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Article ; Online: Preclinical studies for a phase 1 clinical trial of autologous hematopoietic stem cell gene therapy for sickle cell disease.

Urbinati, Fabrizia / Wherley, Jennifer / Geiger, Sabine / Fernandez, Beatriz Campo / Kaufman, Michael L / Cooper, Aaron / Romero, Zulema / Marchioni, Filippo / Reeves, Lilith / Read, Elizabeth / Nowicki, Barbara / Grassman, Elke / Viswanathan, Shivkumar / Wang, Xiaoyan / Hollis, Roger P / Kohn, Donald B

Cytotherapy

2017 Volume 19, Issue 9, Page(s) 1096–1112

Abstract: Background aims: Gene therapy by autologous hematopoietic stem cell transplantation (HSCT) represents a new approach to treat sickle cell disease (SCD). Optimization of the manufacture, characterization and testing of the transduced hematopoietic stem ... ...

Abstract	Background aims: Gene therapy by autologous hematopoietic stem cell transplantation (HSCT) represents a new approach to treat sickle cell disease (SCD). Optimization of the manufacture, characterization and testing of the transduced hematopoietic stem cell final cell product (FCP), as well as an in depth in vivo toxicology study, are critical for advancing this approach to clinical trials. Methods: Data are shown to evaluate and establish the feasibility of isolating, transducing with the Lenti/β Results: Primary and secondary transplantation did not reveal any toxicity from the lentiviral vector. Additionally, vector integration site analysis of murine and human BM cells did not show any clonal skewing caused by insertion of the Lenti/β Conclusions: We present here a complete protocol, thoroughly optimized to manufacture, characterize and establish safety of a FCP for gene therapy of SCD.
Language	English
Publishing date	2017-09
Publishing country	England
Document type	Journal Article
ZDB-ID	2039821-9
ISSN	1477-2566 ; 1465-3249
ISSN (online)	1477-2566
ISSN	1465-3249
DOI	10.1016/j.jcyt.2017.06.002
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Article ; Online: Potentially therapeutic levels of anti-sickling globin gene expression following lentivirus-mediated gene transfer in sickle cell disease bone marrow CD34+ cells.

Urbinati, Fabrizia / Hargrove, Phillip W / Geiger, Sabine / Romero, Zulema / Wherley, Jennifer / Kaufman, Michael L / Hollis, Roger P / Chambers, Christopher B / Persons, Derek A / Kohn, Donald B / Wilber, Andrew

Experimental hematology

2015 Volume 43, Issue 5, Page(s) 346–351

Abstract: Sickle cell disease (SCD) can be cured by allogeneic hematopoietic stem cell transplant. However, this is only possible when a matched donor is available, making the development of gene therapy using autologous hematopoietic stem cells a highly desirable ...

Abstract	Sickle cell disease (SCD) can be cured by allogeneic hematopoietic stem cell transplant. However, this is only possible when a matched donor is available, making the development of gene therapy using autologous hematopoietic stem cells a highly desirable alternative. We used a culture model of human erythropoiesis to directly compare two insulated, self-inactivating, and erythroid-specific lentiviral vectors, encoding for γ-globin (V5m3-400) or a modified β-globin (βAS3-FB) for production of antisickling hemoglobin (Hb) and correction of red cell deformability after deoxygenation. Bone marrow CD34+ cells from three SCD patients were transduced using V5m3-400 or βAS3-FB and compared with mock-transduced SCD or healthy donor CD34+ cells. Lentiviral transduction did not impair cell growth or differentiation, as gauged by proliferation and acquisition of erythroid markers. Vector copy number averaged approximately one copy per cell, and corrective globin mRNA levels were increased more than sevenfold over mock-transduced controls. Erythroblasts derived from healthy donor and mock-transduced SCD cells produced a low level of fetal Hb that was increased to 23.6 ± 4.1% per vector copy for cells transduced with V5m3-400. Equivalent levels of modified normal adult Hb of 17.6 ± 3.8% per vector copy were detected for SCD cells transduced with βAS3-FB. These levels of antisickling Hb production were sufficient to reduce sickling of terminal-stage red blood cells upon deoxygenation. We concluded that the achieved levels of fetal Hb and modified normal adult Hb would likely prove therapeutic to SCD patients who lack matched donors.
MeSH term(s)	Anemia, Sickle Cell/genetics ; Anemia, Sickle Cell/therapy ; Antigens, CD34/metabolism ; Bone Marrow Cells/metabolism ; Fetal Hemoglobin/genetics ; Flow Cytometry ; Gene Expression ; Gene Transfer Techniques ; Genetic Therapy/methods ; Genetic Vectors/genetics ; Hemoglobins/genetics ; Humans ; Lentivirus/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; beta-Globins/genetics ; beta-Globins/metabolism ; gamma-Globins/genetics ; gamma-Globins/metabolism
Chemical Substances	Antigens, CD34 ; Hemoglobins ; beta-Globins ; gamma-Globins ; Fetal Hemoglobin (9034-63-3)
Language	English
Publishing date	2015-02-12
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	185107-x
ISSN	1873-2399 ; 0531-5573 ; 0301-472X
ISSN (online)	1873-2399
ISSN	0531-5573 ; 0301-472X
DOI	10.1016/j.exphem.2015.01.009
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Article: The human ankyrin 1 promoter insulator sustains gene expression in a β-globin lentiviral vector in hematopoietic stem cells.

