Multiple reduced-intensity conditioning regimens facilitate correction of Fabry mice after transplantation of transduced cells. Mol Ther 2007 Mar;15(3):618-27
Date
01/18/2007Pubmed ID
17228315DOI
10.1038/sj.mt.6300075Scopus ID
2-s2.0-33847175575 (requires institutional sign-in at Scopus site) 13 CitationsAbstract
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 x 10(6) gene-modified stem/progenitor cells was nominally effective; none of the RI regimens led to stable alpha-galactosidase A (alpha-gal A) correction. Secondly, transduced cells were preselected for functional transgene expression and transplanted at a higher dose (0.72 x 10(6) cells). Each RI regimen yielded engraftment of functional transgene-positive cells through 180 days along with increased plasma alpha-gal A activity. Importantly, the RI regimens mediated broad organ enzyme correction and were not associated with immune responses against alpha-gal A. RI conditioning thus has an important role in gene therapy for LSDs; a variety of regimens can be effective in this context.
Author List
Liang SB, Yoshimitsu M, Poeppl A, Rasaiah VI, Cai J, Fowler DH, Medin JAAuthor
Jeffrey A. Medin PhD Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBiomarkers
Bone Marrow Transplantation
Fabry Disease
Gene Expression
Genetic Therapy
Humans
Interleukin-2 Receptor alpha Subunit
Male
Mice
Spleen
Transplantation Conditioning
