Enzyme Augmentation in Moderate to Life-Threatening Gaucher Disease

Abstract

ABSTRACT. Gaucher disease type 1 (GD type 1) is the most prevalent lysosomal storage disease and has its highest frequency in the Ashkenazi Jewish population. Deficiency of the enzyme, acid 8-glucosidase, results in the deposition of glucocerebroside primarily in macrophages. The accumulation of such "Gaucher cells" leads to visceromegaly, hepatic and bone marrow dysfunction, hypersplenism, and bony disease. Eleven GD type 1 patients, ages 4-52 y, with moderate to life-threatening manifestations, received 6-12 mo of enzyme augmentation with a macrophage-targeted acid 8-glucosidase preparation.Within 6 mo, substantial increases in Hb levels (mean = +30%) and platelet counts (mean = +39%) were observed. Hepatic and splenic volumes decreased by -20% (range = 3-35%) and -35% (20-52%), respectively. Hematologic and hepatic volume improvements were similar in the splenectomized (n = 4) and nonsplenectomized (n = 7) patient groups. In this patient population, no major differences were observed in the hematologic and visceral improvements with enzyme doses of 30, 50, or 60 IU/kg administered every 2 wk. Normal levels of acid 8-glucosidase activity were present in hepatic autopsy samples from one patient 11 d after enzyme infusion. In comparison, exogenous activity was absent from brain and lung specimens of the same patient. High levels (-10-fold normal) were present in bone marrow samples from two patients obtained at 1 and 11 d after infusions. These studies demonstrate biochemical and clinical improvements by targeted enzyme augmentation in GD type 1, even in far advanced, life-threatening involvement. These and previous studies indicate that earlier intervention in patients with more mild signs may be warranted to obviate the need to rescue extraordinarily ill patients with GD type 1. (Pediatr Res 31': 496-502, 1992) not absence, of the enzyme acid P-glucosidase and results from numerous point mutations at that locus (3

The clinical effectiveness and cost-effectiveness of enzyme replacement therapy for Gaucher's disease: a systematic review

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“…Often dose regimens were described as "individualised". 75,92,95 Adoption of an initial dose programme for a given patient was generally based on clinical judgement relating to disease severity and prognosis, whereas changes in regimen were usually dependent on clinical judgement regarding the speed and extent of response to therapy and the remaining scope for further improvement. The criteria exercised in these clinical judgements were rarely reported other than in descriptive terms (e.g.…”

Murine MHC class II locus control region drives expression of human β-glucocerebrosidase in antigen presenting cells of transgenic mice

“…Although therapeutically effective to some extent (regression of organomegaly, increase in the haemoglobin concentration), 8,9 enzyme replacement is expensive, gives only limited improvement in neuronopathic disease due to the inaccessibility of the CNS 15,16 and the enzyme is not targeted to marrow macrophages. 2 Little activity was found in bone marrow cells, even immediately after marrow infusion.…”

The clinical effectiveness and cost-effectiveness of enzyme replacement therapy for Gaucher’s disease: a systematic review

“…According to Weinreb's analysis of 910 patients in the ICGG Gaucher Registry, 116 pre-ERT platelet numbers of ERT-treated patients averaged 140.8 × 10 3 mm -3 , with splenectomised patients (n = 267) having strikingly higher numbers (mean 28,55,61,75,82,84,87,92,95,96,99,100,111,116,120,121 ) reported change in platelet numbers during ERT. The results are summarised in Figure 7.…”