How ex vivo transduction of hematopoietic stem cells can affect transplant outcome

by Alexey Bersenev on July 23, 2010 · 0 comments

in gene transfer, hematopoietic

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I’d like to bring to your attention 2 studies reveal how ex vivo transduction of hematopoietic stem cells (HSCs) can affect engraftment and transplant outcome. These results can be taking in account for development of clinical protocols for HSCs ex vivo transduction with purposes of gene therapy or expansion.

The first study demonstrates that ex vivo transduced bone marrow Lin(-) cells transplanted in lethally irradiated or submyeloablated mice markedly impaired long-term repopulating ability (measured by competitive repopulation assay) compared with fresh cells.

Only a few published studies have attempted to quantitate the engraftment defect induced by ex vivo culture and/or retroviral transduction; these studies, however, were performed solely in ablated hosts. Qin et al. were among the first to report that transduced HSC were at a relative disadvantage for engraftment, compared to fresh HSC, in ablated hosts. Bryder et al. showed that transduction of murine HSC using an optimized protocol lacking the use of 5-FU and bovine serum markedly reduced competitive engraftment in ablated hosts, but that further ex vivo culture with cytokines could in part reverse the engraftment defect. Our results confirm that transduction with a clinically-relevant protocol impairs engraftment in ablated hosts and extend the findings of Bryder et al. to additionally show a marked engraftment impairment in submyeloablated host.

The article is available in open access.

Authors of second study, published in Molecular Therapy, investigated in depth immunogenicity as a possible reason of engraftment defects after transplant of transduced HSCs in nonablated host.

We investigated whether transgene expression levels influence the immunogenicity of transduced hematopoietic grafts upon transplantation into partially myeloablated mice. To this aim, bone marrow cells (BMCs) transduced with retroviral vectors driving green fluorescent protein (GFP) expression either at high (high-EGFP) or low levels (low-EGFP) were transplanted into congenic recipients conditioned with sublethal doses of total body irradiation (TBI) or busulfan. Virtually all recipients showed evidence of donor engraftment 4 weeks after transplantation. However, as opposed to recipients receiving low-EGFP transduced grafts, the risk of rejecting the EGFP+ cells by 30 days after transplantation was significantly higher in mice conditioned with busulfan and receiving high-EGFP transduced grafts.

Translational impact of the study:

These results show for the first time that transgene expression levels can be critical for the immunogenicity of gene-modified hematopoietic grafts, especially in immunocompetent or in partially immunosuppressed recipients.

Very interesting and important data, worth reading!

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