Glucocerebrosidase Gene Transfer to the Nervous System

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DESCRIPTION (provided by applicant): The neuronopathic types of Gaucher disease still present a challenge for the treatment of the CNS symptoms. One approach would be gene therapy, but despite the fact that the glucocerebrosidase (GC) cDNA has been successfully transferred by retroviral vector to normal murine and human hematopoietic stem cells or by adeno-associated virus vector to muscle cells, and the transduced murine cells successfully transplanted in mice, the three clinical trials conducted to date resulted in either low levels of gene transfer, or a failure of engraftment after infusion, with a single exception. Gene transfer to neurons has been successfully demonstrated using retroviral, lentiviral, and other vectors. Engraftment of transduced neuronal and hematopoietic progenitors has been demonstrated in the brain of recipient animals. We hypothesize that transplantation of hematopoietic or neuronal progenitor cells transduced by retroviral and lentiviral vectors containing the cDNA for human glucocerebrosidase. This study will test the hypothesis that transplantation of hematopoietic or neuronal progenitor cells transduced by retroviral and lentiviral vectors containing the cDNA for human glucocerebrosidase will engraft in recipient Gaucher L444P mutant mice and lead to improved enzyme levels. Gene transfer to neurons has been successfully demonstrated with both retroviral and lentiviral vectors, and engraftment of transduced neuronal and hematopoietic progenitors has been attained in the brains of recipient animals. However, despite this success in animal models, the three clinical trials conducted to date have generally resulted in either low levels of gene transfer or a failure of engraftment after cell infusion. To accomplish this, we will: 1) characterize more completely the newly established Gaucher L444P mutant mouse; 2) intravenously administer retrovirally and lentivirally transduced hematopoietic progenitors to determine the extent of improved glucocerebrosidase enzyme levels in the tissues of the recipient mutant mice; and, 3) transplant by intrathecal administration ex vivo transduced hematopoietic or neuronal progenitors to determine if these cells will repopulate in brain and express glucocerebrosidase activity. At the completion of this study we will have determined whether lentiviral mediated gene transfer of human GC will result in sustained and improved enzyme levels in tissues, particularly brain, of recipient Gaucher mutant mice.