Efficacy and Safety of a Single Dose of Exagamglogene Autotemcel for Transfusion-Dependent β-Thalassemia

Locatelli, Franco; Lang, Peter; Li, Amanda; Corbacioglu, Selim; Fuente, Josu de la; Wall, Donna A.; Liem, Robert I.; Meisel, Roland; Mapara, Markus Y.; Shah, Ami J.; Cappellini, Maria Domenica; Kattamis, Antonis; Sheth, Sujit; Bobruff, Yael; Bower, Laura; Zhang, Lanju; Sharma, A.; Song, Yang; Hobbs, William; Frangoul, Haydar

doi:10.1182/blood-2022-166881

Cited by 14 publications

(20 citation statements)

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“…CTX001 infusion led to the independence from transfusions in almost all patients with TDT (42/44 patients), with a sustained increase in HbF and thereby of total Hb levels (mean of >9 g/dL). All SCD patients ( n = 31) no longer presented severe VOCs after CTX001 infusion with a mean HbF increase of ∼40% at month 4 and attainment of mean Hb levels >11 g/dL ( 18 ).…”

Section: Congenital Anemiasmentioning

confidence: 99%

Rise of the planet of rare anemias: An update on emerging treatment strategies

Fattizzo

Motta²

2023

Front. Med.

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Therapeutic options for rare congenital (hemoglobinopathies, membrane and enzyme defects, congenital dyserythropoietic anemia) and acquired anemias [warm autoimmune hemolytic anemia (wAIHA), cold agglutinin disease CAD, paroxysmal nocturnal hemoglobinuria (PNH), and aplastic anemia (AA)] are rapidly expanding. The use of luspatercept, mitapivat and etavopivat in beta-thalassemia and pyruvate kinase deficiency (PKD) improves transfusion dependence, alleviating iron overload and long-term complications. Voxelotor, mitapivat, and etavopivat reduce vaso-occlusive crises in sickle cell disease (SCD). Gene therapy represents a fascinating approach, although patient selection, the toxicity of the conditioning regimens, and the possible long-term safety are still open issues. For acquired forms, wAIHA and CAD will soon benefit from targeted therapies beyond rituximab, including B-cell/plasma cell targeting agents (parsaclisib, rilzabrutinib, and isatuximab for wAIHA), complement inhibitors (pegcetacoplan and sutimlimab for CAD, ANX005 for wAIHA with complement activation), and inhibitors of extravascular hemolysis in the reticuloendothelial system (fostamatinib and FcRn inhibitors in wAIHA). PNH treatment is moving from the intravenous anti-C5 eculizumab to its long-term analog ravulizumab, and to subcutaneous and oral proximal inhibitors (anti-C3 pegcetacoplan, factor D and factor B inhibitors danicopan and iptacopan). These drugs have the potential to improve patient convenience and ameliorate residual anemia, although patient compliance becomes pivotal, and long-term safety requires further investigation. Finally, the addition of eltrombopag significantly ameliorated AA outcomes, and data regarding the alternative agent romiplostim are emerging. The accelerated evolution of treatment strategies will need further effort to identify the best candidate for each treatment in the precision medicine era.

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Section: Congenital Anemiasmentioning

confidence: 99%

Rise of the planet of rare anemias: An update on emerging treatment strategies

Fattizzo

Motta²

2023

Front. Med.

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“…Subsequent early study results with 31 patients with sickle cell disease reported that after a single exa-cell infusion, all patients in the trial experienced no adverse events related to therapy and no vaso-occlusive crises for 2–32 months after exa-cell therapy (for reference, patients experienced 2–9.5 severe vaso-occlusive crises in the two years preceding exa-cel) [ 93 ]; at six months post infusion, the average percentage of bone marrow CD34 + HSPCs or peripheral blood mononuclear cells (PBMCs) with an edited BCL11A allele was 86.6% or 76.0%, respectively. Additionally, early results from a β-thalassemia trial indicated that out of the 44 individuals in the trial, 42 of them did not require RBC transfusion post therapy in the 1–36 months post exa-cel; the 2 patients that had not stopped RBC transfusion had reduced the transfusion volume by ~80% (for reference, these 44 individuals had received between 15 and 71 RBC transfusions in the two years preceding exa-cell therapy) [ 94 ]; editing efficiencies were somewhat reduced in this study compared to the aforementioned trial for sickle cell disease, with the average percentage of bone marrow CD34 + HSPCs or PBMCs containing an edited BCL11A allele was 74.3% or 63.4%, respectively…”

