Gaucher Disease is the most Common lysosomal storage disorder and is due to an inborn error of glycosphingolipid metabolism resulting from mutations in the gene coding glueocerebrosidase (GC) (E.C. 3.2.1.45). Type 1 disease commonly among Ashkenazi Jews where it is the most prevalent inherited disorder, and accounts for 90% of clinical cases. All patients with Gaucher disease have some clinical complications frequently leading to discomfort and disability. Complications include hepatosplenomegaly, hypersplenism, anemia, thrombocytopenia and degenerative changes in the skeleton. There is urgent need for new forms of therapy for this disease. The objective of this proposal is to evaluate gene therapy for Gaucher disease. The approach involves gene transfer to human hematopoietic cells and transplantation of the genetically corrected cells. Preclinical data in the mouse model of bone marrow transplantation provides evidence of efficient transduction of bone marrow stem cells and long term expression of the human gene in their progeny. Expression of the transferred human GC gene in macrophages derived from the bone marrow of these animals suggests that correction of the enzyme defect by gene transfer is likely to be efficacious, as storage of the undegraded lipid occurs only in this cell and the pathology of the disorder is mediated by macrophages. Preclinical studies with human macrophages and CD34+ cells indicate that transduction of human Gaucher macrophages and CD34+ cells in culture is sufficient to correct their activity to within the normal range or greater. These results suggest that gene transfer and expression of the GC enzyme in human hematopoietic cells is feasible and should modify the disease process. Additional studies confirm that either transplantation of normal bone marrow or correction of macrophage enzymatic activity by enzyme replacement confers a therapeutic benefit. Based on these data, a clinical trial of gene therapy for Gaucher disease has been approved by the recombinant DNA Advisory Committee and the FDA. In this trial, we propose to transduce CD34+ cells from Gaucher patients using a replication defective retroviral vector carrying the human cDNA for glucocerebrosidase. The studies proposed in this application should advance the development of gene therapy for Gaucher disease and serve as a prototype for the investigation of this modality for other lysosomal storage disorders.
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