Therapeutically relevant engraftment of a CRISPR-Cas9-edited HSC-enriched population with HbF reactivation in nonhuman primates
| Autor: | Olivier Negre, Christopher W. Peterson, Christopher T. Lux, Sowmya Reddy, Ray R. Carrillo, Clare Samuelson, Anai M. Perez, Sowmya Pattabhi, Stefan Radtke, Ciaran M. Lee, David J. Rawlings, Jennifer E. Adair, Gang Bao, Lauren E Schefter, Olivier Humbert, Hans-Peter Kiem, Andrew M. Scharenberg |
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| Rok vydání: | 2018 |
| Předmět: |
Primates
Genotype medicine.medical_treatment Population Antigens CD34 Hematopoietic stem cell transplantation Biology Article medicine Autologous transplantation Animals Humans CD90 Progenitor cell education Fetal Hemoglobin Gene Editing education.field_of_study Hematopoietic Stem Cell Transplantation General Medicine Hematopoietic Stem Cells Macaca mulatta Transplantation Haematopoiesis Cancer research Thy-1 Antigens Stem cell CRISPR-Cas Systems |
| Zdroj: | Sci Transl Med |
| ISSN: | 1946-6242 |
| Popis: | 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 circumventing issues associated with scale-up and 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. |
| Databáze: | OpenAIRE |
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