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

doi:10.1038/s41591-021-01650-w

Clinical Trial

. 2022 Jan;28(1):81-88.

doi: 10.1038/s41591-021-01650-w. Epub 2022 Jan 24.

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

Elisa Magrin^#^{1

2}, Michaela Semeraro^#^{3

4}, Nicolas Hebert^#^{5

6}, Laure Joseph¹, Alessandra Magnani^{1

2}, Anne Chalumeau⁷, Aurélie Gabrion^{1

2}, Cécile Roudaut^{1

2}, Jouda Marouene³, Francois Lefrere¹, Jean-Sebastien Diana¹, Adeline Denis⁷, Bénédicte Neven⁸, Isabelle Funck-Brentano⁸, Olivier Negre^{9

10}, Sylvain Renolleau¹¹, Valentine Brousse¹², Laurent Kiger⁵, Fabien Touzot^{1

2}, Catherine Poirot^{13

14}, Philippe Bourget¹⁵, Wassim El Nemer¹⁶, Stéphane Blanche⁸, Jean-Marc Tréluyer^{3

4}, Mohammed Asmal¹⁰, Courtney Walls¹⁰, Yves Beuzard^{5

9}, Manfred Schmidt¹⁷, Salima Hacein-Bey-Abina^{1

2}, Vahid Asnafi¹⁸, Isabelle Guichard¹⁹, Maryline Poirée²⁰, Fabrice Monpoux²¹, Philippe Touraine²², Chantal Brouzes²³, Mariane de Montalembert¹², Emmanuel Payen⁹, Emmanuelle Six⁷, Jean-Antoine Ribeil^{1

2

10}, Annarita Miccio⁷, Pablo Bartolucci^{5

6}, Philippe Leboulch^{24

25}, Marina Cavazzana^{26

27

28}

Affiliations

¹ Biotherapy Department, Hôpital Universitaire Necker Enfants-Malades, GH Paris Centre, Paris, France.
² Centre d'Investigation Clinique-Biothérapie, Hôpital Universitaire Necker Enfants-Malades, GH Paris Centre, Paris, France.
³ Centre d'Investigation Clinique-Unité de Recherche Clinique, Hôpital Universitaire Necker Enfants-Malades, GH Paris Centre, Paris, France.
⁴ Université de Paris, Paris, France.
⁵ Univ Paris Est Creteil, INSERM, EFS, IMRB, Créteil, France.
⁶ Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Université Paris-Est Créteil, Créteil, France.
⁷ IMAGINE Institute, Université de Paris, Sorbonne Paris Cité, Paris, France.
⁸ Pediatric Immunology and Hematology Department, Hôpital Necker Enfants-Malades, Paris, France.
⁹ CEA, INSERM, Université Paris-Saclay, Division of Innovative Therapies, Institut François Jacob, Fontenay aux Roses, France.
¹⁰ Bluebird Bio, Inc., Cambridge, MA, USA.
¹¹ Pediatric Intensive Care Unit, Hôpital Universitaire Necker Enfants-Malades, GH Paris Centre, Paris, France.
¹² Department of General Pediatrics and Pediatric Infectious Diseases, Hôpital Universitaire Necker Enfants-Malades, GH Paris Centre, Paris, France.
¹³ Department of Hematology, Fertility Preservation, Hôpital Saint Louis, Paris, France.
¹⁴ Sorbonne Université, Paris, France.
¹⁵ Pharmacy Department, Hôpital Universitaire Necker Enfants-Malades, GH Paris Centre, Paris, France.
¹⁶ Institut National de la Transfusion Sanguine (INTS), Paris, France.
¹⁷ GeneWerk GmbH, Heidelberg, Germany.
¹⁸ Université de Paris, Institut Necker-Enfants Malades, INSERM U1151, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants-Malades, Paris, France.
¹⁹ Service de Médecine Interne, Hôpital Nord, CHU de Saint-Étienne, Saint-Étienne, Paris, France.
²⁰ Department of Pediatric Hematology-Oncology, Centre Hospitalier Universitaire Lenval, Nice, France.
²¹ Unité d'Hémato-Oncologie Infantile. Hôpital de l'Archet 2, Nice, France.
²² Department of Endocrinology and Reproductive Medicine, Assistance Publique-Hopitaux de Paris, La Pitié-Salpêtrière, and Sorbonne University, Pierre et Marie Curie School of Medicine, Paris, France.
²³ Laboratory of Onco-hematology, Hôpital Necker-Enfants Malades, Paris, France.
²⁴ CEA, INSERM, Université Paris-Saclay, Division of Innovative Therapies, Institut François Jacob, Fontenay aux Roses, France. pleboulch@rics.bwh.harvard.edu.
²⁵ Genetics Division, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA. pleboulch@rics.bwh.harvard.edu.
²⁶ Université de Paris, Paris, France. m.cavazzana@aphp.fr.
²⁷ IMAGINE Institute, Université de Paris, Sorbonne Paris Cité, Paris, France. m.cavazzana@aphp.fr.
²⁸ Biotherapy Department and Clinical Investigation Center, Assistance Publique Hopitaux de Paris, INSERM, Paris, France. m.cavazzana@aphp.fr.

