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Gene Editing AND Thalassemia

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https://www.readbyqxmd.com/read/30228869/blood-relatives-splicing-mechanisms-underlying-erythropoiesis-in-health-and-disease
#1
REVIEW
Kirsten A Reimer, Karla M Neugebauer
During erythropoiesis, hematopoietic stem and progenitor cells transition to erythroblasts en route to terminal differentiation into enucleated red blood cells. Transcriptome-wide changes underlie distinct morphological and functional characteristics at each cell division during this process. Many studies of gene expression have historically been carried out in erythroblasts, and the biogenesis of β-globin mRNA-the most highly expressed transcript in erythroblasts-was the focus of many seminal studies on the mechanisms of pre-mRNA splicing...
2018: F1000Research
https://www.readbyqxmd.com/read/30182035/disruption-of-the-bcl11a-erythroid-enhancer-reactivates-fetal-hemoglobin-in-erythroid-cells-of-patients-with-%C3%AE-thalassemia-major
#2
Nikoletta Psatha, Andreas Reik, Susan Phelps, Yuanyue Zhou, Demetri Dalas, Evangelia Yannaki, Dana N Levasseur, Fyodor D Urnov, Michael C Holmes, Thalia Papayannopoulou
In the present report, we carried out clinical-scale editing in adult mobilized CD34+ hematopoietic stem and progenitor cells (HSPCs) using zinc-finger nuclease-mediated disruption of BCL11a to upregulate the expression of γ-globin (fetal hemoglobin). In these cells, disruption of the erythroid-specific enhancer of the BCL11A gene increased endogenous γ-globin expression to levels that reached or exceeded those observed following knockout of the BCL11A coding region without negatively affecting survival or in vivo long-term proliferation of edited HSPCs and other lineages...
September 21, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/30169977/delivery-approaches-for-crispr-cas9-therapeutics-in-vivo-advances-and-challenges
#3
D C Luther, Y W Lee, H Nagaraj, F Scaletti, V M Rotello
Therapeutic gene editing is becoming a viable biomedical tool with the emergence of the CRISPR/Cas9 system. CRISPR-based technologies have promise as a therapeutic platform for many human genetic diseases previously considered untreatable, providing a flexible approach to high-fidelity gene editing. For many diseases, such as sickle-cell disease and beta thalassemia, curative therapy may already be on the horizon, with CRISPR-based clinical trials slated for the next few years. Translation of CRISPR-based therapy to in vivo application however, is no small feat, and major hurdles remain for efficacious use of the CRISPR/Cas9 system in clinical contexts...
September 2018: Expert Opinion on Drug Delivery
https://www.readbyqxmd.com/read/30040285/-crispr-cas-technique-to-repair-dna-errors-is-a-clinical-breakthrough-near
#4
Henri J van de Vrugt, Martina C Cornel, Rob M F Wolthuis
CRISPR/Cas gene editing makes it much easier to make targeted changes in the DNA of human cells than other forms of gene therapy. This revolutionary technology offers spectacular opportunities to study gene functions; the clinical consequences of gene variations in patients can be determined much faster. The efficacy and accuracy of CRISPR/Cas is so impressive that a breakthrough to therapeutic applications is approaching fast. CRISPR/Cas is already being used in immunotherapy against cancer, and trials for monogenetic blood disorders, such as beta-thalassemia, have been scheduled...
June 29, 2018: Nederlands Tijdschrift Voor Geneeskunde
https://www.readbyqxmd.com/read/30038942/hdad5-35-adenovirus-vector-expressing-anti-crispr-peptides-decreases-crispr-cas9-toxicity-in-human-hematopoietic-stem-cells
#5
Chang Li, Nikoletta Psatha, Sucheol Gil, Hongjie Wang, Thalia Papayannopoulou, André Lieber
We generated helper-dependent HDAd5/35++ adenovirus vectors expressing CRISPR/Cas9 for potential hematopoietic stem cells (HSCs) gene therapy of β-thalassemia and sickle cell disease through re-activation of fetal γ-globin expression (HDAd-globin-CRISPR). The process of CRISPR/Cas9 gene transfer using these vectors was not associated with death of human CD34+ cells and did not affect their in vitro expansion and erythroid differentiation. However, functional assays for primitive HSCs, e.g., multi-lineage progenitor colony formation and engraftment in irradiated NOD/Shi-scid/interleukin-2 receptor γ (IL-2Rγ) null (NSG) mice, revealed toxicity of HDAd-globin-CRISPR vectors related to the prolonged expression and activity of CRISPR/Cas9...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29959116/-regulation-of-%C3%AE-globin-gene-expression-and-its-clinical-applications
#6
Jun Yi Ju, Quan Zhao
Human hemoglobin, a tetramer containing two α globins and two β globins, is responsible for oxygen transportation in the body. Globin genes are clustered in the genome and their expressions are regulated by a variety of cis-acting elements and trans-acting factors, exhibiting a developmental- and tissue-specific manner. β-thalassemia and sickle cell diseases are two of the most common autosomal recessive disorders caused by mutations in the β-globin gene. Besides α- and β-globins, the human genome also has a third globin gene-γ-globin...
June 20, 2018: Yi Chuan, Hereditas
https://www.readbyqxmd.com/read/29946143/in-utero-nanoparticle-delivery-for-site-specific-genome-editing
#7
Adele S Ricciardi, Raman Bahal, James S Farrelly, Elias Quijano, Anthony H Bianchi, Valerie L Luks, Rachael Putman, Francesc López-Giráldez, Süleyman Coşkun, Eric Song, Yanfeng Liu, Wei-Che Hsieh, Danith H Ly, David H Stitelman, Peter M Glazer, W Mark Saltzman
Genetic diseases can be diagnosed early during pregnancy, but many monogenic disorders continue to cause considerable neonatal and pediatric morbidity and mortality. Early intervention through intrauterine gene editing, however, could correct the genetic defect, potentially allowing for normal organ development, functional disease improvement, or cure. Here we demonstrate safe intravenous and intra-amniotic administration of polymeric nanoparticles to fetal mouse tissues at selected gestational ages with no effect on survival or postnatal growth...
June 26, 2018: Nature Communications
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
#8
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, primarily 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 reactivation of fetal γ-globin expression in red blood cells. Because models involving erythroid differentiation of CD34+ cells have limitations in assessing γ-globin reactivation, we focused on human β-globin locus-transgenic (β-YAC) mice...
June 28, 2018: Blood
https://www.readbyqxmd.com/read/29606353/direct-promoter-repression-by-bcl11a-controls-the-fetal-to-adult-hemoglobin-switch
#9
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
#10
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/29458735/gene-therapy-and-genome-editing
#11
REVIEW
Farid Boulad, Jorge Mansilla-Soto, Annalisa Cabriolu, Isabelle Rivière, Michel Sadelain
The β-thalassemias are inherited blood disorders that result from insufficient production of the β-chain of hemoglobin. More than 200 different mutations have been identified. β-Thalassemia major requires life-long transfusions. The only cure for severe β-thalassemia is to provide patients with hematopoietic stem cells. Globin gene therapy promises a curative autologous stem cell transplantation without the immunologic complications of allogeneic transplantation. The future directions of gene therapy include enhancement of lentiviral vector-based approaches, fine tuning of the conditioning regimen, and the design of safer vectors...
April 2018: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/29370156/crispr-cas9-genome-editing-in-human-hematopoietic-stem-cells
#12
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
#13
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
#14
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/29222267/new-therapeutic-targets-in-transfusion-dependent-and-independent-thalassemia
#15
REVIEW
M Domenica Cappellini, Irene Motta
β-Thalassemias are characterized by reduced production of β-globin chain, resulting in α/β-chain unbalance and precipitation of α-globin-heme complexes and determining ineffective erythropoiesis. Ineffective erythropoiesis, chronic hemolytic anemia, and compensatory hematopoietic expansion are the disease hallmarks, and they are related to the severity of the chain unbalance. Several clinical forms of β-thalassemia, including the coinheritance of β-thalassemia with hemoglobin E resulting in hemoglobin E/β-thalassemia, have been described...
December 8, 2017: Hematology—the Education Program of the American Society of Hematology
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
#16
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
#17
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
#18
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/28945022/-progress-of-gene-editing-technologies-and-prospect-in-traditional-chinese-medicine
#19
REVIEW
Yan-Yan Ma, Jing-Zhe Li, Er-Ning Gao, Dan Qian, Ju-Ying Zhong, Chang-Zhen Liu
Gene editing is a kind of technologies that makes precise modification to the genome. It can be used to knock out/in and replace the specific DNA fragment, and make accurate gene editing on the genome level. The essence of the technique is the DNA sequence change with use of non homologous end link repair and homologous recombination repair, combined with specific DNA target recognition and endonuclease.This technology has wide range of development prospects and high application value in terms of scientific research, agriculture, medical treatment and other fields...
January 2017: Zhongguo Zhong Yao za Zhi, Zhongguo Zhongyao Zazhi, China Journal of Chinese Materia Medica
https://www.readbyqxmd.com/read/28540737/investigational-drugs-in-phase-i-and-phase-ii-clinical-trials-for-thalassemia
#20
REVIEW
Irene Motta, Natalia Scaramellini, Maria Domenica Cappellini
Regular transfusion and iron chelation are the current treatment of severe forms of thalassemia. As a consequence of this demanding supportive treatment, there are several unmet therapeutic needs. Due to a deeper understanding in the pathophysiology of thalassemia, new therapeutic strategies have been developed that are now in pre-clinical and clinical trials. Areas covered: Activin receptor ligand traps (luspatercept and sotatercept), drugs targeting ineffective erythropoiesis, showed encouraging results in Phase I and II clinical trials...
July 2017: Expert Opinion on Investigational Drugs
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