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Gaucher disease: a century of delineation and research. Enzyme replacement therapy: model and clinical studies
Abstract:
A number of investigators have attempted to treat Gaucher disease with exogenous glucocerebrosidase. Although at times encouraging biochemical changes and suggestive alterations in organomegaly have been reported, overall, the results of enzyme replacement therapy must be judged to be a failure. In order to understand this lack of success with a promising treatment modality, four aspects of enzyme replacement therapy require examination: 1. The purification of glucocerebrosidase to a form which can hydrolyze glucocerebroside under in vivo conditions; 2. The delivery of the enzyme to cells of the macrophage-monocyte system; 3. The intracellular fate of the administered enzyme; 4. The capacity of the enzyme to effectively contact intracellular glycolipid deposits. A model system for the study of the latter three of these aspects of enzyme replacement therapy has been developed. Monocytes from normal subjects and patients with Gaucher disease were maintained in tissue culture for several months using horse serum-containing culture media. When such cells were "fed" glucocerebrosidase, their enzyme deficiency was corrected for at least 72 hours. Cells from Gaucher disease patients do not spontaneously accumulate glucocerebroside in this system. When loaded with 14C-labeled glucocerebroside, they do not become Gaucher cells but rather manifest a remarkable capacity to catabolize glucocerebroside, so that the labeled fatty acid quickly appears in neutral fats and in phospholipids. Therefore, this model is not yet suitable for study of the effectiveness of enzyme therapy.
Insights
Enzyme replacement therapy for Gaucher disease using glucocerebrosidase has largely failed. Further research is needed to understand enzyme purification, delivery, and intracellular interactions for effective treatment.
Area of Science:
- Biochemistry
- Genetics
- Cell Biology
Background:
- Gaucher disease is a lysosomal storage disorder caused by glucocerebrosidase deficiency.
- Enzyme replacement therapy (ERT) with exogenous glucocerebrosidase has shown limited success in treating Gaucher disease.
- Key challenges in ERT include enzyme purification, cellular delivery, and intracellular efficacy.
Purpose of the Study:
- To investigate the limitations of current enzyme replacement therapy for Gaucher disease.
- To develop and evaluate a model system for studying ERT in Gaucher disease.
Main Methods:
- Monocytes from healthy individuals and Gaucher disease patients were cultured.
- Cells were treated with glucocerebrosidase and/or glucocerebroside.
- Cellular enzyme activity and glucocerebroside metabolism were assessed.
Main Results:
- Cultured Gaucher disease monocytes corrected enzyme deficiency for at least 72 hours after glucocerebrosidase treatment.
- These cells did not spontaneously accumulate glucocerebroside.
- Gaucher disease monocytes efficiently catabolized exogenous glucocerebroside, converting it to neutral fats and phospholipids.
Conclusions:
- The developed cell culture model is not suitable for studying the effectiveness of enzyme replacement therapy in Gaucher disease.
- Further research is required to address challenges in enzyme purification, delivery, and intracellular targeting for successful Gaucher disease treatment.