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Article ; Online: A genome editing primer for the hematologist.

Hoban, Megan D / Bauer, Daniel E

2016 Volume 127, Issue 21, Page(s) 2525–2535

Abstract: Gene editing enables the site-specific modification of the genome. These technologies have rapidly advanced such that they have entered common use in experimental hematology to investigate genetic function. In addition, genome editing is becoming ... ...

Abstract	Gene editing enables the site-specific modification of the genome. These technologies have rapidly advanced such that they have entered common use in experimental hematology to investigate genetic function. In addition, genome editing is becoming increasingly plausible as a treatment modality to rectify genetic blood disorders and improve cellular therapies. Genome modification typically ensues from site-specific double-strand breaks and may result in a myriad of outcomes. Even single-strand nicks and targeted biochemical modifications that do not permanently alter the DNA sequence (epigenome editing) may be powerful instruments. In this review, we examine the various technologies, describe their advantages and shortcomings for engendering useful genetic alterations, and consider future prospects for genome editing to impact hematology.
MeSH term(s)	Animals ; Gene Editing/methods ; Hematologic Diseases/genetics ; Hematologic Diseases/therapy ; Humans ; Targeted Gene Repair/methods
Language	English
Publishing date	2016-04-06
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2016-01-678151
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Article ; Online: Genetic treatment of a molecular disorder: gene therapy approaches to sickle cell disease.

Hoban, Megan D / Orkin, Stuart H / Bauer, Daniel E

Blood

2016 Volume 127, Issue 7, Page(s) 839–848

Abstract: Effective medical management for sickle cell disease (SCD) remains elusive. As a prevalent and severe monogenic disorder, SCD has been long considered a logical candidate for gene therapy. Significant progress has been made in moving toward this goal. ... ...

Abstract	Effective medical management for sickle cell disease (SCD) remains elusive. As a prevalent and severe monogenic disorder, SCD has been long considered a logical candidate for gene therapy. Significant progress has been made in moving toward this goal. These efforts have provided substantial insight into the natural regulation of the globin genes and illuminated challenges for genetic manipulation of the hematopoietic system. The initial γ-retroviral vectors, next-generation lentiviral vectors, and novel genome engineering and gene regulation approaches each share the goal of preventing erythrocyte sickling. After years of preclinical studies, several clinical trials for SCD gene therapies are now open. This review focuses on progress made toward achieving gene therapy, the current state of the field, consideration of factors that may determine clinical success, and prospects for future development.
MeSH term(s)	Anemia, Sickle Cell/genetics ; Anemia, Sickle Cell/therapy ; Clinical Trials as Topic ; Gene Expression Regulation ; Genetic Therapy/methods ; Genetic Vectors/genetics ; Genetic Vectors/therapeutic use ; Genome, Human ; Humans
Language	English
Publishing date	2016-01-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2015-09-618587
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Article ; Online: Delivery of Genome Editing Reagents to Hematopoietic Stem/Progenitor Cells.

Hoban, Megan D / Romero, Zulema / Cost, Gregory J / Mendel, Matthew / Holmes, Michael / Kohn, Donald B

Current protocols in stem cell biology

2016 Volume 36, Page(s) 5B.4.1–5B.4.10

Abstract: This unit describes the protocol for the delivery of reagents for targeted genome editing to CD34(+) hematopoietic stem/progenitor cells (HSPCs). Specifically, this unit focuses on the process of thawing and pre-stimulating CD34(+) HSPCs, as well as the ... ...

Abstract	This unit describes the protocol for the delivery of reagents for targeted genome editing to CD34(+) hematopoietic stem/progenitor cells (HSPCs). Specifically, this unit focuses on the process of thawing and pre-stimulating CD34(+) HSPCs, as well as the details of their electroporation with in vitro-transcribed mRNA-encoding site-specific nucleases [in this case zinc-finger nucleases (ZFNs)]. In addition, discussed is delivery of a gene editing donor template in the form of an oligonucleotide or integrase-defective lentiviral vector (IDLV). Finally, an analysis of cell survival following treatment and downstream culture conditions are presented. While optimization steps might be needed for each specific application with respect to nuclease and donor template amount, adherence to this protocol will serve as an excellent starting point for this further work.
MeSH term(s)	Animals ; Antigens, CD34 ; Drug Delivery Systems/methods ; Electroporation/methods ; Genome, Human ; Hematopoietic Stem Cells/cytology ; Hematopoietic Stem Cells/metabolism ; Humans ; Lentivirus ; Transduction, Genetic/methods
Chemical Substances	Antigens, CD34
Language	English
Publishing date	2016-02-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ISSN	1938-8969
ISSN (online)	1938-8969
DOI	10.1002/9780470151808.sc05b04s36
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Article ; Online: Analyzing CRISPR genome-editing experiments with CRISPResso.

