Multiple Reduced-intensity Conditioning Regimens Facilitate Correction of Fabry Mice After Transplantation of Transduced Cells
| Autor: | Makoto Yoshimitsu, Jeffrey A. Medin, Sheng-Ben Liang, Vanessa I. Rasaiah, Jianhui Cai, Daniel H. Fowler, Armando G. Poeppl |
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| Rok vydání: | 2007 |
| Předmět: |
Male
Transplantation Conditioning Myeloid medicine.medical_treatment Genetic enhancement Gene Expression Context (language use) Biology Mice 03 medical and health sciences 0302 clinical medicine Immune system Drug Discovery Genetics medicine Animals Humans Progenitor cell Molecular Biology Bone Marrow Transplantation 030304 developmental biology Pharmacology 0303 health sciences Chemotherapy Interleukin-2 Receptor alpha Subunit Genetic Therapy 3. Good health Transplantation Regimen medicine.anatomical_structure 030220 oncology & carcinogenesis Immunology Cancer research Fabry Disease Molecular Medicine Biomarkers Spleen |
| Zdroj: | Molecular Therapy. 15:618-627 |
| ISSN: | 1525-0016 |
| DOI: | 10.1038/sj.mt.6300075 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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