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Sci Transl Med. 2019 Jul 31;11(503). pii: eaaw3768. doi: 10.1126/scitranslmed.aaw3768.

Therapeutically relevant engraftment of a CRISPR-Cas9-edited HSC-enriched population with HbF reactivation in nonhuman primates.

Author information

1
Stem Cell and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
2
Seattle Children's Research Institute, Seattle, WA 98101, USA.
3
Bluebird Bio Inc., Cambridge, MA 02142, USA.
4
Department of Bioengineering, Rice University, Houston, TX 77251, USA.
5
Alimentary Pharmabiotic Centre Microbiome Ireland, University College Cork, Cork T12 K8AF, Ireland.
6
Department of Medicine, University of Washington, Seattle, WA 98195, USA.
7
Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
8
Department of Immunology, University of Washington, Seattle, WA 98195, USA.
9
Casebia Therapeutics, Cambridge, MA 02139, USA.
10
Stem Cell and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. hkiem@fredhutch.org.

Abstract

Reactivation of fetal hemoglobin (HbF) is being pursued as a treatment strategy for hemoglobinopathies. Here, we evaluated the therapeutic potential of hematopoietic stem and progenitor cells (HSPCs) edited with the CRISPR-Cas9 nuclease platform to recapitulate naturally occurring mutations identified in individuals who express increased amounts of HbF, a condition known as hereditary persistence of HbF. CRISPR-Cas9 treatment and transplantation of HSPCs purified on the basis of surface expression of the CD34 receptor in a nonhuman primate (NHP) autologous transplantation model resulted in up to 30% engraftment of gene-edited cells for >1 year. Edited cells effectively and stably reactivated HbF, as evidenced by up to 18% HbF-expressing erythrocytes in peripheral blood. Similar results were obtained by editing highly enriched stem cells, defined by the markers CD34+CD90+CD45RA-, allowing for a 10-fold reduction in the number of transplanted target cells, thus considerably reducing the need for editing reagents. The frequency of engrafted, gene-edited cells persisting in vivo using this approach may be sufficient to ameliorate the phenotype for a number of genetic diseases.

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