^# Contributed equally.

PMID: 35075288
DOI: 10.1038/s41591-021-01650-w

Clinical Trial

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

Elisa Magrin et al. Nat Med. 2022 Jan.

. 2022 Jan;28(1):81-88.

doi: 10.1038/s41591-021-01650-w. Epub 2022 Jan 24.

Authors

Affiliations

¹ Biotherapy Department, Hôpital Universitaire Necker Enfants-Malades, GH Paris Centre, Paris, France.
² Centre d'Investigation Clinique-Biothérapie, Hôpital Universitaire Necker Enfants-Malades, GH Paris Centre, Paris, France.
³ Centre d'Investigation Clinique-Unité de Recherche Clinique, Hôpital Universitaire Necker Enfants-Malades, GH Paris Centre, Paris, France.
⁴ Université de Paris, Paris, France.
⁵ Univ Paris Est Creteil, INSERM, EFS, IMRB, Créteil, France.
⁶ Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Université Paris-Est Créteil, Créteil, France.
⁷ IMAGINE Institute, Université de Paris, Sorbonne Paris Cité, Paris, France.
⁸ Pediatric Immunology and Hematology Department, Hôpital Necker Enfants-Malades, Paris, France.
⁹ CEA, INSERM, Université Paris-Saclay, Division of Innovative Therapies, Institut François Jacob, Fontenay aux Roses, France.
¹⁰ Bluebird Bio, Inc., Cambridge, MA, USA.
¹¹ Pediatric Intensive Care Unit, Hôpital Universitaire Necker Enfants-Malades, GH Paris Centre, Paris, France.
¹² Department of General Pediatrics and Pediatric Infectious Diseases, Hôpital Universitaire Necker Enfants-Malades, GH Paris Centre, Paris, France.
¹³ Department of Hematology, Fertility Preservation, Hôpital Saint Louis, Paris, France.
¹⁴ Sorbonne Université, Paris, France.
¹⁵ Pharmacy Department, Hôpital Universitaire Necker Enfants-Malades, GH Paris Centre, Paris, France.
¹⁶ Institut National de la Transfusion Sanguine (INTS), Paris, France.
¹⁷ GeneWerk GmbH, Heidelberg, Germany.
¹⁸ Université de Paris, Institut Necker-Enfants Malades, INSERM U1151, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants-Malades, Paris, France.
¹⁹ Service de Médecine Interne, Hôpital Nord, CHU de Saint-Étienne, Saint-Étienne, Paris, France.
²⁰ Department of Pediatric Hematology-Oncology, Centre Hospitalier Universitaire Lenval, Nice, France.
²¹ Unité d'Hémato-Oncologie Infantile. Hôpital de l'Archet 2, Nice, France.
²² Department of Endocrinology and Reproductive Medicine, Assistance Publique-Hopitaux de Paris, La Pitié-Salpêtrière, and Sorbonne University, Pierre et Marie Curie School of Medicine, Paris, France.
²³ Laboratory of Onco-hematology, Hôpital Necker-Enfants Malades, Paris, France.
²⁴ CEA, INSERM, Université Paris-Saclay, Division of Innovative Therapies, Institut François Jacob, Fontenay aux Roses, France. pleboulch@rics.bwh.harvard.edu.
²⁵ Genetics Division, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA. pleboulch@rics.bwh.harvard.edu.
²⁶ Université de Paris, Paris, France. m.cavazzana@aphp.fr.
²⁷ IMAGINE Institute, Université de Paris, Sorbonne Paris Cité, Paris, France. m.cavazzana@aphp.fr.
²⁸ Biotherapy Department and Clinical Investigation Center, Assistance Publique Hopitaux de Paris, INSERM, Paris, France. m.cavazzana@aphp.fr.

