Multiple Reduced-intensity Conditioning Regimens Facilitate Correction of Fabry Mice After Transplantation of Transduced Cells

Hematopoietic cell transplantation can impact lysosomal storage disorders (LSDs) and will be enhanced by gene therapy. Transduced cells in LSDs often secrete the therapeutic hydrolase, which can be used by bystander cells. However, toxicity associated with myeloablative transplant preparative regimens limits many applications of this approach in gene therapy. We hypothesized that reduced-intensity (RI) conditioning regimens would allow stable engraftment of therapeutically transduced cells and allow correction of Fabry disease. We transplanted transduced cells into Fabry mice receiving eight different clinically relevant chemotherapy- and/or radiotherapy-based RI conditioning regimens generating modest and transient lymphoid/myeloid cell depletion. Two comprehensive transplantation Protocols were performed. Firstly, transplantation of 0.38 × 10 6 gene-modified stem/progenitor cells was nominally effective; none of the RI regimens led to stable α -galactosidase A ( α -gal A) correction. Secondly, transduced cells were preselected for functional transgene expression and transplanted at a higher dose (0.72 × 10 6  cells). Each RI regimen yielded engraftment of functional transgene-positive cells through 180 days along with increased plasma α -gal A activity. Importantly, the RI regimens mediated broad organ enzyme correction and were not associated with immune responses against α -gal A. RI conditioning thus has an important role in gene therapy for LSDs; a variety of regimens can be effective in this context.