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Gene editing sickle cell

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https://www.readbyqxmd.com/read/28530652/cd34-cells-from-dental-pulp-stem-cells-with-a-zfn-mediated-and-homology-driven-repair-mediated-locus-specific-knock-in-of-an-artificial-%C3%AE-globin-gene
#1
S Chattong, O Ruangwattanasuk, W Yindeedej, A Setpakdee, K Manotham
In humans, mutations in the β-globin gene (HBB) have two important clinical manifestations: β-thalassemia and sickle cell disease. The progress in genome editing and stem cell research may be relevant to the treatment of β-globin-related diseases. In this work, we employed zinc finger nuclease (ZFN)-mediated gene integration of synthetic β-globin cDNA into HBB loci, thus correcting almost all β-globin mutations. The integration was achieved in both HEK 293 cells and isolated dental pulp stem cell (DPSCs)...
May 22, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28377044/gene-therapy-for-%C3%AE-hemoglobinopathies
#2
REVIEW
Marina Cavazzana, Chiara Antoniani, Annarita Miccio
β-Thalassemia and sickle cell disease (SCD) are the world's two most widely disseminated hereditary hemoglobinopathies. β-Thalassemia originated in the Mediterranean, Middle Eastern, and Asian regions, and SCD originated in central Africa. However, subsequent population migration means that these two diseases are now global and thus constitute a growing health problem in many countries. Despite remarkable improvements in medical care for patients with β-hemoglobinopathies, there is still only one definitive treatment option: allogeneic hematopoietic stem cell (HSC) transplantation...
May 3, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28344999/long-term-engraftment-and-fetal-globin-induction-upon-bcl11a-gene-editing-in-bone-marrow-derived-cd34-hematopoietic-stem-and-progenitor-cells
#3
Kai-Hsin Chang, Sarah E Smith, Timothy Sullivan, Kai Chen, Qianhe Zhou, Jason A West, Mei Liu, Yingchun Liu, Benjamin F Vieira, Chao Sun, Vu P Hong, Mingxuan Zhang, Xiao Yang, Andreas Reik, Fyodor D Urnov, Edward J Rebar, Michael C Holmes, Olivier Danos, Haiyan Jiang, Siyuan Tan
To develop an effective and sustainable cell therapy for sickle cell disease (SCD), we investigated the feasibility of targeted disruption of the BCL11A gene, either within exon 2 or at the GATAA motif in the intronic erythroid-specific enhancer, using zinc finger nucleases in human bone marrow (BM) CD34(+) hematopoietic stem and progenitor cells (HSPCs). Both targeting strategies upregulated fetal globin expression in erythroid cells to levels predicted to inhibit hemoglobin S polymerization. However, complete inactivation of BCL11A resulting from bi-allelic frameshift mutations in BCL11A exon 2 adversely affected erythroid enucleation...
March 17, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28159390/sickle-cell-disease
#4
REVIEW
Russell E Ware, Mariane de Montalembert, Léon Tshilolo, Miguel R Abboud
Sickle cell disease is a common and life-threatening haematological disorder that affects millions of people worldwide. Abnormal sickle-shaped erythrocytes disrupt blood flow in small vessels, and this vaso-occlusion leads to distal tissue ischaemia and inflammation, with symptoms defining the acute painful sickle-cell crisis. Repeated sickling and ongoing haemolytic anaemia, even when subclinical, lead to parenchymal injury and chronic organ damage, causing substantial morbidity and early mortality. Currently available treatments are limited to transfusions and hydroxycarbamide, although stem cell transplantation might be a potentially curative therapy...
January 31, 2017: Lancet
https://www.readbyqxmd.com/read/28111279/a-comprehensive-ethnically-diverse-library-of-sickle-cell-disease-specific-induced-pluripotent-stem-cells
#5
Seonmi Park, Andreia Gianotti-Sommer, Francisco Javier Molina-Estevez, Kim Vanuytsel, Nick Skvir, Amy Leung, Sarah S Rozelle, Elmutaz Mohammed Shaikho, Isabelle Weir, Zhihua Jiang, Hong-Yuan Luo, David H K Chui, Maria Stella Figueiredo, Abdulraham Alsultan, Amein Al-Ali, Paola Sebastiani, Martin H Steinberg, Gustavo Mostoslavsky, George J Murphy
Sickle cell anemia affects millions of people worldwide and is an emerging global health burden. As part of a large NIH-funded NextGen Consortium, we generated a diverse, comprehensive, and fully characterized library of sickle-cell-disease-specific induced pluripotent stem cells (iPSCs) from patients of different ethnicities, β-globin gene (HBB) haplotypes, and fetal hemoglobin (HbF) levels. iPSCs stand to revolutionize the way we study human development, model disease, and perhaps eventually, treat patients...