^# Contributed equally.

PMID: 35075288
DOI: 10.1038/s41591-021-01650-w

Abstract

Sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT) are the most prevalent monogenic disorders worldwide. Trial HGB-205 ( NCT02151526 ) aimed at evaluating gene therapy by autologous CD34⁺ cells transduced ex vivo with lentiviral vector BB305 that encodes the anti-sickling β^A-T87Q-globin expressed in the erythroid lineage. HGB-205 is a phase 1/2, open-label, single-arm, non-randomized interventional study of 2-year duration at a single center, followed by observation in long-term follow-up studies LTF-303 ( NCT02633943 ) and LTF-307 ( NCT04628585 ) for TDT and SCD, respectively. Inclusion and exclusion criteria were similar to those for allogeneic transplantation but restricted to patients lacking geno-identical, histocompatible donors. Four patients with TDT and three patients with SCD, ages 13-21 years, were treated after busulfan myeloablation 4.6-7.9 years ago, with a median follow-up of 4.5 years. Key primary endpoints included mortality, engraftment, replication-competent lentivirus and clonal dominance. No adverse events related to the drug product were observed. Clinical remission and remediation of biological hallmarks of the disease have been sustained in two of the three patients with SCD, and frequency of transfusions was reduced in the third. The patients with TDT are all transfusion free with improvement of dyserythropoiesis and iron overload.

PubMed Disclaimer

Cited by

CRISPR technology in human diseases.
Feng Q, Li Q, Zhou H, Wang Z, Lin C, Jiang Z, Liu T, Wang D. Feng Q, et al. MedComm (2020). 2024 Jul 29;5(8):e672. doi: 10.1002/mco2.672. eCollection 2024 Aug. MedComm (2020). 2024. PMID: 39081515 Free PMC article. Review.
Gene Editing of the Endogenous Cryptic 3' Splice Site Corrects the RNA Splicing Defect in the β⁶⁵⁴-Thalassemia Mouse Model.
Lu D, Gong X, Guo X, Cai Q, Chen Y, Zhu Y, Sang X, Yang H, Xu M, Zeng Y, Li D, Zeng F. Lu D, et al. Hum Gene Ther. 2024 Oct;35(19-20):825-837. doi: 10.1089/hum.2023.202. Epub 2024 Aug 13. Hum Gene Ther. 2024. PMID: 39078325
Current and Future Therapeutics for Treating Patients with Sickle Cell Disease.
Barak M, Hu C, Matthews A, Fortenberry YM. Barak M, et al. Cells. 2024 May 16;13(10):848. doi: 10.3390/cells13100848. Cells. 2024. PMID: 38786070 Free PMC article. Review.
Interplay between α-thalassemia and β-hemoglobinopathies: Translating genotype-phenotype relationships into therapies.
Vadolas J, Nualkaew T, Voon HPJ, Vilcassim S, Grigoriadis G. Vadolas J, et al. Hemasphere. 2024 May 15;8(5):e78. doi: 10.1002/hem3.78. eCollection 2024 May. Hemasphere. 2024. PMID: 38752170 Free PMC article.
Constitutive hypercoagulability in pediatric sickle cell disease patients with hemoglobin SS genotype.
Sussman RG, Mburu J, Steele M, Bang A, Friedman J, Goldman R, Kirby M, Rand ML, Blanchette VS, Pluthero FG, Williams S, Kahr WHA. Sussman RG, et al. Res Pract Thromb Haemost. 2024 Mar 15;8(3):102374. doi: 10.1016/j.rpth.2024.102374. eCollection 2024 Mar. Res Pract Thromb Haemost. 2024. PMID: 38605827 Free PMC article.

