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Gene editing sickle cell

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https://www.readbyqxmd.com/read/29858048/efficient-delivery-and-nuclear-uptake-is-not-sufficient-to-detect-gene-editing-in-cd34-cells-directed-by-a-ribonucleoprotein-complex
#1
Shirin R Modarai, Dula Man, Pawel Bialk, Natalia Rivera-Torres, Kevin Bloh, Eric B Kmiec
CD34+ cells are prime targets for therapeutic strategies for gene editing, because modified progenitor cells have the capacity to differentiate through an erythropoietic lineage. Although experimental advances have been reported, the associated experimental protocols have largely been less than clear or robust. As such, we evaluated the relationships among cellular delivery; nuclear uptake, often viewed as the benchmark metric of successful gene editing; and single base repair. We took a combinatorial approach using single-stranded oligonucleotide and a CRISPR/Cas9 ribonucleoprotein to convert wild-type HBB into the sickle cell genotype by evaluating conditions for two common delivery strategies of gene editing tools into CD34+ cells...
June 1, 2018: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/29803277/genetic-therapies-for-sickle-cell-disease
#2
REVIEW
Rajeswari Jayavaradhan, Punam Malik
Sickle cell disease is the most prevalent monogenic disorder worldwide and curative therapies are limited to hematopoietic stem cell transplant to the few with matched donors. Gene therapy has curative potential, whereby autologous hematopoietic stem cells are genetically modified and transplanted, which would not be limited by matched donors, resulting in 1-time, life-long correction devoid of immune side effects. Significant progress has been made to clinically translate gene therapy for sickle cell disease using lentivirus vectors carrying antisickling genes...
June 2018: Pediatric Clinics of North America
https://www.readbyqxmd.com/read/29789357/reactivation-of-%C3%AE-globin-in-adult-%C3%AE-yac-mice-after-ex-vivo-and-in-vivo-hematopoietic-stem-cell-genome-editing
#3
Chang Li, Nikoletta Psatha, Pavel Sova, Sucheol Gil, Hongjie Wang, Jiho Kim, Chandana Kulkarni, Cristina Valensisi, R David Hawkins, George Stamatoyannopoulos, André Lieber
Disorders involving β-globin gene mutations, mainly β-thalassemia and sickle cell disease, represent a major target for hematopoietic stem/progenitor cell (HSPC) gene therapy. This includes CRISPR/Cas9-mediated genome editing approaches in adult CD34+ cells aimed toward the re-activation of fetal γ-globin expression in red blood cells. Because models involving erythroid differentiation of CD34+ cells have limitations in assessing γ-globin re-activation, we focused on human β-globin locus transgenic (β-YAC) mice...
May 22, 2018: Blood
https://www.readbyqxmd.com/read/29700043/enhancement-of-red-blood-cell-transfusion-compatibility-using-crispr-mediated-erythroblast-gene-editing
#4
Joseph Hawksworth, Timothy J Satchwell, Marjolein Meinders, Deborah E Daniels, Fiona Regan, Nicole M Thornton, Marieangela C Wilson, Johannes Gg Dobbe, Geert J Streekstra, Kongtana Trakarnsanga, Kate J Heesom, David J Anstee, Jan Frayne, Ashley M Toye
Regular blood transfusion is the cornerstone of care for patients with red blood cell (RBC) disorders such as thalassaemia or sickle-cell disease. With repeated transfusion, alloimmunisation often occurs due to incompatibility at the level of minor blood group antigens. We use CRISPR-mediated genome editing of an immortalised human erythroblast cell line (BEL-A) to generate multiple enucleation competent cell lines deficient in individual blood groups. Edits are combined to generate a single cell line deficient in multiple antigens responsible for the most common transfusion incompatibilities: ABO (Bombay phenotype), Rh (Rhnull ), Kell ( K 0 ), Duffy (Duffynull ), GPB (S- s- U- )...
