Correction of the sickle cell disease mutation in human hematopoietic stem/progenitor cells.
| Publication Type | Academic Article |
| Authors | Hoban M, Cost G, Mendel M, Romero Z, Kaufman M, Joglekar A, Ho M, Lumaquin D, Gray D, Lill G, Cooper A, Urbinati F, Senadheera S, Zhu A, Liu P, Paschon D, Zhang L, Rebar E, Wilber A, Wang X, Gregory P, Holmes M, Reik A, Hollis R, Kohn D |
| Journal | Blood |
| Volume | 125 |
| Issue | 17 |
| Pagination | 2597-604 |
| Date Published | 03/02/2015 |
| ISSN | 1528-0020 |
| Keywords | Anemia, Sickle Cell, Genetic Therapy, Hematopoietic Stem Cells, Mutation, beta-Globins |
| Abstract | Sickle cell disease (SCD) is characterized by a single point mutation in the seventh codon of the β-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 β-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. |
| DOI | 10.1182/blood-2014-12-615948 |
| PubMed ID | 25733580 |
| PubMed Central ID | PMC4408287 |