Romero, Zulema / Campo-Fernandez, Beatriz / Wherley, Jennifer / Kaufman, Michael L / Urbinati, Fabrizia / Cooper, Aaron R / Hoban, Megan D / Baldwin, Kismet M / Lumaquin, Dianne / Wang, Xiaoyan / Senadheera, Shantha / Hollis, Roger P / Kohn, Donald B

Molecular therapy. Methods & clinical development

2015 Volume 2, Page(s) 15012

Abstract: Lentiviral vectors designed for the treatment of the hemoglobinopathies require the inclusion of regulatory and strong enhancer elements to achieve sufficient expression of the β-globin transgene. Despite the inclusion of these elements, the efficacy of ... ...

Abstract	Lentiviral vectors designed for the treatment of the hemoglobinopathies require the inclusion of regulatory and strong enhancer elements to achieve sufficient expression of the β-globin transgene. Despite the inclusion of these elements, the efficacy of these vectors may be limited by transgene silencing due to the genomic environment surrounding the integration site. Barrier insulators can be used to give more consistent expression and resist silencing even with lower vector copies. Here, the barrier activity of an insulator element from the human ankyrin-1 gene was analyzed in a lentiviral vector carrying an antisickling human β-globin gene. Inclusion of a single copy of the Ankyrin insulator did not affect viral titer, and improved the consistency of expression from the vector in murine erythroleukemia cells. The presence of the Ankyrin insulator element did not change transgene expression in human hematopoietic cells in short-term erythroid culture or in vivo in primary murine transplants. However, analysis in secondary recipients showed that the lentiviral vector with the Ankyrin element preserved transgene expression, whereas expression from the vector lacking the Ankyrin insulator decreased in secondary recipients. These studies demonstrate that the Ankyrin insulator may improve long-term β-globin expression in hematopoietic stem cells for gene therapy of hemoglobinopathies.
Language	English
Publishing date	2015-04-22
Publishing country	United States
Document type	Journal Article
ZDB-ID	2872938-9
ISSN	2329-0501 ; 2329-0501
ISSN (online)	2329-0501
ISSN	2329-0501
DOI	10.1038/mtm.2015.12
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Article ; Online: Abnormal microRNA expression in Ts65Dn hippocampus and whole blood: contributions to Down syndrome phenotypes.

Keck-Wherley, Jennifer / Grover, Deepak / Bhattacharyya, Sharmistha / Xu, Xiufen / Holman, Derek / Lombardini, Eric D / Verma, Ranjana / Biswas, Roopa / Galdzicki, Zygmunt

Developmental neuroscience

2011 Volume 33, Issue 5, Page(s) 451–467

Abstract: Down syndrome (DS; trisomy 21) is one of the most common genetic causes of intellectual disability, which is attributed to triplication of genes located on chromosome 21. Elevated levels of several microRNAs (miRNAs) located on chromosome 21 have been ... ...

