Long-term outcomes of lentiviral gene therapy for the β-hemoglobinopathies: the HGB-205 trial

Magrin, Elisa; Semeraro, Michaela; Hebert, Nicolas; Joseph, Laure; Magnani, Alessandra; Chalumeau, Anne; Gabrion, Aurélie; Roudaut, Cécile; Marouene, Jouda; Lefrère, François; Diana, Jean-Sébastien; Denis, Adeline; Neven, Bénédicte; Funck-Brentano, Isabelle; Nègre, Olivier; Renolleau, Sylvain; Brousse, Valentine; Kiger, Laurent; Touzot, Fabien; Poirot, Catherine; Bourget, Philippe; Nemer, Wassim El; Blanche, Stéphane; Tréluyer, Jean‐Marc; Asmal, Mohammed; Walls, Courtney; Beuzard, Yves; Schmidt, Manfred; Hacein‐Bey‐Abina, Salima; Asnafi, Vahid; Guichard, Isabelle; Poirée, Maryline; Monpoux, Fabrice; Touraine, Philippe; Brouzes, Chantal; Montalembert, Mariane de; Payen, Emmanuel; Six, Emmanuelle; Ribeil, Jean-Antoine; Miccio, Annarita; Bartolucci, Pablo; Leboulch, Philippe; Cavazzana, Marina

doi:10.1038/s41591-021-01650-w

Cited by 71 publications

(69 citation statements)

References 34 publications

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“…Secondly, the core HS4 insulator was determined to cause greater genomic instability and lower titers [ 61 ]. Its removal from the U3 region (an original HIV-1-derived promoter) plus the incorporation of the cytomegalovirus promoter to increase vector transcription led to the creation of a new LV, BB305 [ 60 , 62 ]. Thirdly, the HMGA2 integration resulted in clonal dominance without leukemia development.…”

Section: Hsc-targeted Gene Therapy With Lentiviral Gene Addition In Scdmentioning

confidence: 99%

Hematopoietic Stem Cell Gene-Addition/Editing Therapy in Sickle Cell Disease

Germino-Watnick

Hinds

et al. 2022

Cells

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Autologous hematopoietic stem cell (HSC)-targeted gene therapy provides a one-time cure for various genetic diseases including sickle cell disease (SCD) and β-thalassemia. SCD is caused by a point mutation (20A > T) in the β-globin gene. Since SCD is the most common single-gene disorder, curing SCD is a primary goal in HSC gene therapy. β-thalassemia results from either the absence or the reduction of β-globin expression, and it can be cured using similar strategies. In HSC gene-addition therapy, patient CD34+ HSCs are genetically modified by adding a therapeutic β-globin gene with lentiviral transduction, followed by autologous transplantation. Alternatively, novel gene-editing therapies allow for the correction of the mutated β-globin gene, instead of addition. Furthermore, these diseases can be cured by γ-globin induction based on gene addition/editing in HSCs. In this review, we discuss HSC-targeted gene therapy in SCD with gene addition as well as gene editing.

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Section: Hsc-targeted Gene Therapy With Lentiviral Gene Addition In Scdmentioning

confidence: 99%

Hematopoietic Stem Cell Gene-Addition/Editing Therapy in Sickle Cell Disease

Germino-Watnick

Hinds

et al. 2022

Cells

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“…More than 350 patients with different pathologies have been successfully treated with this strategy. Many inherited hematological diseases ( Bueren et al, 2020 ; Ferrari et al, 2021 ), including hemoglobinopathies like β-thalassemia ( Cavazzana-calvo et al, 2010 ; Thompson et al, 2018 ; Locatelli et al, 2021 ; Magrin et al, 2022 ) or SCD ( Holmes et al, 2017 ; Ribeil et al, 2017 ; Kanter et al, 2021 ; Magrin et al, 2022 ), have been addressed ( Figure 1 ). In fact, lentivirally corrected HSPCs have been approved for clinical application in transfusion-Dependent β-thalassemia patients (Zynteglo 2 ).…”

