Abstract

We recently corrected sickle cell disease in our knockin mouse model by reprogramming skin fibroblasts into iPS (induced Pluripotent Stem) cells, replacing the defective sickle beta-globin gene with a normal beta-globin gene, differentiating the corrected iPS cells into hematopoietic progenitors and transplanting these cells into irradiated sickle mouse recipients. The goal of the present proposal is to translate these results to human cells.
The specific aims are (1) to produce human iPS cells from skin biopsy samples of patients with sickle cell disease (2) to correct the sickle mutation in iPS cells derived from patients and (3) to differentiate corrected iPS cells into transplantable hematopoietic stem cells that produce normal erythroid cells.

Public Health Relevance

We recently corrected sickle cell disease in our knockin mouse model by reprogramming skin fibroblasts into iPS (induced Pluripotent Stem) cells, replacing the defective sickle beta-globin gene with a normal beta-globin gene, differentiating the corrected iPS cells into hematopoietic progenitors and transplanting these cells into irradiated sickle mouse recipients. The goal of the present proposal is to translate these results to human cells. These studies will provide a foundation for future clinical trials in humans.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL057619-15
Application #
8206618
Study Section
Erythrocyte and Leukocyte Biology Study Section (ELB)
Program Officer
Qasba, Pankaj
Project Start
1996-09-30
Project End
2014-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
15
Fiscal Year
2012
Total Cost
$431,044
Indirect Cost
$136,816

  Institution

Name
University of Alabama Birmingham
Department
Biochemistry
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294

  Publications

Sun, Chiao-Wang; Wu, Li-Chen; Knopick, Peter L et al. (2017) Sickle cells produce functional immune modulators and cytotoxics. Am J Hematol 92:981-988
Chang, Chia-Wei; Lai, Yi-Shin; Lamb Jr, Lawrence S et al. (2014) Broad T-cell receptor repertoire in T-lymphocytes derived from human induced pluripotent stem cells. PLoS One 9:e97335
Young, Margaret A; Larson, David E; Sun, Chiao-Wang et al. (2012) Background mutations in parental cells account for most of the genetic heterogeneity of induced pluripotent stem cells. Cell Stem Cell 10:570-82
Zhang, Zhuo; Jones, Amanda; Sun, Chiao-Wang et al. (2011) PRC2 complexes with JARID2, MTF2, and esPRC2p48 in ES cells to modulate ES cell pluripotency and somatic cell reprogramming. Stem Cells 29:229-40
Isbell, T Scott; Sun, Chiao-Wang; Wu, Li-Chen et al. (2008) SNO-hemoglobin is not essential for red blood cell-dependent hypoxic vasodilation. Nat Med 14:773-7
Hanna, Jacob; Wernig, Marius; Markoulaki, Styliani et al. (2007) Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science 318:1920-3
Levasseur, Dana N; Ryan, Thomas M; Reilly, Michael P et al. (2004) A recombinant human hemoglobin with anti-sickling properties greater than fetal hemoglobin. J Biol Chem 279:27518-24
Levasseur, Dana N; Ryan, Thomas M; Pawlik, Kevin M et al. (2003) Correction of a mouse model of sickle cell disease: lentiviral/antisickling beta-globin gene transduction of unmobilized, purified hematopoietic stem cells. Blood 102:4312-9
Chen, W; Wu, X; Levasseur, D N et al. (2000) Lentiviral vector transduction of hematopoietic stem cells that mediate long-term reconstitution of lethally irradiated mice. Stem Cells 18:352-9