, D., Ulbrich, K., Rihova, B.
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Rosen, F. S., Bhan, A. K.
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338: 1752-1758
[Full Text]
Onodera, M., Ariga, T., Kawamura, N., Kobayashi, I., Ohtsu, M., Yamada, M., Tame, A., Furuta, H., Okano, M., Matsumoto, S., Kotani, H., McGarrity, G. J., Michael Blaese, R., Sakiyama, Y.
(1998). Successful Peripheral T-Lymphocyte-Directed Gene Transfer for a Patient With Severe Combined Immune Deficiency Caused by Adenosine Deaminase Deficiency. Blood
91: 30-36
[Abstract][Full Text]
Ozsahin, H., Arredondo-Vega, F. X., Santisteban, I., Fuhrer, H., Tuchschmid, P., Jochum, W., Aguzzi, A., Lederman, H. M., Fleischman, A., Winkelstein, J. A., Seger, R. A., Hershfield, M. S.
(1997). Adenosine Deaminase Deficiency in Adults. Blood
89: 2849-2855
[Abstract][Full Text]
Clark, R., Olson, K., Fuh, G., Marian, M., Mortensen, D., Teshima, G., Chang, S., Chu, H., Mukku, V., Canova-Davis, E., Somers, T., Cronin, M., Winkler, M., Wells, J. A.
(1996). Long-acting Growth Hormones Produced by Conjugation with Polyethylene Glycol. J. Biol. Chem.
271: 21969-21977
[Abstract][Full Text]
Bollinger, M. E., Arredondo-Vega, F. X., Santisteban, I., Schwarz, K., Hershfield, M. S., Lederman, H. M.
(1996). Hepatic Dysfunction as a Complication of Adenosine Deaminase Deficiency. NEJM
334: 1367-1372
[Full Text]
Hooftman, G., Herman, S., Schacht, E.
(1996). Review: Poly(Ethylene Glycol)s with Reactive Endgroups. II. Practical Consideration for the Preparation of Protein-PEG Conjugates. Journal of Bioactive and Compatible Polymers
11: 135-159
Bordignon, C., Notarangelo, L. D., Nobili, N., Ferrari, G., Casorati, G., Panina, P., Mazzolari, E., Maggioni, D., Rossi, C., Servida, P., Ugazio, A. G., Mavilio, F.
(1995). Gene Therapy in Peripheral Blood Lymphocytes and Bone Marrow for ADA- Immunodeficient Patients. Science
270: 470-475
[Abstract]
Blaese, R. M., Culver, K. W., Miller, A. D., Carter, C. S., Fleisher, T., Clerici, M., Shearer, G., Chang, L., Chiang, Y., Tolstoshev, P., Greenblatt, J. J., Rosenberg, S. A., Klein, H., Berger, M., Mullen, C. A., Ramsey, W. J., Muul, L., Morgan, R. A., Anderson, W. F.
(1995). T Lymphocyte-Directed Gene Therapy for ADA- SCID: Initial Trial Results After 4 Years. Science
270: 475-480
[Abstract]
Rosen, F. S., Cooper, M. D., Wedgwood, R. J.P.
(1995). The Primary Immunodeficiencies. NEJM
333: 431-440
[Full Text]
Braatz, J. A.
(1994). Biocompatible Polyurethane-Based Hydrogel. J Biomater Appl
9: 71-96
Ferrari, G, Rossini, S, Giavazzi, R, Maggioni, D, Nobili, N, Soldati, M, Ungers, G, Mavilio, F, Gilboa, E, Bordignon, C
(1991). An in vivo model of somatic cell gene therapy for human severe combined immunodeficiency. Science
251: 1363-1366
[Abstract]
Langer, R
(1990). New methods of drug delivery. Science
249: 1527-1533
[Abstract]
Maeda, H., Oda, T., Matsumura, Y., Kimura, M.
(1988). Improvement of Pharmacological Properties of Protein-Drugs by Tailoring with Synthetic Polymers. Journal of Bioactive and Compatible Polymers
3: 27-43
Blackburn, M. R., Aldrich, M., Volmer, J. B., Chen, W., Zhong, H., Kelly, S., Hershfield, M. S., Datta, S. K., Kellems, R. E.
(2000). The Use of Enzyme Therapy to Regulate the Metabolic and Phenotypic Consequences of Adenosine Deaminase Deficiency in Mice. DIFFERENTIAL IMPACT ON PULMONARY AND IMMUNOLOGIC ABNORMALITIES. J. Biol. Chem.
275: 32114-32121
[Abstract][Full Text]
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