Correction of the sickle cell disease mutation in human hematopoietic stem/progenitor cells.
Blood
; 125(17): 2597-604, 2015 Apr 23.
Article
en En
| MEDLINE
| ID: mdl-25733580
ABSTRACT
Sickle cell disease (SCD) is characterized by a single point mutation in the seventh codon of the ß-globin gene. Site-specific correction of the sickle mutation in hematopoietic stem cells would allow for permanent production of normal red blood cells. Using zinc-finger nucleases (ZFNs) designed to flank the sickle mutation, we demonstrate efficient targeted cleavage at the ß-globin locus with minimal off-target modification. By co-delivering a homologous donor template (either an integrase-defective lentiviral vector or a DNA oligonucleotide), high levels of gene modification were achieved in CD34(+) hematopoietic stem and progenitor cells. Modified cells maintained their ability to engraft NOD/SCID/IL2rγ(null) mice and to produce cells from multiple lineages, although with a reduction in the modification levels relative to the in vitro samples. Importantly, ZFN-driven gene correction in CD34(+) cells from the bone marrow of patients with SCD resulted in the production of wild-type hemoglobin tetramers.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Células Madre Hematopoyéticas
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Terapia Genética
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Globinas beta
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Anemia de Células Falciformes
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Mutación
Límite:
Animals
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Humans
Idioma:
En
Revista:
Blood
Año:
2015
Tipo del documento:
Article