Abstract	Down syndrome (DS; trisomy 21) is one of the most common genetic causes of intellectual disability, which is attributed to triplication of genes located on chromosome 21. Elevated levels of several microRNAs (miRNAs) located on chromosome 21 have been reported in human DS heart and brain tissues. The Ts65Dn mouse model is the most investigated DS model with a triplicated segment of mouse chromosome 16 harboring genes orthologous to those on human chromosome 21. Using ABI TaqMan miRNA arrays, we found a set of miRNAs that were significantly up- or downregulated in the Ts65Dn hippocampus compared to euploid controls. Furthermore, miR-155 and miR-802 showed significant overexpression in the Ts65Dn hippocampus, thereby confirming results of previous studies. Interestingly, miR-155 and miR-802 were also overexpressed in the Ts65Dn whole blood but not in lung tissue. We also found overexpression of the miR-155 precursors, pri- and pre-miR-155 derived from the miR-155 host gene, known as B cell integration cluster, suggesting enhanced biogenesis of miR-155. Bioinformatic analysis revealed that neurodevelopment, differentiation of neuroglia, apoptosis, cell cycle, and signaling pathways including ERK/MAPK, protein kinase C, phosphatidylinositol 3-kinase, m-TOR and calcium signaling are likely targets of these miRNAs. We selected some of these potential gene targets and found downregulation of mRNA encoding Ship1, Mecp2 and Ezh2 in Ts65Dn hippocampus. Interestingly, the miR-155 target gene Ship1 (inositol phosphatase) was also downregulated in Ts65Dn whole blood but not in lung tissue. Our findings provide insights into miRNA-mediated gene regulation in Ts65Dn mice and their potential contribution to impaired hippocampal synaptic plasticity and neurogenesis, as well as hemopoietic abnormalities observed in DS.
MeSH term(s)	Animals ; Disease Models, Animal ; Down Syndrome/genetics ; Down Syndrome/metabolism ; Gene Expression Profiling ; Hippocampus/physiology ; Humans ; Mice ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Parietal Lobe/physiology ; Phenotype ; Trisomy
Chemical Substances	MicroRNAs
Language	English
Publishing date	2011-10-27
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	556887-0
ISSN	1421-9859 ; 0378-5866
ISSN (online)	1421-9859
ISSN	0378-5866
DOI	10.1159/000330884
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Article ; Online: Modification of hematopoietic stem/progenitor cells with CD19-specific chimeric antigen receptors as a novel approach for cancer immunotherapy.

De Oliveira, Satiro Nakamura / Ryan, Christine / Giannoni, Francesca / Hardee, Cinnamon L / Tremcinska, Irena / Katebian, Behrod / Wherley, Jennifer / Sahaghian, Arineh / Tu, Andy / Grogan, Tristan / Elashoff, David / Cooper, Laurence J N / Hollis, Roger P / Kohn, Donald B

Human gene therapy

2013 Volume 24, Issue 10, Page(s) 824–839

Abstract: Chimeric antigen receptors (CARs) against CD19 have been shown to direct T-cells to specifically target B-lineage malignant cells in animal models and clinical trials, with efficient tumor cell lysis. However, in some cases, there has been insufficient ... ...

Abstract	Chimeric antigen receptors (CARs) against CD19 have been shown to direct T-cells to specifically target B-lineage malignant cells in animal models and clinical trials, with efficient tumor cell lysis. However, in some cases, there has been insufficient persistence of effector cells, limiting clinical efficacy. We propose gene transfer to hematopoietic stem/progenitor cells (HSPC) as a novel approach to deliver the CD19-specific CAR, with potential for ensuring persistent production of effector cells of multiple lineages targeting B-lineage malignant cells. Assessments were performed using in vitro myeloid or natural killer (NK) cell differentiation of human HSPCs transduced with lentiviral vectors carrying first and second generations of CD19-specific CAR. Gene transfer did not impair hematopoietic differentiation and cell proliferation when transduced at 1-2 copies/cell. CAR-bearing myeloid and NK cells specifically lysed CD19-positive cells, with second-generation CAR including CD28 domains being more efficient in NK cells. Our results provide evidence for the feasibility and efficacy of the modification of HSPC with CAR as a strategy for generating multiple lineages of effector cells for immunotherapy against B-lineage malignancies to augment graft-versus-leukemia activity.
MeSH term(s)	Animals ; Antigens, CD19/immunology ; Cell Differentiation ; Cell Line ; Cytotoxicity, Immunologic ; Disease Models, Animal ; Flow Cytometry ; Gene Order ; Genetic Vectors/genetics ; Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells/cytology ; Hematopoietic Stem Cells/immunology ; Hematopoietic Stem Cells/metabolism ; Humans ; Immunotherapy ; Killer Cells, Natural/cytology ; Killer Cells, Natural/immunology ; Killer Cells, Natural/metabolism ; Lentivirus/genetics ; Lymphocyte Activation/genetics ; Lymphocyte Activation/immunology ; Mice, Transgenic ; Myeloid Cells/cytology ; Myeloid Cells/immunology ; Myeloid Cells/metabolism ; Neoplasms/genetics ; Neoplasms/immunology ; Neoplasms/therapy ; Receptors, Antigen/genetics ; Receptors, Antigen/immunology ; T-Lymphocytes/cytology ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; Transduction, Genetic
Chemical Substances	Antigens, CD19 ; Receptors, Antigen
Language	English
Publishing date	2013-08-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1028152-6
ISSN	1557-7422 ; 1043-0342
ISSN (online)	1557-7422
ISSN	1043-0342
DOI	10.1089/hum.2012.202
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Article ; Online: Nonmyeloablative conditioning regimen to increase engraftment of gene-modified hematopoietic stem cells in young rhesus monkeys.

