Abstract

Severe combined immunodeficiehcy disease due to inherited deficiency of adenosine deaminase (ADA) is a focal point for evaluation of innovative approaches to therapy by enzyme replacement with polyethylene glycol-modified bovine ADA (PEG-ADA) and by somatic cell gene supplementation. The research objectives of this proposal are aimed at understanding the genetic, biochemical and immunologic factors that limit or determine the response of patients to PEG-ADA, and to investigate a strategy that may permit wider application of PEG-enzyme therapy for other inborn errors of metabolism.
Our specific aims are 1) To characterize mutations in ADA alleles of PEG-ADA patients and study the expression of these mutant alleles in vitro and in appropriate cells in order to identify those that allow sufficient residual ADA activity to permit immune reconstitution during enzyme replacement; 2) to investigate the basis for selective expression of certain mutant ADAs in T cells of some patients; and 3) to sequence the cDNA for bovine ADA in order to characterize the binding site of inhibitory antibodies to ADA that develop in patients undergoing treatment with PEG-ADA; and to attempt to 'neutralize' these epitopes with a combination of directed mutagenesis and PEG-modification.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK020902-16
Application #
3226839
Study Section
Medical Biochemistry Study Section (MEDB)
Project Start
1978-01-01
Project End
1994-06-30
Budget Start
1993-07-01
Budget End
1994-06-30
Support Year
16
Fiscal Year
1993
Total Cost
Indirect Cost

  Institution

Name
Duke University
Department
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705

  Publications

Liu, Ping; Santisteban, Ines; Burroughs, Lauri M et al. (2009) Immunologic reconstitution during PEG-ADA therapy in an unusual mosaic ADA deficient patient. Clin Immunol 130:162-74
Alangari, Abdullah; Al-Harbi, Abdullah; Al-Ghonaium, Abdulaziz et al. (2009) Purine nucleoside phosphorylase deficiency in two unrelated Saudi patients. Ann Saudi Med 29:309-12
Gracia, Eduard; Cortes, Antoni; Meana, J Javier et al. (2008) Human adenosine deaminase as an allosteric modulator of human A(1) adenosine receptor: abolishment of negative cooperativity for [H](R)-pia binding to the caudate nucleus. J Neurochem 107:161-70
Engel, Barbara C; Podsakoff, Greg M; Ireland, Joanna L et al. (2007) Prolonged pancytopenia in a gene therapy patient with ADA-deficient SCID and trisomy 8 mosaicism: a case report. Blood 109:503-6
Malacarne, Fabio; Benicchi, Tiziana; Notarangelo, Lucia Dora et al. (2005) Reduced thymic output, increased spontaneous apoptosis and oligoclonal B cells in polyethylene glycol-adenosine deaminase-treated patients. Eur J Immunol 35:3376-86
Lainka, Elke; Hershfield, Michael S; Santisteban, Ines et al. (2005) polyethylene glycol-conjugated adenosine deaminase (ADA) therapy provides temporary immune reconstitution to a child with delayed-onset ADA deficiency. Clin Diagn Lab Immunol 12:861-6
Chan, Belinda; Wara, Diane; Bastian, John et al. (2005) Long-term efficacy of enzyme replacement therapy for adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID). Clin Immunol 117:133-43
Blanchet, Fabien; Cardona, Ana; Letimier, Fabrice A et al. (2005) CD28 costimulatory signal induces protein arginine methylation in T cells. J Exp Med 202:371-7
Gonzalez-Gronow, Mario; Hershfield, Michael S; Arredondo-Vega, Francisco X et al. (2004) Cell surface adenosine deaminase binds and stimulates plasminogen activation on 1-LN human prostate cancer cells. J Biol Chem 279:20993-8
Myers, Laurie A; Hershfield, Michael S; Neale, Wirt T et al. (2004) Purine nucleoside phosphorylase deficiency (PNP-def) presenting with lymphopenia and developmental delay: successful correction with umbilical cord blood transplantation. J Pediatr 145:710-2

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