April 11, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/27891535/gene-therapy-for-hemoglobin-disorders-a-mini-review
#6
Parul Rai, Punam Malik
Gene therapy by either gene insertion or editing is an exciting curative therapeutic option for monogenic hemoglobin disorders like sickle cell disease and β-thalassemia. The safety and efficacy of gene transfer techniques has markedly improved with the use of lentivirus vectors. The clinical translation of this technology has met with good success, although key limitations include number of engraftable transduced hematopoietic stem cells and adequate transgene expression that results in complete correction of β0 thalassemia major...
2016: Journal of Rare Diseases Research & Treatment
https://www.readbyqxmd.com/read/27820943/crispr-cas9-%C3%AE-globin-gene-targeting-in-human-haematopoietic-stem-cells
#7
Daniel P Dever, Rasmus O Bak, Andreas Reinisch, Joab Camarena, Gabriel Washington, Carmencita E Nicolas, Mara Pavel-Dinu, Nivi Saxena, Alec B Wilkens, Sruthi Mantri, Nobuko Uchida, Ayal Hendel, Anupama Narla, Ravindra Majeti, Kenneth I Weinberg, Matthew H Porteus
The β-haemoglobinopathies, such as sickle cell disease and β-thalassaemia, are caused by mutations in the β-globin (HBB) gene and affect millions of people worldwide. Ex vivo gene correction in patient-derived haematopoietic stem cells followed by autologous transplantation could be used to cure β-haemoglobinopathies. Here we present a CRISPR/Cas9 gene-editing system that combines Cas9 ribonucleoproteins and adeno-associated viral vector delivery of a homologous donor to achieve homologous recombination at the HBB gene in haematopoietic stem cells...
November 17, 2016: Nature
https://www.readbyqxmd.com/read/27736664/crispr-cas9-system-and-its-applications-in-human-hematopoietic-cells
#8
REVIEW
Xiaotang Hu
Since 2012, the CRISPR-Cas9 system has been quickly and successfully tested in a broad range of organisms and cells including hematopoietic cells. The application of CRISPR-Cas9 in human hematopoietic cells mainly involves the genes responsible for HIV infection, β-thalassemia and sickle cell disease (SCD). The successful disruption of CCR5 and CXCR4 genes in T cells by CRISPR-Cas9 promotes the prospect of the technology in the functional cure of HIV. More recently, eliminating CCR5 and CXCR4 in induced pluripotent stem cells (iPSCs) derived from patients and targeting the HIV genome have been successfully carried out in several laboratories...
November 2016: Blood Cells, Molecules & Diseases
https://www.readbyqxmd.com/read/27733558/selection-free-genome-editing-of-the-sickle-mutation-in-human-adult-hematopoietic-stem-progenitor-cells
#9
Mark A DeWitt, Wendy Magis, Nicolas L Bray, Tianjiao Wang, Jennifer R Berman, Fabrizia Urbinati, Seok-Jin Heo, Therese Mitros, Denise P Muñoz, Dario Boffelli, Donald B Kohn, Mark C Walters, Dana Carroll, David I K Martin, Jacob E Corn
Genetic diseases of blood cells are prime candidates for treatment through ex vivo gene editing of CD34(+) hematopoietic stem/progenitor cells (HSPCs), and a variety of technologies have been proposed to treat these disorders. Sickle cell disease (SCD) is a recessive genetic disorder caused by a single-nucleotide polymorphism in the β-globin gene (HBB). Sickle hemoglobin damages erythrocytes, causing vasoocclusion, severe pain, progressive organ damage, and premature death. We optimize design and delivery parameters of a ribonucleoprotein (RNP) complex comprising Cas9 protein and unmodified single guide RNA, together with a single-stranded DNA oligonucleotide donor (ssODN), to enable efficient replacement of the SCD mutation in human HSPCs...
