Advanced

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

Dahl, Maria LU ; Doyle, Alexander LU ; Olsson, Karin LU ; Månsson, Jan-Eric; Marques, André R A; Mirzaian, Mina; Aerts, Johannes M; Ehinger, Mats LU ; Rothe, Michael and Modlich, Ute, et al. (2015) In Molecular Therapy 23(5). p.835-844
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Molecular Therapy
volume
23
issue
5
pages
835 - 844
publisher
Nature Publishing Group
external identifiers
  • pmid:25655314
  • wos:000353933200007
  • scopus:84929047508
ISSN
1525-0024
DOI
10.1038/mt.2015.16
language
English
LU publication?
yes
id
89e6c91a-a42c-4339-811c-b877ae7d61af (old id 5145357)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/25655314?dopt=Abstract
date added to LUP
2015-03-04 18:21:48
date last changed
2017-11-19 03:03:02
@article{89e6c91a-a42c-4339-811c-b877ae7d61af,
  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.Molecular Therapy (2015); doi:10.1038/mt.2015.16.},
  author       = {Dahl, Maria and Doyle, Alexander and Olsson, Karin and Månsson, Jan-Eric and Marques, André R A and Mirzaian, Mina and Aerts, Johannes M and Ehinger, Mats and Rothe, Michael and Modlich, Ute and Schambach, Axel and Karlsson, Stefan},
  issn         = {1525-0024},
  language     = {eng},
  number       = {5},
  pages        = {835--844},
  publisher    = {Nature Publishing Group},
  series       = {Molecular Therapy},
  title        = {Lentiviral gene therapy using cellular promoters cures type 1 Gaucher disease in mice.},
  url          = {http://dx.doi.org/10.1038/mt.2015.16},
  volume       = {23},
  year         = {2015},
}