April 26, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29606353/direct-promoter-repression-by-bcl11a-controls-the-fetal-to-adult-hemoglobin-switch
#5
Nan Liu, Victoria V Hargreaves, Qian Zhu, Jesse V Kurland, Jiyoung Hong, Woojin Kim, Falak Sher, Claudio Macias-Trevino, Julia M Rogers, Ryo Kurita, Yukio Nakamura, Guo-Cheng Yuan, Daniel E Bauer, Jian Xu, Martha L Bulyk, Stuart H Orkin
Fetal hemoglobin (HbF, α2 γ2 ) level is genetically controlled and modifies severity of adult hemoglobin (HbA, α2 β2 ) disorders, sickle cell disease, and β-thalassemia. Common genetic variation affects expression of BCL11A, a regulator of HbF silencing. To uncover how BCL11A supports the developmental switch from γ- to β- globin, we use a functional assay and protein binding microarray to establish a requirement for a zinc-finger cluster in BCL11A in repression and identify a preferred DNA recognition sequence...
April 5, 2018: Cell
https://www.readbyqxmd.com/read/29519807/induction-of-fetal-hemoglobin-synthesis-by-crispr-cas9-mediated-editing-of-the-human-%C3%AE-globin-locus
#6
Chiara Antoniani, Vasco Meneghini, Annalisa Lattanzi, Tristan Felix, Oriana Romano, Elisa Magrin, Leslie Weber, Giulia Pavani, Sara El Hoss, Ryo Kurita, Yukio Nakamura, Thomas J Cradick, Ante S Lundberg, Matthew Porteus, Mario Amendola, Wassim El Nemer, Marina Cavazzana, Fulvio Mavilio, Annarita Miccio
Naturally occurring, large deletions in the β-globin locus result in hereditary persistence of fetal hemoglobin, a condition that mitigates the clinical severity of sickle cell disease (SCD) and β-thalassemia. We designed a clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (Cas9) (CRISPR/Cas9) strategy to disrupt a 13.6-kb genomic region encompassing the δ- and β-globin genes and a putative γ-δ intergenic fetal hemoglobin (HbF) silencer. Disruption of just the putative HbF silencer results in a mild increase in γ-globin expression, whereas deletion or inversion of a 13...
April 26, 2018: Blood
https://www.readbyqxmd.com/read/29472357/plerixafor-enables-safe-rapid-efficient-mobilization-of-hematopoietic-stem-cells-in-sickle-cell-disease-patients-after-exchange-transfusion
#7
Chantal Lagresle-Peyrou, François Lefrère, Elisa Magrin, Jean-Antoine Ribeil, Oriana Romano, Leslie Weber, Alessandra Magnani, Hanem Sadek, Clémence Plantier, Aurélie Gabrion, Brigitte Ternaux, Tristan Félix, Chloé Couzin, Aurélie Stanislas, Jean-Marc Tréluyer, Lionel Lamhaut, Laure Joseph, Marianne Delville, Annarita Miccio, Isabelle André-Schmutz, Marina Cavazzana
Sickle cell disease is characterized by chronic anemia and vaso-occlusive crises, which eventually lead to multi-organ damage and premature death. Hematopoietic stem cell transplantation is the only curative treatment but it is limited by toxicity and poor availability of HLA-compatible donors. A gene therapy approach based on the autologous transplantation of lentiviral-corrected hematopoietic stem and progenitor cells was shown to be efficacious in one patient. However, alterations of the bone marrow environment and properties of the red blood cells hamper the harvesting and immunoselection of patients' stem cells from bone marrow...