October 12, 2016: Science Translational Medicine
https://www.readbyqxmd.com/read/27718361/the-regulation-of-human-globin-promoters-by-ccaat-box-elements-and-the-recruitment-of-nf-y
#10
REVIEW
Gabriella E Martyn, Kate G R Quinlan, Merlin Crossley
CCAAT boxes are motifs found within the proximal promoter of many genes, including the human globin genes. The highly conserved nature of CCAAT box motifs within the promoter region of both α-like and β-like globin genes emphasises the functional importance of the CCAAT sequence in globin gene regulation. Mutations within the β-globin CCAAT box result in β-thalassaemia, while mutations within the distal γ-globin CCAAT box cause the Hereditary Persistence of Foetal Haemoglobin, a benign condition which results in continued γ-globin expression during adult life...
October 5, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27695619/the-potential-of-gene-therapy-approaches-for-the-treatment-of-hemoglobinopathies-achievements-and-challenges
#11
REVIEW
Michael A Goodman, Punam Malik
Hemoglobinopathies, including β-thalassemia and sickle cell disease (SCD), are a heterogeneous group of commonly inherited disorders affecting the function or levels of hemoglobin. Disease phenotype can be severe with substantial morbidity and mortality. Bone marrow transplantation is curative, but limited to those patients with an appropriately matched donor. Genetic therapy, which utilizes a patient's own cells, is thus an attractive therapeutic option. Numerous therapies are currently in clinical trials or in development, including therapies utilizing gene replacement therapy using lentiviruses and the latest gene editing techniques...
October 2016: Therapeutic Advances in Hematology
https://www.readbyqxmd.com/read/27601644/genome-editing-using-crispr-cas9-to-create-the-hpfh-genotype-in-hspcs-an-approach-for-treating-sickle-cell-disease-and-%C3%AE-thalassemia
#12
Lin Ye, Jiaming Wang, Yuting Tan, Ashley I Beyer, Fei Xie, Marcus O Muench, Yuet Wai Kan
Hereditary persistence of fetal hemoglobin (HPFH) is a condition in some individuals who have a high level of fetal hemoglobin throughout life. Individuals with compound heterozygous β-thalassemia or sickle cell disease (SCD) and HPFH have milder clinical manifestations. Using RNA-guided clustered regularly interspaced short palindromic repeats-associated Cas9 (CRISPR-Cas9) genome-editing technology, we deleted, in normal hematopoietic stem and progenitor cells (HSPCs), 13 kb of the β-globin locus to mimic the naturally occurring Sicilian HPFH mutation...
September 20, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27525524/a-genome-editing-strategy-to-treat-%C3%AE-hemoglobinopathies-that-recapitulates-a-mutation-associated-with-a-benign-genetic-condition
#13
Elizabeth A Traxler, Yu Yao, Yong-Dong Wang, Kaitly J Woodard, Ryo Kurita, Yukio Nakamura, Jim R Hughes, Ross C Hardison, Gerd A Blobel, Chunliang Li, Mitchell J Weiss
Disorders resulting from mutations in the hemoglobin subunit beta gene (HBB; which encodes β-globin), mainly sickle cell disease (SCD) and β-thalassemia, become symptomatic postnatally as fetal γ-globin expression from two paralogous genes, hemoglobin subunit gamma 1 (HBG1) and HBG2, decreases and adult β-globin expression increases, thereby shifting red blood cell (RBC) hemoglobin from the fetal (referred to as HbF or α2γ2) to adult (referred to as HbA or α2β2) form. These disorders are alleviated when postnatal expression of fetal γ-globin is maintained...
September 2016: Nature Medicine
https://www.readbyqxmd.com/read/27421743/cellular-therapy-for-sickle-cell-disease
#14
REVIEW
Allistair Abraham, David A Jacobsohn, Catherine M Bollard
Sickle cell disease (SCD) is a monogenic red cell disorder affecting more than 300 000 annual births worldwide and leading to significant organ toxicity and premature mortality. Although chronic therapies such as hydroxyurea have improved outcomes, more durable therapeutic and curative options are still being investigated. Newer understanding of the disease has implicated invariant natural killer T cells as a critical immune profile that potentiates SCD. Hence, targeting this cell population may offer a new approach to disease management...
