Lentiviral gene therapy using cellular promoters cures type 1 Gaucher disease in mice.

Maria Dahl, Alexander Doyle, Karin Olsson, Jan-Eric Månsson, André R A Marques, Mina Mirzaian, Johannes M Aerts, Mats Ehinger, Michael Rothe, Ute Modlich, Axel Schambach, Stefan Karlsson

Research output: Contribution to journalArticlepeer-review


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.Molecular Therapy (2015); doi:10.1038/mt.2015.16.
Original languageEnglish
Pages (from-to)835-844
JournalMolecular Therapy
Issue number5
Publication statusPublished - 2015

Bibliographical note

The information about affiliations in this record was updated in December 2015.
The record was previously connected to the following departments: Division of Molecular Medicine and Gene Therapy (013022010), Pathology, (Lund) (013030000)

Subject classification (UKÄ)

  • Medical Genetics


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