May 2018: Haematologica
https://www.readbyqxmd.com/read/29419425/safety-and-efficacy-of-plerixafor-dose-escalation-for-the-mobilization-of-cd34-hematopoietic-progenitor-cells-in-patients-with-sickle-cell-disease-interim-results
#8
Farid Boulad, Tsiporah Shore, Koen van Besien, Caterina Minniti, Mihaela Barbu-Stevanovic, Sylvie Wiener Fedus, Fabiana Perna, June Greenberg, Danielle Guarneri, Vijay Nandi, Audrey Mauguen, Karina Yazdanbakhsh, Michel Sadelain, Patricia A Shi
Gene therapy for sickle cell disease is limited by the yield of hematopoietic progenitor cells that can be harvested for transduction or gene editing. We therefore performed a phase I dose-escalation study of the hematopoietic progenitor cell mobilizing agent plerixafor to evaluate the efficacy and safety of standard dosing on peripheral blood CD34+ cell mobilization. Of 15 patients enrolled to date, only one was chronically transfused and ten were on hydroxyurea. Of eight patients who achieved a CD34+ cell concentration >30 cells/μL, six were on hydroxyurea...
May 2018: Haematologica
https://www.readbyqxmd.com/read/29370156/crispr-cas9-genome-editing-in-human-hematopoietic-stem-cells
#9
Rasmus O Bak, Daniel P Dever, Matthew H Porteus
Genome editing via homologous recombination (HR) (gene targeting) in human hematopoietic stem cells (HSCs) has the power to reveal gene-function relationships and potentially transform curative hematological gene and cell therapies. However, there are no comprehensive and reproducible protocols for targeting HSCs for HR. Herein, we provide a detailed protocol for the production, enrichment, and in vitro and in vivo analyses of HR-targeted HSCs by combining CRISPR/Cas9 technology with the use of rAAV6 and flow cytometry...
February 2018: Nature Protocols
https://www.readbyqxmd.com/read/29357790/a-new-era-for-hemoglobinopathies-more-than-one-curative-option
#10
Nikoletta Psatha, Penelope-Georgia Papayanni, Evangelia Yannaki
Hemoglobinopathies, including severe β-thalassemia and sickle cell disease, represent the most common monogenic disorders worldwide. Allogeneic hematopoietic stem cell transplantation (allo-HCT) is the only approved curative option for these syndromes, albeit limited to patients having a suitable donor. Gene therapy, by making use of the patient's own hematopoietic stem cells to introduce a normal copy of the β-globin gene by viral vectors, bridged the gap between the need for cure of patients with hemoglobinopathies and the lack of a donor, without incurring the immunological risks of allo-HSCT...
2017: Current Gene Therapy
https://www.readbyqxmd.com/read/29336892/gene-therapy-and-gene-editing-strategies-for-hemoglobinopathies
#11
REVIEW
Maria Rosa Lidonnici, Giuliana Ferrari
Gene therapy for hemoglobinopathies is currently based on transplantation of autologous hematopoietic stem cells genetically modified with an integrating lentiviral vector expressing a globin gene under the control of globin transcriptional regulatory elements. Studies and safety works demonstrated the potential therapeutic efficacy and safety of this approach, providing the rationale for clinical translation. The outcomes of early clinical trials, although showing promising results, have highlighted the current limitations to a more general application...
May 2018: Blood Cells, Molecules & Diseases
https://www.readbyqxmd.com/read/29221806/characterization-of-gene-alterations-following-editing-of-the-%C3%AE-globin-gene-locus-in-hematopoietic-stem-progenitor-cells
#12
Joseph Long, Megan D Hoban, Aaron R Cooper, Michael L Kaufman, Caroline Y Kuo, Beatriz Campo-Fernandez, Dianne Lumaquin, Roger P Hollis, Xiaoyan Wang, Donald B Kohn, Zulema Romero
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...
