BSGT 2010 Invited Speaker Presentations

Abstract

Gaucher disease is an autosomal recessive lysosomal storage disorder caused by mutations in the glucosidase, beta, acid gene that encodes the lysosomal enzyme glucosylceramidase (GCase). GCase deficiency leads to characteristic visceral pathologic conditions and, in a minority of patients, to lethal neurologic manifestations. Previous mouse models with GCase deficiency have either been lethal in the perinatal period or viable without displaying clinical features of Gaucher disease. We have generated viable mice with characteristic clinical symptoms of type 1 Gaucher disease (eg, hepatosplenomegaly, anemia) by conditionally deleting GCase exons 9 through 11 on induction postnatally.! Both transplantation of wild-type bone marrow and gene therapy through retroviral transduction of bone marrow from Gaucher disease mice prevented development of disease, as well as corrected an already established Gaucher disease phenotype. The gene therapy approach produced considerably higher GCase activity than transplantation of wild-type bone marrow.! Both therapeutic modalities normalized glucosylceramide levels, and practically no infiltration of Gaucher cells was seen in the bone marrow, spleen, or liver, demonstrating correction 5 to 6 months after treatment. The findings suggest, for the first time, the feasibility of gene therapy for type 1 Gaucher disease in vivo. Using similar approaches, we have generated mouse models for severe neuronopathic Gaucher disease.? To circumvent the lethal skin phenotype observed in several of the previous GCase-deficient animals.l-I we genetically engineered a mouse model with a strong reduction in GCase activity in all tissues except the skin. These mice exhibited rapid motor dysfunction associated with severe neurodegeneration and apoptotic cell death within the brain, which is reminiscent of neuronopathic Gaucher disease. In addition, we created a distinct mouse model in which GCase deficiency was restricted to neural and glial cell progenitors and progeny. These mice developed pathologic conditions similar to the first mouse model but with a delayed onset and slower disease progression, indicating that GCase deficiency within microglial cells, which are of hematopoietic origin, is not the primary determinant of the central nervous system pathology. These findings strongly suggest that normal microglial cells cannot rescue this serious neurodegenerative disease. These mouse models may be used to investigate pathologic mechanisms and develop novel therapies for all types of Gaucher disease. Recently, we used nonmyeloablative conditioning of type 1 Gaucher mice and transplanted them with normal bone marrow cells. Based on the results, ::;10% engraftment is enough to correct the pathology of the disease. Collectively, these findings indicate that gene therapy in type 1 Gaucher disease is likely to be successful and may lead to a cure of the disease.