The Sooner the Better: Rapid Transduction Enhances the Engraftment/Selection of Gene Corrected Fanconi Anemia HSC

Autor:	Michael D. Milsom, David A. Williams, Chad E. Harris, Lars U.W. Müller, Jeff Bailey
Rok vydání:	2007
Předmět:	Genetic enhancement Immunology O-6-methylguanine-DNA methyltransferase Cell Biology Hematology Biology medicine.disease Biochemistry Molecular biology FANCA Viral vector Haematopoiesis medicine.anatomical_structure Fanconi anemia medicine Bone marrow Stem cell
Zdroj:	Blood. 110:194-194
ISSN:	1528-0020 0006-4971
DOI:	10.1182/blood.v110.11.194.194
Popis:	Fanconi anemia (FA) is amenable to genetic correction of hematopoietic stem cells (HSCs). However, as demonstrated in previous clinical gene therapy trials, successful extension of murine studies into human therapies is limited by low numbers of target HSC and poor engraftment of transduced FA HSC (Kelly et al., Mol Ther, 2007). To examine the potential biological consequences/benefits of shortened transduction we used a FA mouse model in which HSC are deficient and prone to excessive loss during in vitro manipulation. We applied a rapid transduction protocol (Mostoslavsky et al., Mol Ther, 2005) utilizing lentiviral vectors and demonstrate that this shortened transduction preserves engraftment of FA HSC to the level of C57BL/6 wt cells. Lin− Sca-1+ c-Kit+ bone marrow cells were isolated from Fanca−/− CD45.2 mice and underwent 4-hr rapid (RT) vs. 96-hr conventional (CT) transduction. An equivalent number of transduced cells were transplanted into lethally irradiated CD45.1 BoyJ mice. Analysis of engraftment chimerism three months post transplantation revealed a significantly higher level of engraftment in animals receiving RT vs. CT cells (90% +/− 14% vs. 26% +/− 31%, respectively, p=
Databáze:	OpenAIRE
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