November 2016: Cytotherapy
https://www.readbyqxmd.com/read/27406980/crispr-cas9-mediated-correction-of-the-sickle-mutation-in-human-cd34-cells
#15
Megan D Hoban, Dianne Lumaquin, Caroline Y Kuo, Zulema Romero, Joseph Long, Michelle Ho, Courtney S Young, Michelle Mojadidi, Sorel Fitz-Gibbon, Aaron R Cooper, Georgia R Lill, Fabrizia Urbinati, Beatriz Campo-Fernandez, Carmen F Bjurstrom, Matteo Pellegrini, Roger P Hollis, Donald B Kohn
Targeted genome editing technology can correct the sickle cell disease mutation of the β-globin gene in hematopoietic stem cells. This correction supports production of red blood cells that synthesize normal hemoglobin proteins. Here, we demonstrate that Transcription Activator-Like Effector Nucleases (TALENs) and the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 nuclease system can target DNA sequences around the sickle-cell mutation in the β-globin gene for site-specific cleavage and facilitate precise correction when a homologous donor template is codelivered...
September 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/27340226/hemoglobin-genetics-recent-contributions-of-gwas-and-gene-editing
#16
REVIEW
Elenoe C Smith, Stuart H Orkin
The β-hemoglobinopathies are inherited disorders resulting from altered coding potential or expression of the adult β-globin gene. Impaired expression of β-globin reduces adult hemoglobin (α2β2) production, the hallmark of β-thalassemia. A single-base mutation at codon 6 leads to formation of HbS (α2β(S)2) and sickle cell disease. While the basis of these diseases is known, therapy remains largely supportive. Bone marrow transplantation is the only curative therapy. Patients with elevated levels of fetal hemoglobin (HbF, α2γ2) as adults exhibit reduced symptoms and enhanced survival...
October 1, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/27314256/treating-hemoglobinopathies-using-gene-correction-approaches-promises-and-challenges
#17
REVIEW
Renee N Cottle, Ciaran M Lee, Gang Bao
Hemoglobinopathies are genetic disorders caused by aberrant hemoglobin expression or structure changes, resulting in severe mortality and health disparities worldwide. Sickle cell disease (SCD) and β-thalassemia, the most common forms of hemoglobinopathies, are typically treated using transfusions and pharmacological agents. Allogeneic hematopoietic stem cell transplantation is the only curative therapy, but has limited clinical applicability. Although gene therapy approaches have been proposed based on the insertion and forced expression of wild-type or anti-sickling β-globin variants, safety concerns may impede their clinical application...
September 2016: Human Genetics
https://www.readbyqxmd.com/read/27021486/cell-and-gene-therapy-for-the-beta-thalassemias-advances-and-prospects
#18
REVIEW
Jorge Mansilla-Soto, Isabelle Riviere, Farid Boulad, Michel Sadelain
The beta-thalassemias are inherited anemias caused by mutations that severely reduce or abolish expression of the beta-globin gene. Like sickle cell disease, a related beta-globin gene disorder, they are ideal candidates for performing a genetic correction in patient hematopoietic stem cells (HSCs). The most advanced approach utilizes complex lentiviral vectors encoding the human β-globin gene, as first reported by May et al. in 2000. Considerable progress toward the clinical implementation of this approach has been made in the past five years, based on effective CD34+ cell mobilization and improved lentiviral vector manufacturing...
April 2016: Human Gene Therapy
https://www.readbyqxmd.com/read/26866328/recent-advances-in-globin-research-using-genome-wide-association-studies-and-gene-editing
#19
Stuart H Orkin
A long-sought goal in the hemoglobin field has been an improved understanding of the mechanisms that regulate the switch from fetal (HbF) to adult (HbA) hemoglobin during development. With such knowledge, the hope is that strategies for directed reactivation of HbF in adults could be devised as an approach to therapy for the β-hemoglobinopathies thalassemia and sickle cell disease. Recent genome-wide association studies (GWAS) led to identification of three loci (BCL11A, HBS1L-MYB, and the β-globin cluster itself) in which natural genetic variation is correlated with different HbF levels in populations...
March 2016: Annals of the New York Academy of Sciences
https://www.readbyqxmd.com/read/26375765/hemoglobin-switching-s-surprise-the-versatile-transcription-factor-bcl11a-is-a-master-repressor-of-fetal-hemoglobin
#20
REVIEW
Daniel E Bauer, Stuart H Orkin
The major disorders of β-globin, sickle cell disease and β-thalassemia, may be ameliorated by expression of the fetal gene paralog γ-globin. Uncertainty regarding the mechanisms repressing fetal hemoglobin in the adult stage has served as a puzzle of developmental gene regulation as well as a barrier to rational therapeutic design. Recent genome-wide association studies implicated the zinc-finger transcriptional repressor BCL11A in fetal hemoglobin regulation. Extensive genetic analyses have validated BCL11A as a potent repressor of fetal hemoglobin level...
August 2015: Current Opinion in Genetics & Development
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