title: Lentiviral gene therapy using cellular promoters cures type 1 Gaucher disease in mice.
abstract: Gaucher disease is caused by an inherited deficiency of the enzyme glucosylceramidase. Due to the lack of a fully functional enzyme, there is progressive build-up of the lipid component glucosylceramide. Insufficient glucosylceramidase activity results in hepatosplenomegaly, cytopenias, and bone disease in patients. Gene therapy represents a future therapeutic option for patients unresponsive to enzyme replacement therapy and lacking a suitable bone marrow donor. By proof-of-principle experiments, we have previously demonstrated a reversal of symptoms in a murine disease model of type 1 Gaucher disease, using gammaretroviral vectors harboring strong viral promoters to drive glucosidase β-acid (GBA) gene expression. To investigate whether safer vectors can correct the enzyme deficiency, we utilized self-inactivating lentiviral vectors (SIN LVs) with the GBA gene under the control of human phosphoglycerate kinase (PGK) and CD68 promoter, respectively. Here, we report prevention of, as well as reversal of, manifest disease symptoms after lentiviral gene transfer. Glucosylceramidase activity above levels required for clearance of glucosylceramide from tissues resulted in reversal of splenomegaly, reduced Gaucher cell infiltration and a restoration of hematological parameters. These findings support the use of SIN-LVs with cellular promoters in future clinical gene therapy protocols for type 1 Gaucher disease.
authors: Department of Molecular Medicine and Gene Therapy, Lund University, Lund, Sweden; Lund Strategic Center for Stem Cell Biology and Cell Therapy, Lund University Hospital, Lund, Sweden.
authors: Maria
authors: M
authors: Dahl
authors: Department of Molecular Medicine and Gene Therapy, Lund University, Lund, Sweden; Lund Strategic Center for Stem Cell Biology and Cell Therapy, Lund University Hospital, Lund, Sweden.
authors: Alexander
authors: A
authors: Doyle
authors: Department of Molecular Medicine and Gene Therapy, Lund University, Lund, Sweden; Lund Strategic Center for Stem Cell Biology and Cell Therapy, Lund University Hospital, Lund, Sweden.
authors: Karin
authors: K
authors: Olsson
authors: Department of Clinical Chemistry, Institute of Biomedicine, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors: Jan-Eric
authors: JE
authors: Månsson
authors: Department of Medical Biochemistry, University of Amsterdam, Amsterdam, The Netherlands.
authors: André R A
authors: ARA
authors: Marques
authors: Department of Medical Biochemistry, University of Amsterdam, Amsterdam, The Netherlands.
authors: Mina
authors: M
authors: Mirzaian
authors: Department of Medical Biochemistry, University of Amsterdam, Amsterdam, The Netherlands.
authors: Johannes M
authors: JM
authors: Aerts
authors: Department of Pathology, Lund University Hospital, Lund, Sweden.
authors: Mats
authors: M
authors: Ehinger
authors: Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.
authors: Michael
authors: M
authors: Rothe
authors: Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.
authors: Ute
authors: U
authors: Modlich
authors: Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.
authors: Axel
authors: A
authors: Schambach
authors: Department of Molecular Medicine and Gene Therapy, Lund University, Lund, Sweden; Lund Strategic Center for Stem Cell Biology and Cell Therapy, Lund University Hospital, Lund, Sweden. Electronic address: Stefan.Karlsson@med.lu.se.
authors: Stefan
authors: S
authors: Karlsson
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005776:Gaucher Disease / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D015870:Gene Expression; D023061:Gene Order; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics*; D005962:Glucosylceramidase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity / Q000235:genetics; D010641:Phenotype; D011401:Promoter Regions, Genetic; D014161:Transduction, Genetic; D019076:Transgenes; D016662:Virus Integration; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D005962:Glucosylceramidase; C067980:CD68 antigen, human; D000097382:CD68 Molecule
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