The 3rd International Congress on

Rare Diseases

Gaucher disease (GD) is a lysosomal storage disorder caused by an inherited deficiency in the gene encoding glucocerebrosidase (GCase). The defective enzyme does not degrade sufficient glucocerebroside and it accumulates in macrophages throughout the body, producing Gaucher cells, the hallmark feature of GD.1 Enzyme replacement therapy is the standard treatment for GD patients. It reduces signs and symptoms, but it is not curative and restricts patients to lifelong infusions of the enzyme.1 Our work has been focused on development of a GCase lentiviral vector for correction of the genetic defect underlying GD. The first step in this process was creation of a viable model with pathology and clinical symptoms characteristic of type 1 GD. This was accomplished by conditionally deleting GCase exons 9–11 upon postnatal induction.2 In studies supported by AVROBIO, tThis mouse model was used to evaluate a clinical, Good Manufacturing Practices produced, single gene self-inactivating lentiviral vector (LV2) containing the glucocerebrosidase gene driven by the elongation factor 1α short (EFS) promoter.1,3 Lineage negative bone marrow cells were transduced with the LV2 vector and transplanted into irradiated GD type 1 mice, 2-3 months after induction of the gene deletion (early intervention) or 5-8 months after induction of disease (late intervention, when considerable splenomegaly has developed). Vector integration analysis demonstrated a typical lentiviral integration profile, with no integrations in high-risk proto-oncogenes and an oligoclonal integration site pattern.1,3 Mass spectrometric analysis of bone marrow, spleen, and liver demonstrated highly significant reductions in glucocerebroside accumulation in vector treated animals with both early and late intervention. Glucocerebroside levels were close to those in normal mice by 4 months after treatment. Histopathology demonstrated great reduction or disappearance of Gaucher cells in bone marrow and spleen by 4 months after vector treatment. In the late intervention study, hemoglobin and hematocrit were both normalized in vector treated animals.1,3 These data strongly support that gene therapy of GD type 1 mice using this clinical lentiviral vector is very efficient and demonstrates robust efficacy in the mouse disease model.