Section: Additional Gene Therapy: Current Successesmentioning

confidence: 99%

Gene Editing for Inherited Red Blood Cell Diseases

et al. 2022

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Today gene therapy is a real therapeutic option to address inherited hematological diseases that could be beneficial for thousands of patients worldwide. Currently, gene therapy is used to treat different monogenic hematological pathologies, including several red blood cell diseases such as β-thalassemia, sickle cell disease and pyruvate kinase deficiency. This approach is based on addition gene therapy, which consists of the correction of hematopoietic stem cells (HSCs) using lentiviral vectors, which integrate a corrected version of the altered gene. Lentivirally-corrected HSCs generate healthy cells that compensate for the deficiency caused by genetic mutations. Despite its successful results, this approach lacks both control of the integration of the transgene into the genome and endogenous regulation of the therapeutic gene, both of which are important aspects that might be a cause for concern. To overcome these limitations, gene editing is able to correct the altered gene through more precise and safer approaches. Cheap and easy-to-design gene editing tools, such as the CRISPR/Cas9 system, allow the specific correction of the altered gene without affecting the rest of the genome. Inherited erythroid diseases, such as thalassemia, sickle cell disease and Pyruvate Kinase Deficiency, have been the test bed for these gene editing strategies, and promising results are currently being seen. CRISPR/Cas9 system has been successfully used to manipulate globin regulation to re-activate fetal globin chains in adult red blood cells and to compensate for hemoglobin defects. Knock-in at the mutated locus to express the therapeutic gene under the endogenous gene regulatory region has also been accomplished successfully. Thanks to the lessons learned from previous lentiviral gene therapy research and trials, gene editing for red blood cell diseases is rapidly moving from its proof-of-concept to its first exciting results in the clinic. Indeed, patients suffering from β-thalassemia and sickle cell disease have already been successfully treated with gene editing, which will hopefully inspire the use of gene editing to cure erythroid disorders and many other inherited diseases in the near future.

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“…23 In two patients with sickle cell disease treated with LentiGlobin gene therapy, and achieving HbA T87Q levels of about 46%, P 50 was 27-29 torr compared with 32 torr in untreated sickle cell disease controls. 24 Although it is unlikely that high HbF levels, even 100% that occurs after CRISPR-Cas9 gene editing the BCL11A enhancer in β thalassemia, will be physiologically detrimental, LentiGlobin treatment should not incur the same issues of hemoglobin-O 2 affinity raised with HbF induction.…”

Section: Effects Of 40% Hbf On P 5 0 In Sickle Cell Anemiamentioning

confidence: 99%

Fetal hemoglobin in β hemoglobinopathies: Is enough too much?

Steinberg

2022

American J Hematol

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Cell-based therapies inducing about 40% fetal hemoglobin (HbF), or a HbF-like hemoglobin in most erythrocytes, can-at least in the shortterm-effect a cure or near-cure of β hemoglobinopathies, which are humankind's most common Mendelian diseases. [1][2][3] In sickle cell disease, a point mutation in the normal β-globin gene (HBB) directs the synthesis of sickle hemoglobin (HbS), which polymerizes on deoxygenation, damaging the red cell and triggering a complex pathophysiology. HbF exerts a powerful anti-polymerization effect because the chances of both the HbF tetramer (α 2 γ 2 ) and the hybrid tetramer α 2 γβ S entering the polymer phase are nearly nil. 4 Hundreds of different HBB mutations cause β thalassemia where insufficient β-globin synthesis allows free unpaired α globin to accumulate, leading to ineffective erythropoiesis and severe anemia. γ-Globin pairs with α globin forming HbF and preventing, at its earliest stage, the pathophysiology of the β thalassemia phenotype.

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Long-term outcomes of lentiviral gene therapy for the β-hemoglobinopathies: the HGB-205 trial

Cited by 71 publications

References 34 publications

Hematopoietic Stem Cell Gene-Addition/Editing Therapy in Sickle Cell Disease

Hematopoietic Stem Cell Gene-Addition/Editing Therapy in Sickle Cell Disease

Gene Editing for Inherited Red Blood Cell Diseases

Fetal hemoglobin in β hemoglobinopathies: Is enough too much?

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