February 7, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29164808/a-universal-approach-to-correct-various-hbb-gene-mutations-in-human-stem-cells-for-gene-therapy-of-beta-thalassemia-and-sickle-cell-disease
#13
Liuhong Cai, Hao Bai, Vasiliki Mahairaki, Yongxing Gao, Chaoxia He, Yanfei Wen, You-Chuan Jin, You Wang, Rachel L Pan, Armaan Qasba, Zhaohui Ye, Linzhao Cheng
Beta-thalassemia is one of the most common recessive genetic diseases, caused by mutations in the HBB gene. Over 200 different types of mutations in the HBB gene containing three exons have been identified in patients with β-thalassemia (β-thal) whereas a homozygous mutation in exon 1 causes sickle cell disease (SCD). Novel therapeutic strategies to permanently correct the HBB mutation in stem cells that are able to expand and differentiate into erythrocytes producing corrected HBB proteins are highly desirable...
January 2018: Stem Cells Translational Medicine
https://www.readbyqxmd.com/read/29159826/pharmacological-and-molecular-approaches-for-the-treatment-of-%C3%AE-hemoglobin-disorders
#14
REVIEW
Neelam Lohani, Nupur Bhargava, Anjana Munshi, Sivaprakash Ramalingam
β-hemoglobin disorders, such as β-thalassemia and sickle cell anemia are among the most prevalent inherited genetic disorders worldwide. These disorders are caused by mutations in the gene encoding hemoglobin-β (HBB), a vital protein found in red blood cells (RBCs) that carries oxygen from lungs to all parts of the human body. As a consequence, there has been an enduring interest in this field in formulating therapeutic strategies for the treatment of these diseases. Currently, there is no cure available for hemoglobin disorders, although, some patients have been treated with bone marrow transplantation, whose scope is limited because of the difficulty in finding a histocompatible donor and also due to transplant-associated clinical complications that can arise during the treatment...
June 2018: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29127682/genome-editing-for-the-%C3%AE-hemoglobinopathies
#15
Matthew H Porteus
The β-hemoglobinopathies are diverse set of disorders caused by mutations in the β-globin (HBB) gene. Because HBB protein is a critical component (along with α-globin, heme, and iron) of hemoglobin, the molecule essential for oxygen delivery to tissues, mutations in HBB can result in lethal diseases or diseases with multi-organ dysfunction. HBB mutations can be roughly divided into two categories: those that cause a dysfunctional protein (such as sickle cell disease but also including varied diseases caused by high-affinity hemoglobins, low-affinity hemoglobins, and methemoglobinemia) and those that cause the insufficient production of HBB protein (β-thalassemia)...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28893518/curative-approaches-for-sickle-cell-disease-a-review-of-allogeneic-and-autologous-strategies
#16
Daniel E Bauer, Christian Brendel, Courtney D Fitzhugh
Despite sickle cell disease (SCD) first being reported >100years ago and molecularly characterized >50years ago, patients continue to experience severe morbidity and early mortality. Although there have been substantial clinical advances with immunizations, penicillin prophylaxis, hydroxyurea treatment, and transfusion therapy, the only cure that can be offered is hematopoietic stem cell transplantation (HSCT). In this work, we summarize the various allogeneic curative approaches reported to date and discuss open and upcoming clinical research protocols...
September 2017: Blood Cells, Molecules & Diseases
https://www.readbyqxmd.com/read/28610635/cellular-function-reinstitution-of-offspring-red-blood-cells-cloned-from-the-sickle-cell-disease-patient-blood-post-crispr-genome-editing
#17
Jianguo Wen, Wenjing Tao, Suyang Hao, Youli Zu
BACKGROUND: Sickle cell disease (SCD) is a disorder of red blood cells (RBCs) expressing abnormal hemoglobin-S (HbS) due to genetic inheritance of homologous HbS gene. However, people with the sickle cell trait (SCT) carry a single allele of HbS and do not usually suffer from SCD symptoms, thus providing a rationale to treat SCD. METHODS: To validate gene therapy potential, hematopoietic stem cells were isolated from the SCD patient blood and treated with CRISPR/Cas9 approach...
June 13, 2017: Journal of Hematology & Oncology
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
#18
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)...
July 2017: Gene Therapy
https://www.readbyqxmd.com/read/28377044/gene-therapy-for-%C3%AE-hemoglobinopathies
#19
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
#20
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
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