115. Correction of the Sickle-Cell Disease Mutation in Human Hematopoietic Stem/Progenitor Cells
Year: 2015
Type: article
Abstract: Sickle-cell disease (SCD) is characterized by a single point mutation in the seventh codon of the beta-globin gene. Site-specific correction of the sickle mutation in hematopoietic stem cells (HSCs) would allow for permanent production of normal red blood cells. Using zinc-finger nucleases (ZFNs) designed to flank the sickle mutation, we demonstrated efficient targeted cleavage at the beta-globin locus with minimal off-target modification. By co-delivering a homologous donor template (either an integrase-defective lentiviral vector [IDLV] or a DNA oligonucleotide), high levels of gene modification were achieved in CD34+ hematopoietic stem and progenitor cells (HSPCs). Modified cells maintained their ability to engraft NOD/SCID/IL2rgnull (NSG) mice and to produce cells from multiple lineages. Importantly, ZFN-driven gene correction in CD34+ cells from the bone marrow of sickle patients resulted in the production of wild-type hemoglobin tetramers.
Source: Molecular Therapy
Authors: Megan D. Hoban, Matthew C. Mendel, Zulema Romero, Michael L. Kaufman, Alok V. Joglekar, Michelle Ho, Dianne Lumaquin, David Gray, Georgia R. Lill, Aaron R. Cooper, Fabrizia Urbinati, Shantha Senadheera, Allen Zhu, Pei-Qi Liu, David E. Paschon, Lei Zhang, Edward J. Rebar, Andrew Wilber, Xiaoyan Wang, Philip D. Gregory, Michael C. Holmes, Andreas Reik, Roger P. Hollis, Donald B. Kohn, Gregory J. Cost
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
OpenAlex ID: W2567510243