Recent Progress in Gene Therapy and Other Targeted Therapeutic Approaches for Beta Thalassemia

2019 ◽  
Vol 20 (16) ◽  
pp. 1603-1623 ◽  
Author(s):  
Eman M. Hamed ◽  
Mohamed Hussein Meabed ◽  
Usama Farghaly Aly ◽  
Raghda R.S. Hussein
Keyword(s):  
Gene Therapy ◽  
Cell Transplantation ◽  
B Cell Lymphoma ◽  
Thalassemia Major ◽  
Phase Iii ◽  
Beta Thalassemia ◽  
Ineffective Erythropoiesis ◽  
Hematopoietic Stem ◽  
Beta Thalassemia Major ◽  
Autologous Cell Transplantation

Beta-thalassemia is a genetic disorder characterized by the impaired synthesis of the betaglobin chain of adult hemoglobin. The disorder has a complex pathophysiology that affects multiple organ systems. The main complications of beta thalassemia are ineffective erythropoiesis, chronic hemolytic anemia and hemosiderosis-induced organ dysfunction. Regular blood transfusions are the main therapy for beta thalassemia major; however, this treatment can cause cardiac and hepatic hemosiderosis – the most common cause of death in these patients. This review focuses on unique future therapeutic interventions for thalassemia that reverse splenomegaly, reduce transfusion frequency, decrease iron toxicity in organs, and correct chronic anemia. The targeted effective protocols include hemoglobin fetal inducers, ineffective erythropoiesis correctors, antioxidants, vitamins, and natural products. Resveratrol is a new herbal therapeutic approach which serves as fetal Hb inducer in beta thalassemia. Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for beta thalassemia major and is preferred over iron chelation and blood transfusion for ensuring long life in these patients. Meanwhile, several molecular therapies, such as ActRIIB/IgG1 Fc recombinant protein, have emerged to address complications of beta thalassemia or the adverse effects of current drugs. Regarding gene correction strategies, a phase III trial called HGB-207 (Northstar-2; NCT02906202) is evaluating the efficacy and safety of autologous cell transplantation with LentiGlobin. Advanced gene-editing approaches aim to cut DNA at a targeted site and convert HbF to HbA during infancy, such as the suppression of BCL11A (B cell lymphoma 11A), HPFH (hereditary persistence of fetal hemoglobin) and zinc-finger nucleases. Gene therapy is progressing rapidly, with multiple clinical trials being conducted in many countries and the promise of commercial products to be available in the near future.

Bench to Bedside-Gene Therapy for Thalassemia and Sickle Cell Disease

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. SCI-18-SCI-18 ◽  
Author(s):  
Philippe Leboulch
Keyword(s):  
Gene Therapy ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Thalassemia Major ◽  
Beta Thalassemia ◽  
Cell Disease ◽  
Hematopoietic Stem ◽  
Beta Thalassemia Major ◽  
Transfusion Independence ◽  
Novel Therapeutic

Abstract The beta-hemoglobinopathies (beta-thalassemia and sickle cell disease) are the most prevalent inherited disorders worldwide and affect millions. Patients with beta-thalassemia major cannot survive without monthly, lifelong transfusions together with iron chelation therapy, and severe cases of sickle cell disease suffer from multiple life-threatening complications. Both categories of patients often have a shortened life expectancy in spite of supportive therapies, which impose an enormous financial burden on affected countries. The only available curative therapy is allogeneic hematopoietic stem cell transplantation, although most patients do not have an HLA-matched sibling donor, and those who do still risk graft rejection or graft-versus-host disease with associated morbidity and early mortality. This is why autologous gene therapy, by ex vivo transfer into the patient's own hematopoietic stem cells of a derivative of the normal beta-globin gene whose expression is appropriately regulated, is an attractive novel therapeutic modality. In addition, the very large number of known mutations causing beta-thalassemia makes gene therapy by gene addition ideally suited for regulatory product approval rather than the many mutation-specific products that would be required for site-specific gene correction. However, gene therapy of these disorders is especially challenging given the requirement for massive hemoglobin production in a lineage specific manner and the lack of selective advantage for corrected hematopoietic stem cells. During the past two decades, we and others have devised lentiviral vectors and applicable protocols to achieve the permanent correction of mouse models of the beta-hemoglobinopathies. The first approved human clinical trial worldwide resulted in the conversion to transfusion-independence of a patient with severe betaE/beta0-thalassemia, who required monthly transfusions since early childhood. This patient demonstrated prolonged transfusion-independent for over 8 years after gene therapy, and the initially identified partially dominant integration site (HMGA2) is no longer preeminent. A further optimized vector with high-grade purification is now being used in subsequent multi-center clinical trials in the USA, France, Australia, and Thailand both for beta-thalassemia major and severe sickle cell disease. As of the last public disclosure in June 2015, 34 subjects have been enrolled, of whom 12 and 2 patients with beta-thalassemia major and severe sickle cell disease, respectively, have undergone the gene therapy procedure. Currently analysable patients with beta-thalassemia major have rapidly decreased their transfusional needs or become completely transfusion-independent, often with near normal hemoglobin values and polyclonal distribution of vector bearing progenitors. Interestingly, conversion to transfusion-independence also occurred in a Cooley's anemia patient of the beta0/beta0 genotype. With regard to the first analysable patient with sickle cell disease, the anti-sickling globin variant utilized in the vector (βT87Q) is expressed at 40% level of all hemoglobin chains - a level well above the expected sickling inhibitory threshold - resulting in improvements in disease-specific biological markers and no hospitalization for sickle cell complications or acute episode despite weaning off transfusions, which this patient was receiving regularly for the prevention of stroke relapse. Prospects for bringing this novel therapeutic approach to medical practice and for complementary approaches to increase safety and efficacy will be discussed. Disclosures Leboulch: bluebird bio: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

