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Minimal conditioning in Fanconi anemia promotes multi-lineage marrow engraftment at 10-fold lower cell doses.

Authors
  • Haworth, Kevin G1
  • Ironside, Christina1
  • Ramirez, Megan A1
  • Weitz, Sarah1
  • Beard, Brian C2
  • Schwartz, Jonathan D2
  • Adair, Jennifer E1, 3
  • Kiem, Hans-Peter1, 3, 4
  • 1 Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • 2 Rocket Pharmaceuticals Ltd, New York City, NY, USA.
  • 3 Department of Medicine, University of Washington, Seattle, WA, USA.
  • 4 Department of Pathology, University of Washington, Seattle, WA, USA.
Type
Published Article
Journal
The Journal of Gene Medicine
Publisher
Wiley (John Wiley & Sons)
Publication Date
Oct 01, 2018
Volume
20
Issue
10-11
Identifiers
DOI: 10.1002/jgm.3050
PMID: 30129972
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Gene therapy approaches for the treatment of Fanconi anemia (FA) hold promise for patients without a suitably matched donor for an allogeneic bone marrow transplant. However, significant limitations include the collection of sufficient stem cell numbers from patients, the fragility of these cells during ex vivo manipulation, and clinically meaningful engraftment following transplantation. With these challenges in mind, we were interested in determining (i) whether gene-corrected cells at progressively lower numbers can successfully engraft in FA; (ii) whether low-dose conditioning facilitates this engraftment; and (iii) whether these cells can be selected for post-transplant. Utilizing a well characterized mouse model of FA, we infused donor bone marrow from healthy heterozygote littermates that are unaffected carriers of the FANCA mutation to mimic a gene-corrected product, after administering low-dose conditioning. Once baseline engraftment was observed, we administered a second, very-low selective dose to determine whether gene-corrected cells could be selected for in vivo. We demonstrate that upfront low-dose conditioning greatly increases successful engraftment of hematopoietic corrected cells in a pre-clinical animal model of FA. Additionally, without conditioning, cells can still engraft and demonstrate a selective advantage in vivo over time following transplantation, and these corrected cells can be directly selected for in vivo after engraftment. Minimal conditioning prior to bone marrow transplant in Fanconi anemia promotes the multi-lineage engraftment of 10-fold fewer cells compared to nonconditioned controls. These data provide important insights into the potential of minimally toxic conditioning protocols for FA gene therapy applications. © 2018 John Wiley & Sons, Ltd.

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