See all "Cited by" articles

References

1. Cao, A. & Galanello, R. Beta-thalassemia. Genet. Med. 12, 61–76 (2010). - DOI
1. Pasricha, S. R. & Drakesmith, H. Hemoglobinopathies in the fetal position. N. Engl. J. Med. 379, 1675–1677 (2018). - DOI
1. Shah, F. T., Sayani, F., Trompeter, S., Drasar, E. & Piga, A. Challenges of blood transfusions in β-thalassemia. Blood Rev. 37, 100588 (2019). - DOI
1. Cappellini, M. D. et al. A phase 3 trial of luspatercept in patients with transfusion-dependent β-thalassemia. N. Engl. J. Med. 382, 1219–1231 (2020). - DOI
1. Niihara, Y. et al. A phase 3 trial of ʟ-glutamine in sickle cell disease. N. Engl. J. Med. 379, 226–235 (2018). - DOI

Publication types

Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Associated data

Actions
- Search in PubMed
- Search in ClinicalTrials.gov
Actions
- Search in PubMed
- Search in ClinicalTrials.gov
Actions
- Search in PubMed
- Search in ClinicalTrials.gov

LinkOut - more resources

Full Text Sources
- Nature Publishing Group
Medical
- MedlinePlus Health Information
Miscellaneous
- NCI CPTAC Assay Portal

[1] Cao, A. & Galanello, R. Beta-thalassemia. Genet. Med. 12, 61–76 (2010). - DOI

[2] Cao, A. & Galanello, R. Beta-thalassemia. Genet. Med. 12, 61–76 (2010). - DOI

[3] Pasricha, S. R. & Drakesmith, H. Hemoglobinopathies in the fetal position. N. Engl. J. Med. 379, 1675–1677 (2018). - DOI

[4] Pasricha, S. R. & Drakesmith, H. Hemoglobinopathies in the fetal position. N. Engl. J. Med. 379, 1675–1677 (2018). - DOI

[5] Shah, F. T., Sayani, F., Trompeter, S., Drasar, E. & Piga, A. Challenges of blood transfusions in β-thalassemia. Blood Rev. 37, 100588 (2019). - DOI

[6] Shah, F. T., Sayani, F., Trompeter, S., Drasar, E. & Piga, A. Challenges of blood transfusions in β-thalassemia. Blood Rev. 37, 100588 (2019). - DOI

[7] Cappellini, M. D. et al. A phase 3 trial of luspatercept in patients with transfusion-dependent β-thalassemia. N. Engl. J. Med. 382, 1219–1231 (2020). - DOI

[8] Cappellini, M. D. et al. A phase 3 trial of luspatercept in patients with transfusion-dependent β-thalassemia. N. Engl. J. Med. 382, 1219–1231 (2020). - DOI

[9] Niihara, Y. et al. A phase 3 trial of ʟ-glutamine in sickle cell disease. N. Engl. J. Med. 379, 226–235 (2018). - DOI

[10] Niihara, Y. et al. A phase 3 trial of ʟ-glutamine in sickle cell disease. N. Engl. J. Med. 379, 226–235 (2018). - DOI

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Similar articles

Cited by

References

Publication types

MeSH terms

Associated data

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous

Abstract

Similar articles

Cited by

References

Publication types

MeSH terms

Associated data

Related information

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous