Effective cell and gene therapy in a murine model of Gaucher disease

Abstract

Gaucher disease (GD) is a lysosomal storage disorder due to an inherited deficiency in the enzyme glucosylceramidase (GCase) that causes hepatosplenomegaly, cytopenias, and bone disease as key clinical symptoms. Previous mouse models with GCase deficiency have been lethal in the perinatal period or viable without displaying the clinical features of GD. We have generated viable mice with characteristic clinical symptoms of type 1 GD by conditionally deleting GCase exons 9 -11 upon postnatal induction. Both transplantation of WT bone marrow (BM) and gene therapy through retroviral transduction of BM from GD mice prevented development of disease and corrected an already established GD phenotype. The gene therapy approach generated considerably higher GCase activity than transplantation of WT BM. Strikingly, both therapeutic modalities normalized glucosylceramide levels and practically no infiltration of Gaucher cells could be observed in BM, spleen, and liver, demonstrating correction at 5-6 months after treatment. The findings demonstrate the feasibility of gene therapy for type 1 GD in vivo. Our type 1 GD mice will serve as an excellent tool in the continued efforts toward development of safe and efficient cell and gene therapy for type 1 GD.

Lyso-glycosphingolipid abnormalities in different murine models of lysosomal storage disorders

“…We investigated Twitcher mice deficient in galactocerebrosidase (GALC, EC 3.2.1.46), a model for Krabbe disease [12,13]; mice lacking LIMP-2, deficient in lysosomal glucocerebrosidase (GBA, EC 3.2.1.45) due to anomalous targeting of the enzyme to lysosomes, a model for Action Myoclonus Renal Failure syndrome (AMRF) [14,15]; genetically modified mice with an inducible GBA deficiency in the white blood cell lineage, a model for type 1 GD [16]; and mice deficient in α-galactosidase A (GLA, EC 3.2.1.22) due to the knock out of the GLA gene, a model for classic FD [17]. Additionally, we investigated two mouse models of NPC disease: the Npc1 nih mouse characterized by a null allele due to an early truncation of the NPC1 protein and mimicking the severe early infantile form of the disease [18], and the Npc1 nmf164 mouse expressing NPC1…”

Gaucher disease geneGBAfunctions in immune regulation

“…Recently, we and others successfully recapitulated the phenotype of human type 1 GD in mice through the conditional inactivation of GBA gene in hematopoietic (HSCs) and mesenchymal stem cells (MSCs), using an Mx1-driven Cre recombinase (3,19). The reduced differentiation of MSCs resulted in impaired osteoblastogenesis and bone formation, causing severe osteoporosis.…”

Terapia gênica, doping genético e esporte: fundamentação e implicações para o futuro

“…Since it is still in eminently experimental character stage, there are problems in the gene therapy application, being its risks control one of the most important (7)(8)(9)(10)(11) . However, studies in animal models (2,(12)(13)(14)(15) as well as some studies in humans (1,(6)(7)(16)(17)(18)(19) have presented promising results.…”

“…It is believed that gene therapy represents a possibility of effective treatment for several diseases whose treatments are little effective and/or restricted to symptoms (1)(2)(3)(4)(5)(6)(7) . Since it is still in eminently experimental character stage, there are problems in the gene therapy application, being its risks control one of the most important (7)(8)(9)(10)(11) .…”