The potential of gene therapy approaches for the treatment of hemoglobinopathies: achievements and challenges

Goodman, Michael

doi:10.1177/2040620716653729

Cited by 35 publications

(32 citation statements)

References 84 publications

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“…Traditional gene therapies currently in clinical trials consist of inserting an additional globin gene via a lentiviral vector that integrates into the host cell's genome. After full or partial myeloablation, the genetically modified autologous HSPCs are returned to the patient where the modified cells repopulate the haematopoietic compartment [51]. While engraftment of only a small population of corrected HSPCs can result in amelioration of a hemoglobinopathy, highly efficient gene transfer must occur in order to modify a sufficient number of cells able to achieve long-term engraftment.…”

Section: Gene Therapymentioning

confidence: 99%

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

Kababi

Khalfi

Maani

et al. 2020

IBRR

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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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Section: Gene Therapymentioning

confidence: 99%

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

Kababi

Khalfi

Maani

et al. 2020

IBRR

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“…For example, b-thalassemia results from mutations that decrease b-globin levels, resulting in an imbalance in the ratio of a-globin to b-globin, and aggregation of the excess a-globin. 27 Thus, the aggregation is not caused by a change in a-globin's aggregation propensity, but instead by a change in the concentration of its binding partner. Protein levels and molecular interacting partners vary from organism to organism, from tissue to tissue, and even between subcellular compartments, potentially explaining why many aggregation-based diseases only affect specific tissues.…”

Section: Protein Expression and Abundancementioning

confidence: 99%

Manipulating the aggregation activity of human prion-like proteins

Cascarina

Paul

Ross

2017

Prion

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Considerable advances in understanding the protein features favoring prion formation in yeast have facilitated the development of effective yeast prion prediction algorithms. Here we discuss a recent study in which we systematically explored the utility of the yeast prion prediction algorithm PAPA for designing mutations to modulate the aggregation activity of the human prion-like protein hnRNPA2B1. Mutations in hnRNPA2B1 cause multisystem proteinopathy in humans, and accelerate aggregation of the protein in vitro. Additionally, mutant hnRNPA2B1 forms cytoplasmic inclusions when expressed in Drosophila, and the mutant prion-like domain can substitute for a portion of a yeast prion domain in supporting prion activity in yeast. PAPA was quite successful at predicting the effects of PrLD mutations on prion activity in yeast and on in vitro aggregation propensity. Additionally, PAPA successfully predicted the effects of most, but not all, mutations in the PrLD of the hnRNPA2B1 protein when expressed in Drosophila. These results suggest that PAPA is quite effective at predicting the effects of mutations on intrinsic aggregation propensity, but that intracellular factors can influence aggregation and prion-like activity in vivo. A more complete understanding of these intracellular factors may inform the next generation of prion prediction algorithms.

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“…4,5 The concept of gene therapy for b-thalassemia has moved from bench to bedside and is a promising treatment approach for patients with no matching donor available. [6][7][8][9] While long-term studies are underway in multiple centers in Europe and the United States, proof-of-principle of efficacy and safety has already been obtained in patients with b-thalassemia. [10][11][12] In addition to safety and effectiveness, the cost of gene therapy versus other options needs to be considered.…”

Section: Introductionmentioning

confidence: 99%

Innovative Curative Treatment of Beta Thalassemia: Cost-Efficacy Analysis of Gene Therapy Versus Allogenic Hematopoietic Stem-Cell Transplantation

et al. 2019

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Seventy-five percent of patients with beta thalassemia (b-thalassemia) do not have human leukocyte antigen-matched siblings and until recently had no access to a curative treatment. Gene therapy is a promising treatment that can be proposed to these patients. This study estimates its cost and efficacy. In a monocentric retrospective study and cost-efficacy analysis, this study compared the two-year outcomes and costs of patients with b-thalassemia treated by gene therapy and hematopoietic stem-cell transplantation (HSCT). Grade III and grade IV complications, hospitalizations, and length of stay were extracted from the hospital discharge data. Costs were estimated from hospital accounting information and national cost studies. A total of seven patients with b-thalassemia treated between 2009 and 2016 were included, of whom four received gene therapy. Patients treated by gene therapy were older and had fewer complications and hospital admissions. Infectious complications were three times more frequent for patients treated with HSCT than for gene therapy. Average costs were e608,086 for patients treated by gene therapy and e215,571 for HSCT. The total cost of the vector was 48% of the total cost of gene therapy. Gene therapy as a curative alternative for patients lacking human leukocyte antigen-matched donors was costlier but resulted in fewer complications than HSCT.

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The potential of gene therapy approaches for the treatment of hemoglobinopathies: achievements and challenges

Cited by 35 publications

References 84 publications

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

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

Manipulating the aggregation activity of human prion-like proteins

Innovative Curative Treatment of Beta Thalassemia: Cost-Efficacy Analysis of Gene Therapy Versus Allogenic Hematopoietic Stem-Cell Transplantation

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