title: Successful low-risk hematopoietic cell therapy in a mouse model of type 1 Gaucher disease.
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.
authors.affiliation: Institute of Laboratory Medicine and the Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University, Sweden.
authors.forename: Ida Berglin
authors.initials: IB
authors.lastname: Enquist
authors.forename: Eva
authors.initials: E
authors.lastname: Nilsson
authors.forename: Jan-Eric
authors.initials: JE
authors.lastname: Månsson
authors.forename: Mats
authors.initials: M
authors.lastname: Ehinger
authors.forename: Johan
authors.initials: J
authors.lastname: Richter
authors.forename: Stefan
authors.initials: S
authors.lastname: Karlsson
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D002066:Busulfan / Q000627:therapeutic use; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005776:Gaucher Disease / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D005962:Glucosylceramidase / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D051379:Mice; D019172:Transplantation Conditioning / Q000379:methods
chemical_list: D007166:Immunosuppressive Agents; D005962:Glucosylceramidase; D002066:Busulfan