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

被引：66

作者：

Magrin, Elisa ^{[1
,2
]}

Semeraro, Michaela ^{[3
,4
]}

Hebert, Nicolas ^{[5
,6
]}

Joseph, Laure ^{[1
]}

Magnani, Alessandra ^{[1
,2
]}

Chalumeau, Anne ^{[7
]}

Gabrion, Aurelie ^{[1
,2
]}

Roudaut, Cecile ^{[1
,2
]}

Marouene, Jouda ^{[3
]}

Lefrere, Francois ^{[1
]}

Diana, Jean-Sebastien ^{[1
]}

Denis, Adeline ^{[7
]}

Neven, Benedicte ^{[8
]}

Funck-Brentano, Isabelle ^{[8
]}

Negre, Olivier ^{[9
,10
]}

Renolleau, Sylvain ^{[11
]}

Brousse, Valentine ^{[12
]}

Kiger, Laurent ^{[5
]}

Touzot, Fabien ^{[1
,2
]}

Poirot, Catherine ^{[13
,14
]}

Bourget, Philippe ^{[15
]}

El Nemer, Wassim ^{[16
]}

Blanche, Stephane ^{[8
]}

Treluyer, Jean-Marc ^{[3
,4
]}

Asmal, Mohammed ^{[10
]}

Walls, Courtney ^{[10
]}

Beuzard, Yves ^{[5
,9
]}

Schmidt, Manfred ^{[17
]}

Hacein-Bey-Abina, Salima ^{[1
,2
]}

Asnafi, Vahid ^{[18
]}

Guichard, Isabelle ^{[19
]}

Poiree, Maryline ^{[20
]}

Monpoux, Fabrice ^{[21
]}

Touraine, Philippe ^{[22
,23
]}

Brouzes, Chantal ^{[24
]}

de Montalembert, Mariane ^{[12
]}

Payen, Emmanuel ^{[9
]}

Six, Emmanuelle ^{[7
]}

Ribeil, Jean-Antoine ^{[1
,2
,10
]}

Miccio, Annarita ^{[7
]}

Bartolucci, Pablo ^{[5
,6
]}

Leboulch, Philippe ^{[9
,25
,26
]}

Cavazzana, Marina ^{[4
,7
,27
,28
]}

机构：

[1] Hop Univ Necker Enfants Malad, GH Paris Ctr, Biotherapy Dept, Paris, France

[2] Hop Univ Necker Enfants Malad, GH Paris Ctr, Ctr Invest Clin Biotherapie, Paris, France

[3] Hop Univ Necker Enfants Malad, GH Paris Ctr, Ctr Invest Clin, Unite Rech Clin, Paris, France

[4] Univ Paris, Paris, France

[5] Univ Paris Est Creteil, INSERM, EFS, IMRB, Creteil, France

[6] Univ Paris Est Creteil, Hop Henri Mondor, AP HP, Creteil, France

[7] Univ Paris, Sorbonne Paris Cite, IMAGINE Inst, Paris, France

[8] Hop Necker Enfants Malad, Pediat Immunol & Hematol Dept, Paris, France

[9] Univ Paris Saclay, INSERM, CEA, Div Innovat Therapies,Inst Francois Jacob, Fontenay Aux Roses, France

[10] Bluebird Bio Inc, Cambridge, MA USA

[11] Hop Univ Necker Enfants Malad, GH Paris Ctr, Pediat Intens Care Unit, Paris, France

[12] Hop Univ Necker Enfants Malad, GH Paris Ctr, Dept Gen Pediat & Pediat Infect Dis, Paris, France

[13] Hop St Louis, Fertil Preservat, Dept Hematol, Paris, France

[14] Sorbonne Univ, Paris, France

[15] Hop Univ Necker Enfants Malad, GH Paris Ctr, Pharm Dept, Paris, France

[16] Inst Natl Transfus Sanguine INTS, Paris, France

[17] GeneWerk GmbH, Heidelberg, Germany

[18] Univ Paris, Hop Necker Enfants Malad, AP HP, Inst Necker Enfants Malad,INSERM U1151, Paris, France

