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CRISPR/Cas9 β-globin gene targeting in human haematopoietic stem cells
Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review
DOI
- https://doi.org/10.1038/nature20134
Forlagets udgivne version
- Daniel P Dever, Stanford University ,
- Rasmus O Bak
- Andreas Reinisch, Stanford University ,
- Joab Camarena, Stanford University ,
- Gabriel Washington, Stanford University ,
- Carmencita E Nicolas, Stanford University ,
- Mara Pavel-Dinu, Stanford University ,
- Nivi Saxena, Stanford University ,
- Alec B Wilkens, Stanford University ,
- Sruthi Mantri, Stanford University ,
- Nobuko Uchida, Stem Cells, Inc. 7707 Gateway Blvd., Suite 140, Newark, California 94560, USA. ,
- Ayal Hendel, Stanford University ,
- Anupama Narla, Stanford University ,
- Ravindra Majeti, Stanford University ,
- Kenneth I Weinberg, Stanford University ,
- Matthew H Porteus, Stanford University
The β-haemoglobinopathies, such as sickle cell disease and β-thalassaemia, are caused by mutations in the β-globin (HBB) gene and affect millions of people worldwide. Ex vivo gene correction in patient-derived haematopoietic stem cells followed by autologous transplantation could be used to cure β-haemoglobinopathies. Here we present a CRISPR/Cas9 gene-editing system that combines Cas9 ribonucleoproteins and adeno-associated viral vector delivery of a homologous donor to achieve homologous recombination at the HBB gene in haematopoietic stem cells. Notably, we devise an enrichment model to purify a population of haematopoietic stem and progenitor cells with more than 90% targeted integration. We also show efficient correction of the Glu6Val mutation responsible for sickle cell disease by using patient-derived stem and progenitor cells that, after differentiation into erythrocytes, express adult β-globin (HbA) messenger RNA, which confirms intact transcriptional regulation of edited HBB alleles. Collectively, these preclinical studies outline a CRISPR-based methodology for targeting haematopoietic stem cells by homologous recombination at the HBB locus to advance the development of next-generation therapies for β-haemoglobinopathies.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Nature |
| Vol/bind | 539 |
| Nummer | 7629 |
| Sider (fra-til) | 384-389 |
| Antal sider | 6 |
| ISSN | 0028-0836 |
| DOI | |
| Status | Udgivet - 17 nov. 2016 |
| Eksternt udgivet | Ja |
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