Tarantal, Alice F / Giannoni, Francesca / Lee, C Chang I / Wherley, Jennifer / Sumiyoshi, Teiko / Martinez, Michele / Kahl, Christoph A / Elashoff, David / Louie, Stan G / Kohn, Donald B

Molecular therapy : the journal of the American Society of Gene Therapy

2012 Volume 20, Issue 5, Page(s) 1033–1045

Abstract: Immune responses to transgene products may lead to rejection of transduced cells, limiting successful gene therapy for genetic diseases. While moderate dosages of chemotherapeutic agents such as busulfan may increase hematopoietic stem cells (HSC) ... ...

Abstract	Immune responses to transgene products may lead to rejection of transduced cells, limiting successful gene therapy for genetic diseases. While moderate dosages of chemotherapeutic agents such as busulfan may increase hematopoietic stem cells (HSC) engraftment, they are not immune suppressive and do not abrogate immune responses to transgene products. Studies focused on nonmyeloablative conditioning with busulfan ± fludarabine in a clinically relevant monkey model to induce immune suppression to allow cells expressing a foreign transgene product to persist. Bone marrow CD34(+) HSC were transduced in two equal fractions using simian immunodeficiency virus (SIV)-based lentiviral vectors carrying a nonexpressed DNA sequence tag (NoN) and the green fluorescent protein (GFP) reporter gene. Post-transplant there was no evidence of elimination of cells containing the potentially immunogenic GFP gene; several recipients had stable persistence of cells, and no differences were detected with fludarabine, which was rapidly cleared. Antibodies and cellular immune responses to GFP developed in recipients with the highest levels of GFP-marked cells, although these cells were not eliminated. These studies establish a clinically relevant pediatric primate model to assess the effects of conditioning regimens on the engraftment of transduced HSC and the immune responses to cells expressing a foreign gene product.
MeSH term(s)	Animals ; Animals, Newborn ; Busulfan/administration & dosage ; Genes, Reporter ; Genetic Vectors ; Graft Survival/drug effects ; Graft Survival/immunology ; Green Fluorescent Proteins ; Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells/immunology ; Immune Tolerance ; Immunosuppressive Agents/administration & dosage ; Lentivirus/genetics ; Macaca mulatta ; Simian Immunodeficiency Virus/genetics ; Transduction, Genetic ; Transgenes ; Transplantation Conditioning/methods ; Vidarabine/administration & dosage ; Vidarabine/analogs & derivatives
Chemical Substances	Immunosuppressive Agents ; Green Fluorescent Proteins (147336-22-9) ; Vidarabine (FA2DM6879K) ; Busulfan (G1LN9045DK) ; fludarabine (P2K93U8740)
Language	English
Publishing date	2012-01-31
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2010592-7
ISSN	1525-0024 ; 1525-0016
ISSN (online)	1525-0024
ISSN	1525-0016
DOI	10.1038/mt.2011.312
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Article: Abnormal MicroRNA Expression in Ts65Dn Hippocampus and Whole Blood: Contributions to Down Syndrome Phenotypes

Keck-Wherley, Jennifer / Grover, Deepak / Bhattacharyya, Sharmistha / Xu, Xiufen / Holman, Derek / Lombardini, Eric D. / Verma, Ranjana / Biswas, Roopa / Galdzicki, Zygmunt

