Successful low-risk hematopoietic cell therapy in a mouse model of type 1 Gaucher disease.

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.