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Successful Low-Risk Hematopoietic Cell Therapy in a Mouse Model of Type 1 Gaucher Disease

Berglin-Enquist, Ida LU ; Nilsson, Eva C LU ; Mansson, Jan-Eric; Ehinger, Mats LU ; Richter, Johan LU and Karlsson, Stefan LU (2009) In Stem Cells 27(3). p.744-752
Abstract
Hematopoietic stem cell-based gene therapy offers the possibility of permanent correction for genetic disorders of the hematopoietic system. However, optimization of present protocols is required before gene therapy can be safely applied as general treatment of genetic diseases. In this study we have used a mouse model of type 1 Gaucher disease (GD) to demonstrate the feasibility of a low-risk conditioning regimen instead of standard radiation, which is associated with severe adverse effects. We first wanted to establish what level of engraftment and glucosylceramidase (GCase) activity is required to correct the pathology of the type 1 GD mouse. Our results demonstrate that a median wild-type (WT) cell engraftment of 7%, corresponding to... (More)
Hematopoietic stem cell-based gene therapy offers the possibility of permanent correction for genetic disorders of the hematopoietic system. However, optimization of present protocols is required before gene therapy can be safely applied as general treatment of genetic diseases. In this study we have used a mouse model of type 1 Gaucher disease (GD) to demonstrate the feasibility of a low-risk conditioning regimen instead of standard radiation, which is associated with severe adverse effects. We first wanted to establish what level of engraftment and glucosylceramidase (GCase) activity is required to correct the pathology of the type 1 GD mouse. Our results demonstrate that a median wild-type (WT) cell engraftment of 7%, corresponding to GCase activity levels above 10 nmoles/hour and mg protein, was sufficient to reverse pathology in bone marrow and spleen in the GD mouse. Moreover, we applied nonmyeloablative doses of busulfan as a pretransplant conditioning regimen and show that even WT cell engraftment in the range of 1%-10% can confer a beneficial therapeutical outcome in this disease model. Taken together, our data provide encouraging evidence for the possibility of developing safe and efficient conditioning protocols for diseases that require only a low level of normal or gene-corrected cells for a permanent and beneficial therapeutic outcome. STEM CELLS 2009; 27: 744-752 (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Hematopoietic stem cell, Gaucher disease, Disease model, transplantation, Busulfan
in
Stem Cells
volume
27
issue
3
pages
744 - 752
publisher
AlphaMed Press
external identifiers
  • wos:000264706900025
  • scopus:65249168134
ISSN
1549-4918
DOI
10.1634/stemcells.2008-0844
language
English
LU publication?
yes
id
b09eb6cb-cc6c-4db3-8ef4-60fe5d9f0e97 (old id 1400822)
date added to LUP
2009-06-15 12:57:44
date last changed
2017-05-21 04:12:44
@article{b09eb6cb-cc6c-4db3-8ef4-60fe5d9f0e97,
  abstract     = {Hematopoietic stem cell-based gene therapy offers the possibility of permanent correction for genetic disorders of the hematopoietic system. However, optimization of present protocols is required before gene therapy can be safely applied as general treatment of genetic diseases. In this study we have used a mouse model of type 1 Gaucher disease (GD) to demonstrate the feasibility of a low-risk conditioning regimen instead of standard radiation, which is associated with severe adverse effects. We first wanted to establish what level of engraftment and glucosylceramidase (GCase) activity is required to correct the pathology of the type 1 GD mouse. Our results demonstrate that a median wild-type (WT) cell engraftment of 7%, corresponding to GCase activity levels above 10 nmoles/hour and mg protein, was sufficient to reverse pathology in bone marrow and spleen in the GD mouse. Moreover, we applied nonmyeloablative doses of busulfan as a pretransplant conditioning regimen and show that even WT cell engraftment in the range of 1%-10% can confer a beneficial therapeutical outcome in this disease model. Taken together, our data provide encouraging evidence for the possibility of developing safe and efficient conditioning protocols for diseases that require only a low level of normal or gene-corrected cells for a permanent and beneficial therapeutic outcome. STEM CELLS 2009; 27: 744-752},
  author       = {Berglin-Enquist, Ida and Nilsson, Eva C and Mansson, Jan-Eric and Ehinger, Mats and Richter, Johan and Karlsson, Stefan},
  issn         = {1549-4918},
  keyword      = {Hematopoietic stem cell,Gaucher disease,Disease model,transplantation,Busulfan},
  language     = {eng},
  number       = {3},
  pages        = {744--752},
  publisher    = {AlphaMed Press},
  series       = {Stem Cells},
  title        = {Successful Low-Risk Hematopoietic Cell Therapy in a Mouse Model of Type 1 Gaucher Disease},
  url          = {http://dx.doi.org/10.1634/stemcells.2008-0844},
  volume       = {27},
  year         = {2009},
}