Developmental Neuroscience

2011 Volume 33, Issue 5, Page(s) 451–467

Institution	Departments of Pediatrics and Anatomy, Physiology and Genetics, School of Medicine Graduate School of Nursing, and Comparative Pathology Division, Veterinary Sciences Department, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Md., USA
Abstract	Down syndrome (DS; trisomy 21) is one of the most common genetic causes of intellectual disability, which is attributed to triplication of genes located on chromosome 21. Elevated levels of several microRNAs (miRNAs) located on chromosome 21 have been reported in human DS heart and brain tissues. The Ts65Dn mouse model is the most investigated DS model with a triplicated segment of mouse chromosome 16 harboring genes orthologous to those on human chromosome 21. Using ABI TaqMan miRNA arrays, we found a set of miRNAs that were significantly up- or downregulated in the Ts65Dn hippocampus compared to euploid controls. Furthermore, miR-155 and miR-802 showed significant overexpression in the Ts65Dn hippocampus, thereby confirming results of previous studies. Interestingly, miR-155 and miR-802 were also overexpressed in the Ts65Dn whole blood but not in lung tissue. We also found overexpression of the miR-155 precursors, pri- and pre-miR-155 derived from the miR-155 host gene, known as B cell integration cluster, suggesting enhanced biogenesis of miR-155. Bioinformatic analysis revealed that neurodevelopment, differentiation of neuroglia, apoptosis, cell cycle, and signaling pathways including ERK/MAPK, protein kinase C, phosphatidylinositol 3-kinase, m-TOR and calcium signaling are likely targets of these miRNAs. We selected some of these potential gene targets and found downregulation of mRNA encoding Ship1, Mecp2 and Ezh2 in Ts65Dn hippocampus. Interestingly, the miR-155 target gene Ship1 (inositol phosphatase) was also downregulated in Ts65Dn whole blood but not in lung tissue. Our findings provide insights into miRNA-mediated gene regulation in Ts65Dn mice and their potential contribution to impaired hippocampal synaptic plasticity and neurogenesis, as well as hemopoietic abnormalities observed in DS.
Keywords	miR-155 ; miR-802 ; miR-214 ; miR-223 ; Ship1 ; Ezh2 ; Mecp2 ; Blood ; Lung ; Creb1
Language	English
Publishing date	2011-10-27
Publisher	S. Karger AG
Publishing place	Basel, Switzerland
Document type	Article
Note	Down Syndrome/Original Paper
ZDB-ID	556887-0
ISBN	978-3-8055-9886-6 ; 978-3-8055-9887-3 ; 3-8055-9886-6 ; 3-8055-9887-4
ISSN	1421-9859 ; 0378-5866
ISSN (online)	1421-9859
ISSN	0378-5866
DOI	10.1159/000330884
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Article ; Online: Allelic exclusion and peripheral reconstitution by TCR transgenic T cells arising from transduced human hematopoietic stem/progenitor cells.

Giannoni, Francesca / Hardee, Cinnamon L / Wherley, Jennifer / Gschweng, Eric / Senadheera, Shantha / Kaufman, Michael L / Chan, Rebecca / Bahner, Ingrid / Gersuk, Vivian / Wang, Xiaoyan / Gjertson, David / Baltimore, David / Witte, Owen N / Economou, James S / Ribas, Antoni / Kohn, Donald B

Molecular therapy : the journal of the American Society of Gene Therapy

2013 Volume 21, Issue 5, Page(s) 1044–1054

Abstract: Transduction and transplantation of human hematopoietic stem/progenitor cells (HSPC) with the genes for a T-cell receptor (TCR) that recognizes a tumor-associated antigen may lead to sustained long-term production of T cells expressing the TCR and confer ...

