Enzyme replacement therapy for Gaucher disease

Beutler, Ernest; Kay, Andrea; Saven, Alan; Garver, Paul; Thurston, Dennis; Dawson, Arthur; Rosenbloom, Barry E.

doi:10.1182/blood.v78.5.1183.1183

Cited by 144 publications

(27 citation statements)

References 19 publications

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“…Dose and dose regimen of enzyme replacement for treatment of Gaucher disease has been a topic of controversy (Figuero et al 1992). Suggested dose and dose regimens vary from 60 U k g administered biweekly to 2 U k g administered every other day or 2.3 U k g administered 3 times per week (Beutler et al 1991b). A review of all the available data on ERT conducted by a panel assembled by the Office of the panel concluded that no dose or schedule of treatments could be endorsed based upon the data presented and published.…”

Section: Discussionmentioning

confidence: 99%

“…(Recombinant glucocerebrosidase received FDA approval in May 1994 but is not yet readily available.) Enzyme therapy with mannoseterminated glucocerebrosidase has been shown to be highly effective in treatment of type 1 Gaucher dis-ease , Barton et al 1991, Beutler et al 1991b, Fallet et al 1992 and presently more than 1000 Gaucher patients worldwide are being treated. Indicators of reversal of disease symptoms include an increase in hemoglobin, an increase in platelet count, a decrease in acid phosphatase and angiotensin converting enzyme, and a decrease in hepatosplenomegaly.…”

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confidence: 99%

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Gaucher disease: studies of phenotype, molecular diagnosis and treatment

et al. 1996

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This report summarizes the results on 39 patients with Gaucher disease who have been genotyped, evaluated, and/or followed at this center. Mutation analysis for 4 common mutations; N370S, L444P, 84gg and IVS2 (+1), was performed for all patients. Mutation analysis identified both mutant alleles in 69% and at least one mutant allele in 90% of all chromosomes. This study group of 39 patients included 32 type 1, four type 2 and three type 3 patients. We include the details of the clinical course of two patients with Gaucher disease treated with enzyme replacement therapy (ERT). One patient with chronic neuronopathic Gaucher disease has been treated with enzyme replacement therapy (ERT) at a dose of 60 U/kg every 2 weeks since 2.5 years of age and has shown no progression of neurologic involvement. A second patient with non‐neuronopathic Gaucher disease has demonstrated an unusually delayed response to ERT. No clinical response was noted following 17 months of treatment at 60 U/kg every 2 weeks. Only after the dose was increased to 60 U/kg every week was a clinical response evident. Response to treatment at 15 U/kg every 2 weeks was variable in the four type 1 patients treated at the lower dose. In two of these patients with identical genotypes, one patient demonstrated a positive clinical response to low dose treatment while the other patient did not.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Gaucher disease: studies of phenotype, molecular diagnosis and treatment

et al. 1996

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“…The clinical benefits of enzyme replacement in patients with type 1 Gaucher disease has been repeatedly confirmed (Beutler et al 1991;Fallet et al 1992;Mistry et al 1992). Recombinantly produced glucocerebrosidase that was targeted by the same treatment with exoglycosidases has been shown to be as effective as the macrophagetargeted placental enzyme (Grabowski et al 1993).…”

Section: Clinical Effectiveness Of Macrophage-targeted Glucocerebrosimentioning

confidence: 90%

Modifying exogenous glucocerebrosidase for effective replacement therapy in Gaucher disease

Brady

Murray

Barton

1994

J of Inher Metab Disea

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Important therapeutic principles were established in developing effective enzyme replacement therapy for patients with Gaucher disease. The background and sequence of the investigations that led to effective delivery of exogenous glucocerebrosidase to the lipid-storing macrophages in patients with Gaucher disease are described. The principle of targeting the intravenously injected enzyme to the mannose lectin on the surface of these cells by engineering the glycoform of the enzyme is a useful model of an essential requirement for effective enzyme therapy. Similar strategies are expected to be effective for the treatment of a number of hereditary metabolic disorders of humans.

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“…Hence, with a high efficacy and an excellent safety profile, the major disadvantages of ERT are the very-high cost of therapy and the apparent lifetime dependency on intravenous infusions. 21,[24][25][26][27][28][29][30][31][32][33][34][35][36] In addition, the dosing issue has become a major source of controversy, with only few centers adopting the low-dose regimen [37][38][39][40][41] and the majority of centers advocating high-dose ERT to ensure better clinical results. 42,43 Recently, however, a few studies have reported an increasing number of complications that are not directly associated with the known consequences of GD and that, paradoxically, may be related to the long-term use of ERT.…”

Section: Is There a Selective Evolutionary Advantage For Patients Witmentioning

confidence: 99%

Glucocerebroside: an evolutionary advantage for patients with Gaucher disease and a new immunomodulatory agent

2009

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Gaucher disease (GD) is caused by the reduced activity of a lysosomal enzyme, glucocerebrosidase, leading to the accumulation of glucocerebroside (GC). The relatively high prevalence of this disease within an ethnic group is believed to reflect a selective advantage. Treatment with enzyme replacement therapy (ERT) is safe and effective in ameliorating the primary symptoms of the disease, yet there have been reports that some patients on ERT have developed type 2 diabetes or metabolic syndrome, malignancies and central nervous system disorders. A series of animal studies suggest that these complications may be related to the reduction of GC levels by the enzyme administered. GC has been shown to have an immunomodulatory effect through the promotion of dendritic cells, natural killer T cells, and regulatory T cells. The break down of GC to ceramide can underline part of these findings. Clinical trials suggested a beneficial effect of GC in type 2 diabetes or nonalcoholic steatohepatitis. This review of the data from animal models and humans proposes that the increased level of GC may provide an evolutionary advantage for patients with GD. Indirectly, these data support treating symptomatic patients with mild/moderate GD with lowdose ERT and re-evaluating the use of ERT in asymptomatic patients.

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Enzyme replacement therapy for Gaucher disease

Cited by 144 publications

References 19 publications

Gaucher disease: studies of phenotype, molecular diagnosis and treatment

Gaucher disease: studies of phenotype, molecular diagnosis and treatment

Modifying exogenous glucocerebrosidase for effective replacement therapy in Gaucher disease

Glucocerebroside: an evolutionary advantage for patients with Gaucher disease and a new immunomodulatory agent

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