Talasemi Majör Hastalarında Kök Hücre Transplantasyonu Sonrası Immün Yeniden Yapılanmanın Değerlendirilmesi

2020 ◽  
Vol 8 (3) ◽  
pp. 113-119
Author(s):  
Baran ERMAN ◽  
Başak ADAKLI AKSOY
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Immune Reconstitution ◽  
Thalassemia Major ◽  
Lymphoid Cells ◽  
Beta Thalassemia ◽  
Cell Recovery ◽  
Hematopoietic Stem ◽  
Hematologic Disorder

Introduction: Beta‐thalassemia (β‐TM) is one of the most common, autosomal recessive inherited hematologic disorder in the world. Since hematopoietic stem cell transplantation (HSCT) is the only curative treatment, determination of cellular immune reconstitution is crucial for understanding of a successful clinical outcome. Here, we evaluated lymphoid reconstitution in pediatric patients with thalassemia major after stem cell transplantation. Material and Methods: The study included 20 patients with beta‐thalassemia major who underwent HSCT. We assessed the clinical and laboratory information of the patients retrospectively. Results: After one year from transplantation, all patients were alive and blood transfusion independent. CD4+ T cell recovery was poor and CD4/CD8 ratio was impaired in the vast majority of the patients. Percentages and absolute counts of the other lymphoid cells generally reached the normal levels within 12 months. Seventeen patients had full donor chimerism while only 3 of 20 had low chimerism levels ranging between 55–86%. Conclusion: Although a successful clinical course and immune reconstitution were observed, the patients should be followed up carefully. Because, the poor engraftment of CD4+ T lymphocytes may lead severe infections in the patients. Keywords: beta‐thalassemia, stem cell transplantation, immune reconstitution

scholarly journals Advances in stem cell transplantation and gene therapy in the β-hemoglobinopathies

Hematology ◽  
2012 ◽  
Vol 2012 (1) ◽  
pp. 276-283 ◽  
Author(s):  
Emmanuel Payen ◽  
Philippe Leboulch
Keyword(s):  
Gene Therapy ◽  
Stem Cell ◽  
Thalassemia Major ◽  
Beta Thalassemia ◽  
Hematopoietic Stem ◽  
Transfer Vectors ◽  
Lentiviral Gene Therapy ◽  
High Level ◽  
Cell Gene ◽  
Level Production

Abstract High-level production of β-globin, γ-globin, or therapeutic mutant globins in the RBC lineage by hematopoietic stem cell gene therapy ameliorates or cures the hemoglobinopathies sickle cell disease and beta thalassemia, which are major causes of morbidity and mortality worldwide. Considerable efforts have been made in the last 2 decades in devising suitable gene-transfer vectors and protocols to achieve this goal. Five years ago, the first βE/β0-thalassemia major (transfusion-dependent) patient was treated by globin lentiviral gene therapy without injection of backup cells. This patient has become completely transfusion independent for the past 4 years and has global amelioration of the thalassemic phenotype. Partial clonal dominance for an intragenic site (HMGA2) of chromosomal integration of the vector was observed in this patient without a loss of hematopoietic homeostasis. Other patients are now receiving transplantations while researchers are carefully weighing the benefit/risk ratio and continuing the development of further modified vectors and protocols to improve outcomes further with respect to safety and efficacy.

scholarly journals Beta Thalassemia Major: Overview of Molecular Etiology, Pathophysiology, Current and Novel Therapeutic Approaches

2020 ◽  
pp. 1-15
Author(s):  
S. El Kababi ◽  
B. El Khalfi ◽  
K. El Maani ◽  
A. Soukri
Keyword(s):  
Iron Overload ◽  
Therapeutic Potential ◽  
Clinical Manifestations ◽  
Thalassemia Major ◽  
Severe Form ◽  
Definitive Treatment ◽  
Beta Thalassemia ◽  
Globin Genes ◽  
Ineffective Erythropoiesis ◽  
Hematopoietic Stem

Major beta thalassemia is a severe form of thalassemia caused by the alteration of two beta globin genes resulting in a defective synthesis of hemoglobin. It is characterized by chronic severe anemia, ineffective erythropoiesis (IE) and iron overload. However although the thransfusion and chelation assosciated constitute the basis of the traitement curently recommended, they do not allow always to control the iron overload induced by pathology and repeated transfusions. Hematopoietic stem cell transplantation (HSCT) has proven to be a definitive treatment for beta thalassemia. However, this procedure is confronted to immunological complications and the small nomber of histocompatible donors. In the face of these therapeutic blocks, much research has been undertaken in recent years leading to the development of a number of promising therapeutic strategies in order to reduce the constraints linked to current chronic treatments, and to move towards an access to healing for all patients. Among other three approaches are envisaged and are in the experimental phase: Gene therapy to restore globin chain imbalance, Improve ineffective erythropoiesis and Improve iron dysregulation. In this article we give a view on the pathophysiology, clinical manifestations, genetic origin of beta-thalassaemia major. The second part presents the therapeutic arsenal currently used, and its limits leading to therapeutic impasse. The last part explores the scientific tracks that present a real therapeutic potential in β-Thalassemia.

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