Multiple reduced-intensity conditioning regimens facilitate correction of Fabry mice after transplantation of transduced cells.
Multiple reduced-intensity conditioning regimens facilitate correction of Fabry mice after transplantation of transduced cells.
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多种降低强度的调理方案有利于法布里小鼠移植转导细胞后的矫正。
DOI：
10.1038/sj.mt.6300075
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发表时间：
2007
期刊：
影响因子：
--
通讯作者：
Medin,JeffreyA
中科院分区：
文献类型：
--
作者：
Liang,Sheng-Ben;Yoshimitsu,Makoto;Poeppl,Armando;Rasaiah,VanessaI;Cai,Jianhui;Fowler,DanielH;Medin,JeffreyA
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 × 106gene-modified stem/progenitor cells was nominally effective; none of the RI regimens led to stableα-galactosidase A (α-gal A) correction. Secondly, transduced cells were preselected for functional transgene expression and transplanted at a higher dose (0.72 × 106cells). Each RI regimen yielded engraftment of functional transgene-positive cells through 180 days along with increased plasmaα-gal A activity. Importantly, the RI regimens mediated broad organ enzyme correction and were not associated with immune responses againstα-gal A. RI conditioning thus has an important role in gene therapy for LSDs; a variety of regimens can be effective in this context.