Section: Current Use Of Crispr-cas Systems In Clinical Trialsmentioning

confidence: 99%

CRISPR-Cas System: The Current and Emerging Translational Landscape

Bhokisham

Laudermilch

Traeger

et al. 2023

Cells

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CRISPR-Cas technology has rapidly changed life science research and human medicine. The ability to add, remove, or edit human DNA sequences has transformative potential for treating congenital and acquired human diseases. The timely maturation of the cell and gene therapy ecosystem and its seamless integration with CRISPR-Cas technologies has enabled the development of therapies that could potentially cure not only monogenic diseases such as sickle cell anemia and muscular dystrophy, but also complex heterogenous diseases such as cancer and diabetes. Here, we review the current landscape of clinical trials involving the use of various CRISPR-Cas systems as therapeutics for human diseases, discuss challenges, and explore new CRISPR-Cas-based tools such as base editing, prime editing, CRISPR-based transcriptional regulation, CRISPR-based epigenome editing, and RNA editing, each promising new functionality and broadening therapeutic potential. Finally, we discuss how the CRISPR-Cas system is being used to understand the biology of human diseases through the generation of large animal disease models used for preclinical testing of emerging therapeutics.

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“…Exagamglogene autotemcel (exa‐cel) is a gene editing approach that utilizes CRISPR‐Cas9 technology to edit a target GATA1 binding site at +58 in the erythroid specific enhancer of the BCL11A gene in autologous CD34+ HSPCs 50,51 . The BCL11A protein is a repressor of γ‐globin; therefore, gene editing at the erythroid enhanced region of BCL11A will reduce expression of BCL11A specifically in erythroid cells and reactivate synthesis of HbF 50,51 .…”

Section: Clinical Trials Of Gene Addition and Gene Editing Approaches...mentioning

confidence: 99%

Defining curative endpoints for transfusion‐dependent β‐thalassemia in the era of gene therapy and gene editing

Corbacioglu,

Frangoul,

Locatelli

et al. 2023

American J Hematol

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Abstractβ‐thalassemia is a monogenic disease that results in varying degrees of anemia. In the most severe form, known as transfusion‐dependent β‐thalassemia (TDT), the clinical hallmarks are ineffective erythropoiesis and a requirement of regular, life‐long red blood cell transfusions, with the development of secondary clinical complications such as iron overload, end‐organ damage, and a risk of early mortality. With the exception of allogeneic hematopoietic cell transplantation, current treatments for TDT address disease symptoms and not the underlying cause of disease. Recently, a growing number of gene addition and gene editing‐based treatments for patients with TDT with the potential to provide a one‐time functional cure have entered clinical trials. A key challenge in the design and evaluation of these trials is selecting endpoints to evaluate if these novel genetic therapies have a curative versus an ameliorative effect. Here, we present an overview of the pathophysiology of TDT, review emerging gene addition or gene editing therapeutic approaches for TDT currently in clinical trials, and identify a series of endpoints that can quantify therapeutic effects, including a curative outcome.

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Efficacy and Safety of a Single Dose of Exagamglogene Autotemcel for Transfusion-Dependent β-Thalassemia

Cited by 14 publications

References 0 publications

Rise of the planet of rare anemias: An update on emerging treatment strategies

Rise of the planet of rare anemias: An update on emerging treatment strategies

CRISPR-Cas System: The Current and Emerging Translational Landscape

Defining curative endpoints for transfusion‐dependent β‐thalassemia in the era of gene therapy and gene editing

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