| 1. |
|
|
| 2. |
|
|
| 3. |
|
|
| 4. |
- Berglin-Enquist, Ida, et al.
(författare)
-
Murine models of acute neuronopathic Gaucher disease
- 2007
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 104:44, s. 17483-17488
-
Tidskriftsartikel (refereegranskat)abstract
- Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by mutations in the glucosidase, beta, acid (GBA) gene that encodes the lysosomal enzyme glucosylceramidase (GCase). GCase deficiency leads to characteristic visceral pathology and, in some patients, lethal neurological manifestations. Here, we report the generation of mouse models with the severe neuronopathic form of GD. To circumvent the lethal skin phenotype observed in several of the previous GCase-deficient animals, we genetically engineered a mouse model with strong reduction in GCase activity in all tissues except the skin. These mice exhibit rapid motor dysfunction associated with severe neurodegeneration and apoptotic cell death within the brain, reminiscent of neuronopathic GD. In addition, we have created a second mouse model, in which GCase deficiency is restricted to neural and glial cell progenitors and progeny. These mice develop similar pathology as the first mouse model, but with a delayed onset and slower disease progression, which indicates that GCase deficiency within microglial cells that are of hematopoietic origin is not the primary determinant of the CNS pathology. These findings also demonstrate that normal microglial cells cannot rescue this neurodegenerative disease. These mouse models have significant implications for the development of therapy for patients with neuronopathic GD.
|
|
| 5. |
- Berglin-Enquist, Ida, et al.
(författare)
-
Successful Low-Risk Hematopoietic Cell Therapy in a Mouse Model of Type 1 Gaucher Disease
- 2009
-
Ingår i: Stem Cells. - : Oxford University Press (OUP). - 1549-4918 .- 1066-5099. ; 27:3, s. 744-752
-
Tidskriftsartikel (refereegranskat)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
|
|
| 6. |
- Berglin-Enquist, Ida, et al.
(författare)
-
Successful low-risk hematopoietic cell therapy in a mouse model of type 1 Gaucher disease.
- 2008
-
Ingår i: - : Mary Ann Liebert Inc. ; , s. 1189-1190
-
Konferensbidrag (refereegranskat)abstract
- Hematopoietic stem cell (HSC) 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 WT cell engraftment of 7 % corresponding to GCase activity levels above 10 nmol/hr and mg protein was sufficient to reverse pathology within bone marrow (BM) and spleen in the GD mouse. Moreover, we applied non-myeloablative doses of busulphan 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 to develop safe and efficient conditioning protocols for diseases that only require a low level of normal or gene corrected cells for a permanent and beneficial therapeutic outcome. ______________________________________________________________________________ Author contributions: I.B.E.: Conception and design, collection and assembly of data, data analysis and interpretation, manuscript writing; E.N.: Collection of data, data analysis and interpretation; J.-E.M.: Collection and assembly of data, data analysis and interpretation; M.E.: Collection and assembly of data, data analysis and interpretation; J.R.: Data analysis and interpretation, manuscript writing; S.K.: Conception and design, financial support, data analysis and interpretation, manuscript writing, final approval of manuscript.
|
|
| 7. |
|
|
| 8. |
- Gerhardsson, Lars, 1952, et al.
(författare)
-
Vascular and nerve damage in workers exposed to vibrating tools. The importance of objective measurements of exposure time.
- 2005
-
Ingår i: Applied ergonomics. - : Elsevier BV. - 0003-6870 .- 1872-9126. ; 36:1, s. 55-60
-
Tidskriftsartikel (refereegranskat)abstract
- The aim of the present study was to compare the development of vibration white fingers (VWF) in workers in relation to different ways of exposure estimation, and their relationship to the standard ISO 5349, annex A. Nineteen vibration exposed (grinding machines) male workers completed a questionnaire followed by a structured interview including questions regarding their estimated hand-held vibration exposure. Neurophysiological tests such as fractionated nerve conduction velocity in hands and arms, vibrotactile perception thresholds and temperature thresholds were determined. The subjective estimation of the mean daily exposure-time to vibrating tools was 192 min (range 18-480 min) among the workers. The estimated mean exposure time calculated from the consumption of grinding wheels was 42 min (range 18-60 min), approximately a four-fold overestimation (Wilcoxon's signed ranks test, p<0.001). Thus, objective measurements of the exposure time, related to the standard ISO 5349, which in this case were based on the consumption of grinding wheels, will in most cases give a better basis for adequate risk assessment than self-exposure assessment.
|
|
| 9. |
|
|
| 10. |
|
|
