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Lentiviral Gene Therapy Using Cellular Promoters Cures Type 1 Gaucher Disease in Mice

Journal article
Authors M. Dahl
A. Doyle
K. Olsson
Jan-Eric Månsson
A. R. A. Marques
M. Mirzaian
J. M. Aerts
M. Ehinger
M. Rothe
U. Modlich
A. Schambach
S. Karlsson
Published in Molecular Therapy
Volume 23
Issue 5
Pages 835-844
ISSN 1525-0016
Publication year 2015
Published at Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine
Pages 835-844
Language en
Links dx.doi.org/10.1038/mt.2015.16
Keywords CHRONIC GRANULOMATOUS-DISEASE, BONE-MARROW TRANSPLANTATION, ENZYME, REPLACEMENT THERAPY, IN-VIVO, MOUSE MODEL, HEMATOPOIETIC-CELLS, RETROVIRAL VECTOR, EXPRESSION, CD68, GLUCOCEREBROSIDASE, Biotechnology & Applied Microbiology, Genetics & Heredity, Medicine, Research & Experimental
Subject categories Microbiology, Medical Biotechnology

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 beta-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.

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