Multiplex CRISPR/Cas9 genome editing in hematopoietic stem cells for fetal hemoglobin reinduction generates chromosomal translocations.

Autor:	Samuelson C; Stem Cell and Gene Therapy Program, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA., Radtke S; Stem Cell and Gene Therapy Program, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA., Zhu H; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA., Llewellyn M; Stem Cell and Gene Therapy Program, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA., Fields E; Stem Cell and Gene Therapy Program, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA., Cook S; Stem Cell and Gene Therapy Program, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA., Huang MW; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA., Jerome KR; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA.; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle WA 98109-1024, USA., Kiem HP; Stem Cell and Gene Therapy Program, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA.; Department of Medicine, University of Washington, Seattle, WA 98195, USA., Humbert O; Stem Cell and Gene Therapy Program, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Methods & clinical development [Mol Ther Methods Clin Dev] 2021 Oct 28; Vol. 23, pp. 507-523. Date of Electronic Publication: 2021 Oct 28 (Print Publication: 2021).
DOI:	10.1016/j.omtm.2021.10.008
Abstrakt:	Sickle cell disease and β-thalassemia are common monogenic disorders that cause significant morbidity and mortality globally. The only curative treatment currently is allogeneic hematopoietic stem cell transplantation, which is unavailable to many patients due to a lack of matched donors and carries risks including graft-versus-host disease. Genome editing therapies targeting either the BCL11A erythroid enhancer or the HBG promoter are already demonstrating success in reinducing fetal hemoglobin. However, where a single locus is targeted, reliably achieving levels high enough to deliver an effective cure remains a challenge. We investigated the application of a CRISPR/Cas9 multiplex genome editing approach, in which both the BCL11A erythroid enhancer and HBG promoter are disrupted within human hematopoietic stem cells. We demonstrate superior fetal hemoglobin reinduction with this dual-editing approach without compromising engraftment or lineage differentiation potential of edited cells post-xenotransplantation. However, multiplex editing consistently resulted in the generation of chromosomal rearrangement events that persisted in vivo following transplantation into immunodeficient mice. The risk of oncogenic events resulting from such translocations therefore currently prohibits its clinical translation, but it is anticipated that, in the future, alternative editing platforms will help alleviate this risk. Competing Interests: H.P.K. has received support as the inaugural recipient of the José Carreras/E. Donnall Thomas Endowed Chair for Cancer Research and the Stephanus Family Endowed Chair for Cell and Gene Therapy. H.P.K is or was a consultant to and has or had ownership interests with Rocket Pharmaceuticals, Homology Medicines, VOR Biopharma, and Ensoma. H.P.K has also been a consultant to CSL and Magenta. Other authors have no competing interests. (© 2021 The Authors.)
Databáze:	MEDLINE
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