Abstract	Transduction and transplantation of human hematopoietic stem/progenitor cells (HSPC) with the genes for a T-cell receptor (TCR) that recognizes a tumor-associated antigen may lead to sustained long-term production of T cells expressing the TCR and confer specific antitumor activity. We evaluated this using a lentiviral vector (CCLc-MND-F5) carrying cDNA for a human TCR specific for an HLA-A0201-restricted peptide of Melanoma Antigen Recognized by T cells (MART-1). CD34(+) HSPC were transduced with the F5 TCR lentiviral vector or mock transduced and transplanted into neonatal NSG mice or NSG mice transgenic for human HLA-A0201 (NSG-A2). Human CD8(+) and CD4(+) T cells expressing the human F5 TCR were present in the thymus, spleen, and peripheral blood after 4-5 months. Expression of human HLA-A*0201 in NSG-A2 recipient mice led to significantly increased numbers of human CD8(+) and CD4(+) T cells expressing the F5 TCR, compared with control NSG recipients. Transduction of the human CD34(+) HSPC by the F5 TCR transgene caused a high degree of allelic exclusion, potently suppressing rearrangement of endogenous human TCR-β genes during thymopoiesis. In summary, we demonstrated the feasibility of engineering human HSPC to express a tumor-specific TCR to serve as a long-term source of tumor-targeted mature T cells for immunotherapy of melanoma.
MeSH term(s)	Alleles ; Animals ; Antigens, CD34/metabolism ; Blood Cells/cytology ; Blood Cells/metabolism ; Bone Marrow Cells/cytology ; Bone Marrow Cells/metabolism ; Complementarity Determining Regions/chemistry ; Complementarity Determining Regions/genetics ; Epitopes, T-Lymphocyte/immunology ; Female ; Gene Order ; Genetic Vectors/genetics ; Graft Survival ; Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells/metabolism ; Humans ; Interferon-gamma/biosynthesis ; Lentivirus/genetics ; Male ; Melanoma/genetics ; Melanoma/immunology ; Melanoma/therapy ; Mice ; Receptors, Antigen, T-Cell/genetics ; Receptors, Antigen, T-Cell/metabolism ; Receptors, Antigen, T-Cell, alpha-beta/chemistry ; Receptors, Antigen, T-Cell, alpha-beta/genetics ; T-Lymphocyte Subsets/cytology ; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/metabolism ; Thymocytes/cytology ; Thymocytes/metabolism ; Transduction, Genetic ; Transplantation, Heterologous
Chemical Substances	Antigens, CD34 ; Complementarity Determining Regions ; Epitopes, T-Lymphocyte ; Receptors, Antigen, T-Cell ; Receptors, Antigen, T-Cell, alpha-beta ; Interferon-gamma (82115-62-6)
Language	English
Publishing date	2013-02-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2010592-7
ISSN	1525-0024 ; 1525-0016
ISSN (online)	1525-0024
ISSN	1525-0016
DOI	10.1038/mt.2013.8
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Article ; Online: β-globin gene transfer to human bone marrow for sickle cell disease.

Romero, Zulema / Urbinati, Fabrizia / Geiger, Sabine / Cooper, Aaron R / Wherley, Jennifer / Kaufman, Michael L / Hollis, Roger P / de Assin, Rafael Ruiz / Senadheera, Shantha / Sahagian, Arineh / Jin, Xiangyang / Gellis, Alyse / Wang, Xiaoyan / Gjertson, David / Deoliveira, Satiro / Kempert, Pamela / Shupien, Sally / Abdel-Azim, Hisham / Walters, Mark C /

Meiselman, Herbert J / Wenby, Rosalinda B / Gruber, Theresa / Marder, Victor / Coates, Thomas D / Kohn, Donald B

The Journal of clinical investigation

2013

Abstract: Autologous hematopoietic stem cell gene therapy is an approach to treating sickle cell disease (SCD) patients that may result in lower morbidity than allogeneic transplantation. We examined the potential of a lentiviral vector (LV) (CCL-βAS3-FB) encoding ...

Abstract	Autologous hematopoietic stem cell gene therapy is an approach to treating sickle cell disease (SCD) patients that may result in lower morbidity than allogeneic transplantation. We examined the potential of a lentiviral vector (LV) (CCL-βAS3-FB) encoding a human hemoglobin (HBB) gene engineered to impede sickle hemoglobin polymerization (HBBAS3) to transduce human BM CD34+ cells from SCD donors and prevent sickling of red blood cells produced by in vitro differentiation. The CCL-βAS3-FB LV transduced BM CD34+ cells from either healthy or SCD donors at similar levels, based on quantitative PCR and colony-forming unit progenitor analysis. Consistent expression of HBBAS3 mRNA and HbAS3 protein compromised a fourth of the total β-globin-like transcripts and hemoglobin (Hb) tetramers. Upon deoxygenation, a lower percentage of HBBAS3-transduced red blood cells exhibited sickling compared with mock-transduced cells from sickle donors. Transduced BM CD34+ cells were transplanted into immunodeficient mice, and the human cells recovered after 2-3 months were cultured for erythroid differentiation, which showed levels of HBBAS3 mRNA similar to those seen in the CD34+ cells that were directly differentiated in vitro. These results demonstrate that the CCL-βAS3-FB LV is capable of efficient transfer and consistent expression of an effective anti-sickling β-globin gene in human SCD BM CD34+ progenitor cells, improving physiologic parameters of the resulting red blood cells.
Language	English
Publishing date	2013-07-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI67930
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