Correction of the sickle cell disease mutation in human hematopoietic stem/progenitor cells.
نویسندگان
چکیده
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.
منابع مشابه
Specification of Hemato-Endothelial-Like Structures and Generation of Hematopoietic Progenitor Cells from Human Pluripotent Stem Cells
Background and purpose: Human pluripotent stem cells (hPSCs) with the ability to differentiate into adult cells have provided a new perspective for treatment of some diseases. But, the efficiency of differentiation methods to generate hematopoietic progenitor cells (HPCs) is faced with multiple challenges. In the present study, we investigated the formation of hemato-endothelial-like structure...
متن کاملA review of Biology and clinical use of Mesenchymal stem cell: an immune -modulator progenitor cell
Human mesenchymal stem cells (hMSCs), which also called mesenchymal stromal cells, are multipotent stem cell. Human MSCs typically are positive for the surface markers CD44, CD73, CD90, CD105, CD106, and also negative for hematopoietic markers CD34 and CD45.These cells can be isolated from postnatal bone marrow, adipose tissue, placenta, and scalp tissue, as well as from various fetal tissues. ...
متن کاملبررسی اثر آگونیست -آدرنرژیکی ایزوپروترنول بر بیان miR-886-3p و miR-23a در سلولهای بنیادی مزانشیمی مغز استخوان انسان
Background and Objective: Mobilization of Hematopoietic Stem Cells (HSCs) for transplantation and the importance of -adrenergic signals in induction of this process have been well investigated. However, little is known about the role of -adrenergic signals in mobilization of HSCs and factors influenced by these signals. The Chemokine Stromal Derived Factor -1 (SDF-1) which is expressed by hum...
متن کاملExpansion of Non-Enriched Cord Blood Stem/Progenitor Cells CD34+ CD38- Using Liver Cells
Many investigators have used xenogeneic, especially murine stromal cells and fetal calf serum to maintain and expand human stem cells. The proliferation and expansion of human hematopoietic stem cells in ex vivo culture were examined with the goal of generating a suitable protocol for expanding hematopoietic stem cells for patient transplantation. Using primary fetal liver cells, we established...
متن کاملHematopoietic stem cell transplant therapy, clinical trials, complications, and quality of life for patients with Sickle cell anemia: Clinical potential and future perspectives
Background: Sickle cell anemia (SCA) is an inherited monogenic disorder. The clinical symptoms of SCA are protean, including vaso-occlusion, hemolysis, early stroke, leg ulcers, multi-organ failure, and increased risk of premature death. Hematopoietic stem cell transplantation is the only treatment identified to reduce SCA-related organ damage. Unfortunately, graft rejection is a significant im...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Blood
دوره 125 17 شماره
صفحات -
تاریخ انتشار 2015