| 书目名称 | Gene and Cell Therapies for Beta-Globinopathies | | 编辑 | Punam Malik,John Tisdale | | 视频video | | | 概述 | This book offers a combined review of state of the art in gene and cell therapies for hemoglobinopathies.Short, succinct and comprehensive review of the current state of the field.Prospects of gene an | | 丛书名称 | Advances in Experimental Medicine and Biology | | 图书封面 |  | | 描述 | .Hemoglobin defects, specifically sickle cell disease & thalassemia, combined, constitute the most common monogenic disorders in the world. In fact, nearly 2% of the world’s population carries a globin gene mutation. The transfer of the corrective globin gene through the HSC compartment by allogeneic HSC transplantation (HSCT) has already proven curative in both SCD and thalassemia patients, and provides the proof of concept that genetic manipulation of the defective organ might be equally therapeutic. However, procedural toxicities and the requirement of an HLA-matched sibling donor limit this approach to a fraction of affected individuals. The editors review the progress & the state of the field in HSCT for hemoglobinopathies & shed light on the major changes expected in the next decade. Although allogeneic HSCT is a curative option, it is limited by the availability of matched donors, which are often available only to 15-20% of patients. An alternative to allogeneic HS.CT is genetic correction of autologous HSCs, to overcome donor availability & immune side effects. This Book reviews the progress made on additive gene therapy approaches & the current state of the field. Finally, | | 出版日期 | Book 2017 | | 关键词 | Beta-Globinopathies; Hemoglobinopathies; cell therapy; gene therapy; thalassemias | | 版次 | 1 | | doi | https://doi.org/10.1007/978-1-4939-7299-9 | | isbn_softcover | 978-1-4939-8446-6 | | isbn_ebook | 978-1-4939-7299-9Series ISSN 0065-2598 Series E-ISSN 2214-8019 | | issn_series | 0065-2598 | | copyright | Springer Science+Business Media LLC 2017 |
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Front Matter |
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Abstract
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,Clinical Features of β-Thalassemia and Sickle Cell Disease, |
Patrick T. McGann,Alecia C. Nero,Russell E. Ware |
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Abstract
Sickle cell disease (SCD) and β-thalassemia are among the most common inherited diseases, affecting millions of persons globally. It is estimated that 5–7% of the world’s population is a carrier of a significant hemoglobin variant. Without early diagnosis followed by initiation of preventative and therapeutic care, both SCD and β-thalassemia result in significant morbidity and early mortality. Despite great strides in the understanding of the molecular basis and pathophysiology of these conditions, the burden of disease remains high, particularly in limited resource settings. Current therapy relies heavily upon the availability and safety of erythrocyte transfusions to treat acute and chronic complications of these conditions, but frequent transfusions results in significant iron overload, as well as challenges from acquired infections and alloimmunization. Hydroxyurea is a highly effective treatment for SCD but less so for β-thalassemia, and does not represent curative therapy. As technology and use of cellular and gene therapies expand, SCD and thalassemia should be among the highest disease priorities.
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,Genetic Basis and Genetic Modifiers of β-Thalassemia and Sickle Cell Disease, |
Swee Lay Thein |
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Abstract
β-thalassemia and sickle cell disease (SCD) are prototypical Mendelian single gene disorders, both caused by mutations affecting the adult β-globin gene. Despite the apparent genetic simplicity, both disorders display a remarkable spectrum of phenotypic severity and share two major genetic modifiers—α-globin genotype and innate ability to produce fetal hemoglobin (HbF, α.γ.)..This article provides an overview of the genetic basis for SCD and β-thalassemia, and genetic modifiers identified through phenotype correlation studies. Identification of the genetic variants modifying HbF production in combination with α-globin genotype provide some prediction of disease severity for β-thalassemia and SCD but generation of a personalized genetic risk score to inform prognosis and guide management requires a larger panel of genetic modifiers yet to be discovered..Nonetheless, genetic studies have been successful in characterizing some of the key variants and pathways involved in HbF regulation, providing new therapeutic targets for HbF reactivation.
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,Current Standards of Care and Long Term Outcomes for Thalassemia and Sickle Cell Disease, |
Satheesh Chonat,Charles T. Quinn |
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Abstract
Thalassemia and sickle cell disease (SCD) are disorders of hemoglobin that affect millions of people worldwide. The carrier states for these diseases arose as common, balanced polymorphisms during human history because they afforded protection against severe forms of malaria. These complex, multisystem diseases are reviewed here with a focus on current standards of clinical management and recent research findings. The importance of a comprehensive, multidisciplinary and lifelong system of care is also emphasized.
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,Allogeneic/Matched Related Transplantation for β-Thalassemia and Sickle Cell Anemia, |
Françoise Bernaudin,Corinne Pondarré,Claire Galambrun,Isabelle Thuret |
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Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) can cure single gene disorders such as thalassemia and sickle cell anemia (SCA). These non-malignant diseases have in common severe hemolytic anemia and high proliferative bone marrow, requiring frequent transfusions. The risk of rejection is high and graft-vs-host disease is not desirable. Important progress has been made in the management of these diseases, including leukocyte depletion of blood products, and chelation therapy, for both diseases, and erythrocytapheresis and hydroxycarbamide for SCA. However, morbidity and quality of life are still of concern. Results have also significantly improved for HSCT, with the reduction of rejection by using anti-thymocyte globulin (ATG), which also decreases the risk of chronic graft-vs-host disease. Current data show a more than 90% chance of cure with myeloablative conditioning in children with hemoglobinopathy and a geno-identical donor. Results are similar whether the cell source is cord blood or bone marrow. Because of the risk of conditioning-related infertility, ovarian and/or testis cryopreservation should be discussed. Non-myeloablative conditioning regimens have also bee
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,Alternative Donor/Unrelated Donor Transplants for the β-Thalassemia and Sickle Cell Disease, |
Courtney D. Fitzhugh,Allistair Abraham,Matthew M. Hsieh |
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Abstract
Considerable progress with respect to donor source has been achieved in allogeneic stem cell transplant for patients with hemoglobin disorders, with matched sibling donors in the 1980s, matched unrelated donors and cord blood sources in the 1990s, and haploidentical donors in the 2000s. Many studies have solidified hematopoietic progenitors from matched sibling marrow, cord blood, or mobilized peripheral blood as the best source—with the lowest graft rejection and graft versus host disease (GvHD), and highest disease-free survival rates. For patients without HLA-matched sibling donors, but who are otherwise eligible for transplant, fully allelic matched unrelated donor (8/8 HLA-A, B, C, DRB1) appears to be the next best option, though an ongoing study in patients with sickle cell disease will provide data that are currently lacking. There are high GvHD rates and low engraftment rates in some of the unrelated cord transplant studies. Haploidentical donors have emerged in the last decade to have less GvHD; however, improvements are needed to increase the engraftment rate. Thus the decision to use unrelated cord blood units or haploidentical donors may depend on the institutional expe
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,Gene Addition Strategies for β-Thalassemia and Sickle Cell Anemia, |
Alisa C. Dong,Stefano Rivella |
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Abstract
Beta-thalassemia and sickle cell anemia are two of the most common diseases related to the hemoglobin protein. In these diseases, the beta-globin gene is mutated, causing severe anemia and ineffective erythropoiesis. Patients can additionally present with a number of life-threatening co-morbidities, such as stroke or spontaneous fractures. Current treatment involves transfusion and iron chelation; allogeneic bone marrow transplant is the only curative option, but is limited by the availability of matching donors and graft-versus-host disease. As these two diseases are monogenic diseases, they make an attractive setting for gene therapy. Gene therapy aims to correct the mutated beta-globin gene or add back a functional copy of beta- or gamma-globin. Initial gene therapy work was done with oncoretroviral vectors, but has since shifted to lentiviral vectors. Currently, there are a few clinical trials underway to test the curative potential of some of these lentiviral vectors. This review will highlight the work done thus far, and present the challenges still facing gene therapy, such as genome toxicity concerns and achieving sufficient transgene expression to cure those with the most
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,Reactivation of Fetal Hemoglobin for Treating β-Thalassemia and Sickle Cell Disease, |
Shuaiying Cui,James Douglas Engel |
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Abstract
Reactivation of fetal hemoglobin (HbF) in adult hematopoietic cells has the potential for great clinical benefit in patients bearing deleterious mutations in the β-globin gene, such as β-thalassemia and sickle cell disease (SCD), since increasing the production of HbF can compensate for underproduction of β-globin chains (in β-thalassemia) and it can also disrupt sickle hemoglobin polymerization (in SCD). Thus for the past few decades, concerted efforts have been made to identify an effective way to induce the synthesis of HbF in adult erythroid cells for potential therapeutic relief from the effects of these β-globinopathies. Chemical inducers of HbF as well as a number of transcription factors that are able to reactivate HbF synthesis in vitro and in vivo in adult erythroid cells have been identified. However, there has been only limited success in attempts to manipulate either the drugs or regulatory proteins, and in only a fraction of patients, and there is wide variation in individual response to these drugs or transcription factors. These studies highlight the importance for understanding the molecular mechanisms underlying hemoglobin switching so that future studies can be d
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,Genome Editing for the β-Hemoglobinopathies, |
Matthew H. Porteus |
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Abstract
The β-hemoglobinopathies are diverse set of disorders caused by mutations in the β-globin (.) 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 . can result in lethal diseases or diseases with multi-organ dysfunction. . 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). Sickle cell disease and β-thalassemia are both the most prevalent and the most devastating of the β-hemoglobinopathies.
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,Gene and Cell Therapy for β-Thalassemia and Sickle Cell Disease with Induced Pluripotent Stem Cells |
Eirini P. Papapetrou |
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Abstract
In recent years, breakthroughs in human pluripotent stem cell (hPSC) research, namely cellular reprogramming and the emergence of sophisticated genetic engineering technologies, have opened new frontiers for cell and gene therapy. The prospect of using hPSCs, either autologous or histocompatible, as targets of genetic modification and their differentiated progeny as cell products for transplantation, presents a new paradigm of regenerative medicine of potential tremendous value for the treatment of blood disorders, including beta-thalassemia (BT) and sickle cell disease (SCD). Despite advances at a remarkable pace and great promise, many roadblocks remain before clinical translation can be realistically considered. Here we discuss the theoretical advantages of cell therapies utilizing hPSC derivatives, recent proof-of-principle studies and the main challenges towards realizing the potential of hPSC therapies in the clinic.
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Back Matter |
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Abstract
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发表于 2025-3-21 19:19:50
