Erythrocyte metabolism in purine nucleoside phosphorylase deficiency after enzyme replacement therapy by infusion of erythrocytes.

Abstract

A B S T R A C T Purine nucleoside phosphorylase deficiency is associated with a severely defective T-cell immunity. A patient with purine nucleoside phosphorylase deficiency was treated with transfusions of irradiated erythrocytes and plasma. This resulted in a remarkable correction of the metabolic disturbances in the patient. The urinary excretion of inosine, deoxyinosine, guanosine, and deoxyguanosine decreased, whereas uric acid excretion as well as serum uric acid concentration increased. It could be shown that the enzyme activity of the circulating erythrocytes correlated inversely with the urinary excretion of nucleosides and directly with the excretion of uric acid. As a consequence of the therapy, several glycolytic intermediates ofthe erythrocytes were increased, especially 2,3-diphosphoglycerate. The high 2,3-diphosphoglycerate level caused a shift to the right of the oxygen dissociation curve (P50 = 32.9 mm Hg).The immunological status of the patient showed definite improvement after the enzyme replacement therapy.

Immucillin H, a powerful transition-state analog inhibitor of purine nucleoside phosphorylase, selectively inhibits human T lymphocytes

“…The challenge of inhibitor design for PNP arises from the abundance of the enzyme in human tissues. Individuals with genetic deficiencies of PNP that retain as little as 5% of normal catalytic activity do not exhibit manifestations of T cell deficiency and do not accumulate circulating dGuo (4,19). Therefore, nearly complete inhibition of PNP (Ͼ95%) must be achieved to increase the dGuo concentration to the level required for T cell toxicity (4,19).…”

Design of vectors for efficient expression of human purine nucleoside phosphorylase in skin fibroblasts from enzyme-deficient humans.

“…Although transplantation of normal bone marrow into these patients should be curative, none of the patients has been so treated because of clinical deterioration or lack of a suitable donor. In four patients treated with infusions of erythrocytes as a source of active PNP, two showed improved immunological function (1,5,6). This observation suggests that the transfer of an active PNP gene into virtually any of a patient's somatic cells should initiate normal deoxyguanosine metabolism and enable T-lymphocyte function to develop.…”

Successful HLA‐identical hematopoietic stem cell transplantation in a patient with purine nucleoside phosphorylase deficiency

“…Therapeutic interventions (15) as transfusion with irradiated red cells have offered limited improvement. In our patient, administration of different immunosuppressive agents did not result in any remission.…”