Pinello, Luca / Canver, Matthew C / Hoban, Megan D / Orkin, Stuart H / Kohn, Donald B / Bauer, Daniel E / Yuan, Guo-Cheng

Nature biotechnology

2016 Volume 34, Issue 7, Page(s) 695–697

MeSH term(s)	Algorithms ; Animals ; CRISPR-Cas Systems/genetics ; Clustered Regularly Interspaced Short Palindromic Repeats/genetics ; Computer Simulation ; Gene Editing/methods ; High-Throughput Nucleotide Sequencing/methods ; Humans ; Models, Genetic ; Sequence Analysis, DNA/methods ; Software
Language	English
Publishing date	2016-07-11
Publishing country	United States
Document type	Letter ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1311932-1
ISSN	1546-1696 ; 1087-0156
ISSN (online)	1546-1696
ISSN	1087-0156
DOI	10.1038/nbt.3583
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Zs.A 2167: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Dissecting the mechanism of histone deacetylase inhibitors to enhance the activity of zinc finger nucleases delivered by integrase-defective lentiviral vectors.

Joglekar, Alok V / Stein, Libby / Ho, Michelle / Hoban, Megan D / Hollis, Roger P / Kohn, Donald B

Human gene therapy

2014 Volume 25, Issue 7, Page(s) 599–608

Abstract: Integrase-defective lentiviral vectors (IDLVs) have been of limited success in the delivery of zinc finger nucleases (ZFNs) to human cells, due to low expression. A reason for reduced gene expression has been proposed to involve the epigenetic silencing ... ...

Abstract	Integrase-defective lentiviral vectors (IDLVs) have been of limited success in the delivery of zinc finger nucleases (ZFNs) to human cells, due to low expression. A reason for reduced gene expression has been proposed to involve the epigenetic silencing of vector genomes, carried out primarily by histone deacetylases (HDACs). In this study, we tested valproic acid (VPA), a known HDAC inhibitor (HDACi), for its ability to increase transgene expression from IDLVs, especially in the context of ZFN delivery. Using ZFNs targeting the human adenosine deaminase (ADA) gene in K562 cells, we demonstrated that treatment with VPA enhanced ZFN expression by up to 3-fold, resulting in improved allelic disruption at the ADA locus. Furthermore, three other U.S. Food and Drug Administration-approved HDACis (vorinostat, givinostat, and trichostatin-A) exhibited a similar effect on the activity of ZFN-IDLVs in K562 cells. In primary human CD34(+) cells, VPA- and vorinostat-treated cells showed higher levels of expression of both green fluorescent protein (GFP) as well as ZFNs from IDLVs. A major mechanism for the effects of HDAC inhibitors on improving expression was from their modulation of the cell cycle, and the influence of heterochromatinization was determined to be a lesser contributing factor.
MeSH term(s)	Deoxyribonucleases/biosynthesis ; Deoxyribonucleases/genetics ; Genetic Vectors ; Histone Deacetylase Inhibitors/pharmacology ; Humans ; Integrases ; K562 Cells ; Lentivirus ; Transduction, Genetic ; Viral Proteins ; Zinc Fingers
Chemical Substances	Histone Deacetylase Inhibitors ; Viral Proteins ; Integrases (EC 2.7.7.-) ; Deoxyribonucleases (EC 3.1.-)
Language	English
Publishing date	2014-04-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1028152-6
ISSN	1557-7422 ; 1043-0342
ISSN (online)	1557-7422
ISSN	1043-0342
DOI	10.1089/hum.2013.211
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Zs.A 2988: Show issues

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Article ; Online: Characterization of Gene Alterations following Editing of the β-Globin Gene Locus in Hematopoietic Stem/Progenitor Cells.

Long, Joseph / Hoban, Megan D / Cooper, Aaron R / Kaufman, Michael L / Kuo, Caroline Y / Campo-Fernandez, Beatriz / Lumaquin, Dianne / Hollis, Roger P / Wang, Xiaoyan / Kohn, Donald B / Romero, Zulema

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

2017 Volume 26, Issue 2, Page(s) 468–479

Abstract: The use of engineered nucleases combined with a homologous DNA donor template can result in targeted gene correction of the sickle cell disease mutation in hematopoietic stem and progenitor cells. However, because of the high homology between the ... ...

Abstract	The use of engineered nucleases combined with a homologous DNA donor template can result in targeted gene correction of the sickle cell disease mutation in hematopoietic stem and progenitor cells. However, because of the high homology between the adjacent human β- and δ-globin genes, off-target cleavage is observed at δ-globin when using some endonucleases targeted to the sickle mutation in β-globin. Introduction of multiple double-stranded breaks by endonucleases has the potential to induce intergenic alterations. Using a novel droplet digital PCR assay and high-throughput sequencing, we characterized the frequency of rearrangements between the β- and δ-globin paralogs when delivering these nucleases. Pooled CD34
MeSH term(s)	Gene Conversion ; Gene Editing ; Gene Rearrangement ; Gene Targeting ; Genetic Variation ; Hematopoietic Stem Cells/metabolism ; High-Throughput Nucleotide Sequencing ; Humans ; Nucleic Acid Amplification Techniques ; Translocation, Genetic ; beta-Globins/genetics
Chemical Substances	beta-Globins
Language	English
Publishing date	2017-11-09
Publishing country	United States
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	2010592-7
ISSN	1525-0024 ; 1525-0016
ISSN (online)	1525-0024
ISSN	1525-0016
DOI	10.1016/j.ymthe.2017.11.001
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Article ; Online: Site-Specific Gene Editing of Human Hematopoietic Stem Cells for X-Linked Hyper-IgM Syndrome.

Kuo, Caroline Y / Long, Joseph D / Campo-Fernandez, Beatriz / de Oliveira, Satiro / Cooper, Aaron R / Romero, Zulema / Hoban, Megan D / Joglekar, Alok V / Lill, Georgia R / Kaufman, Michael L / Fitz-Gibbon, Sorel / Wang, Xiaoyan / Hollis, Roger P / Kohn, Donald B

Cell reports

2018 Volume 23, Issue 9, Page(s) 2606–2616

Abstract: X-linked hyper-immunoglobulin M (hyper-IgM) syndrome (XHIM) is a primary immunodeficiency due to mutations in CD40 ligand that affect immunoglobulin class-switch recombination and somatic hypermutation. The disease is amenable to gene therapy using ... ...

Abstract	X-linked hyper-immunoglobulin M (hyper-IgM) syndrome (XHIM) is a primary immunodeficiency due to mutations in CD40 ligand that affect immunoglobulin class-switch recombination and somatic hypermutation. The disease is amenable to gene therapy using retroviral vectors, but dysregulated gene expression results in abnormal lymphoproliferation in mouse models, highlighting the need for alternative strategies. Here, we demonstrate the ability of both the transcription activator-like effector nuclease (TALEN) and clustered regularly interspaced short palindromic repeats-associated protein 9 (CRISPR/Cas9) platforms to efficiently drive integration of a normal copy of the CD40L cDNA delivered by Adeno-Associated Virus. Site-specific insertion of the donor sequence downstream of the endogenous CD40L promoter maintained physiologic expression of CD40L while overriding all reported downstream mutations. High levels of gene modification were achieved in primary human hematopoietic stem cells (HSCs), as well as in cell lines and XHIM-patient-derived T cells. Notably, gene-corrected HSCs engrafted in immunodeficient mice at clinically relevant frequencies. These studies provide the foundation for a permanent curative therapy in XHIM.
MeSH term(s)	Animals ; Antigens, CD34/metabolism ; Base Sequence ; CD40 Ligand/metabolism ; CRISPR-Associated Protein 9/metabolism ; CRISPR-Cas Systems/genetics ; Cell Differentiation ; Cell Line ; Colony-Forming Units Assay ; DNA Repair ; DNA, Complementary/genetics ; Gene Editing ; Genetic Diseases, X-Linked/genetics ; Hematopoietic Stem Cells/metabolism ; Humans ; Hyper-IgM Immunodeficiency Syndrome/genetics ; Mice ; T-Lymphocytes/metabolism ; Transcription Activator-Like Effector Nucleases/metabolism
Chemical Substances	Antigens, CD34 ; DNA, Complementary ; CD40 Ligand (147205-72-9) ; CRISPR-Associated Protein 9 (EC 3.1.-) ; Transcription Activator-Like Effector Nucleases (EC 3.1.-)
Language	English
Publishing date	2018-06-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2018.04.103
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Article ; Online: Editing the Sickle Cell Disease Mutation in Human Hematopoietic Stem Cells: Comparison of Endonucleases and Homologous Donor Templates.

Romero, Zulema / Lomova, Anastasia / Said, Suzanne / Miggelbrink, Alexandra / Kuo, Caroline Y / Campo-Fernandez, Beatriz / Hoban, Megan D / Masiuk, Katelyn E / Clark, Danielle N / Long, Joseph / Sanchez, Julie M / Velez, Miriam / Miyahira, Eric / Zhang, Ruixue / Brown, Devin / Wang, Xiaoyan / Kurmangaliyev, Yerbol Z / Hollis, Roger P / Kohn, Donald B

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

2019 Volume 27, Issue 8, Page(s) 1389–1406

Abstract: Site-specific correction of a point mutation causing a monogenic disease in autologous hematopoietic stem and progenitor cells (HSPCs) can be used as a treatment of inherited disorders of the blood cells. Sickle cell disease (SCD) is an ideal model to ... ...

Abstract	Site-specific correction of a point mutation causing a monogenic disease in autologous hematopoietic stem and progenitor cells (HSPCs) can be used as a treatment of inherited disorders of the blood cells. Sickle cell disease (SCD) is an ideal model to investigate the potential use of gene editing to transvert a single point mutation at the β-globin locus (HBB). We compared the activity of zinc-finger nucleases (ZFNs) and CRISPR/Cas9 for editing, and homologous donor templates delivered as single-stranded oligodeoxynucleotides (ssODNs), adeno-associated virus serotype 6 (AAV6), integrase-deficient lentiviral vectors (IDLVs), and adenovirus 5/35 serotype (Ad5/35) to transvert the base pair responsible for SCD in HBB in primary human CD34+ HSPCs. We found that the ZFNs and Cas9 directed similar frequencies of nuclease activity. In vitro, AAV6 led to the highest frequencies of homology-directed repair (HDR), but levels of base pair transversions were significantly reduced when analyzing cells in vivo in immunodeficient mouse xenografts, with similar frequencies achieved with either AAV6 or ssODNs. AAV6 also caused significant impairment of colony-forming progenitors and human cell engraftment. Gene correction in engrafting hematopoietic stem cells may be limited by the capacity of the cells to mediate HDR, suggesting additional manipulations may be needed for high-efficiency gene correction in HSPCs.
MeSH term(s)	Anemia, Sickle Cell/genetics ; Anemia, Sickle Cell/metabolism ; Anemia, Sickle Cell/therapy ; CRISPR-Cas Systems ; Endonucleases/genetics ; Gene Editing ; Gene Expression ; Gene Targeting ; Genetic Therapy ; Genetic Vectors/genetics ; Hematopoietic Stem Cells/metabolism ; Humans ; Mutation ; Parvovirinae/genetics ; Tissue Donors ; Transduction, Genetic ; Zinc Finger Nucleases/genetics ; beta-Globins/genetics
Chemical Substances	beta-Globins ; Endonucleases (EC 3.1.-) ; Zinc Finger Nucleases (EC 3.1.-)
Language	English
Publishing date	2019-05-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2010592-7
ISSN	1525-0024 ; 1525-0016
ISSN (online)	1525-0024
ISSN	1525-0016
DOI	10.1016/j.ymthe.2019.05.014
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Article ; Online: Site-Specific Gene Editing of Human Hematopoietic Stem Cells for X-Linked Hyper-IgM Syndrome

Caroline Y. Kuo / Joseph D. Long / Beatriz Campo-Fernandez / Satiro de Oliveira / Aaron R. Cooper / Zulema Romero / Megan D. Hoban / Alok V. Joglekar / Georgia R. Lill / Michael L. Kaufman / Sorel Fitz-Gibbon / Xiaoyan Wang / Roger P. Hollis / Donald B. Kohn

Cell Reports, Vol 23, Iss 9, Pp 2606-

2018 Volume 2616

Abstract	X-linked hyper-immunoglobulin M (hyper-IgM) syndrome (XHIM) is a primary immunodeficiency due to mutations in CD40 ligand that affect immunoglobulin class-switch recombination and somatic hypermutation. The disease is amenable to gene therapy using retroviral vectors, but dysregulated gene expression results in abnormal lymphoproliferation in mouse models, highlighting the need for alternative strategies. Here, we demonstrate the ability of both the transcription activator-like effector nuclease (TALEN) and clustered regularly interspaced short palindromic repeats-associated protein 9 (CRISPR/Cas9) platforms to efficiently drive integration of a normal copy of the CD40L cDNA delivered by Adeno-Associated Virus. Site-specific insertion of the donor sequence downstream of the endogenous CD40L promoter maintained physiologic expression of CD40L while overriding all reported downstream mutations. High levels of gene modification were achieved in primary human hematopoietic stem cells (HSCs), as well as in cell lines and XHIM-patient-derived T cells. Notably, gene-corrected HSCs engrafted in immunodeficient mice at clinically relevant frequencies. These studies provide the foundation for a permanent curative therapy in XHIM.
Keywords	X-linked hyper-IgM syndrome ; gene editing ; gene therapy ; primary immunodeficiency ; CD40 ligand ; hematopoietic stem cell ; CRISPR/Cas9 ; TALEN ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2018-05-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
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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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