[19] CHU St Etienne, Hop Nord, Serv Med Interne, Paris, France

[20] Ctr Hosp Univ Lenval, Dept Pediat Hematol Oncol, Nice, France

[21] Hop Archet 2, Unite Hematooncol Infantile, Nice, France

[22] La Pitie Salpetriere, AP HP, Dept Endocrinol & Reprod Med, Paris, France

[23] Sorbonne Univ, Pierre & Marie Curie Sch Med, Paris, France

[24] Hop Necker Enfants Malad, Lab Oncohematol, Paris, France

[25] Brigham & Womens Hosp, Dept Med, Div Genet, 75 Francis St, Boston, MA 02115 USA

[26] Harvard Med Sch, Boston, MA 02115 USA

[27] AP HP, INSERM, Biotherapy Dept, Paris, France

[28] AP HP, INSERM, Clin Invest Ctr, Paris, France

来源：

NATURE MEDICINE | 2022年 / 28卷 / 01期

关键词：

SICKLE-CELL-DISEASE; PHASE-3; TRIAL; INTEGRATION; VECTOR; TRANSPLANTATION; THALASSEMIA; RISK;

D O I：

10.1038/s41591-021-01650-w

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Sickle cell disease (SCD) and transfusion-dependent beta-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 beta(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.

引用

页码：81 / +

页数：23

共 35 条

[1] Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease
Ataga, K. I.
Kutlar, A.
Kanter, J.
Liles, D.
Cancado, R.
Friedrisch, J.
Guthrie, T. H.
Knight-Madden, J.
Alvarez, O. A.
Gordeuk, V. R.
Gualandro, S.
Colella, M. P.
Smith, W. R.
Rollins, S. A.
Stocker, J. W.
Rother, R. P.
[J]. NEW ENGLAND JOURNAL OF MEDICINE, 2017, 376 (05) : 429 - 439
[2] HLA-haploidentical bone marrow transplantation with posttransplant cyclophosphamide expands the donor pool for patients with sickle cell disease
Bolanos-Meade, Javier
Fuchs, Ephraim J.
Luznik, Leo
Lanzkron, Sophie M.
Gamper, Christopher J.
Jones, Richard J.
Brodsky, Robert A.
[J]. BLOOD, 2012, 120 (22) : 4285 - 4291
[3] Increased risk of leukemia among sickle cell disease patients in California
Brunson, Ann
Keegan, Theresa H. M.
Bang, Heejung
Mahajan, Anjlee
Paulukonis, Susan
Wun, Ted
[J]. BLOOD, 2017, 130 (13) : 1597 - 1599
[4] Brusson, 2021, NOVEL LENTIVIRAL VEC
[5] Cao A, 2010, GENET MED, V12, P61, DOI [10.1038/gim.2016.173, 10.1097/GIM.0b013e3181cd68ed]
[6] A Phase 3 Trial of Luspatercept in Patients with Transfusion-Dependent β-Thalassemia
Cappellini, M. D.
Viprakasit, V.
Taher, A. T.
Georgiev, P.
Kuo, K. H. M.
Coates, T.
Voskaridou, E.
Liew, H. -K.
Pazgal-Kobrowski, I.
Forni, G. L.
Perrotta, S.
Khelif, A.
Lal, A.
Kattamis, A.
Vlachaki, E.
Origa, R.
Aydinok, Y.
Bejaoui, M.
Ho, P. J.
Chew, L. -P.
Bee, P. -C.
Lim, S. -M.
Lu, M. -Y.
Tantiworawit, A.
Ganeva, P.
Gercheva, L.
Shah, F.
Neufeld, E. J.
Thompson, A.
Laadem, A.
Shetty, J. K.
Zou, J.
Zhang, J.
Miteva, D.
Zinger, T.
Linde, P. G.
Sherman, M. L.
Hermine, O.
Porter, J.
Piga, A.
[J]. NEW ENGLAND JOURNAL OF MEDICINE, 2020, 382 (13) : 1219 - 1231
[7] Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia
Cavazzana-Calvo, Marina
Payen, Emmanuel
Negre, Olivier
Wang, Gary
Hehir, Kathleen
Fusil, Floriane
Down, Julian
Denaro, Maria
Brady, Troy
Westerman, Karen
Cavallesco, Resy
Gillet-Legrand, Beatrix
Caccavelli, Laure
Sgarra, Riccardo
Maouche-Chretien, Leila
Bernaudin, Francoise
Girot, Robert
Dorazio, Ronald
Mulder, Geert-Jan
Polack, Axel
Bank, Arthur
Soulier, Jean
Larghero, Jerome
Kabbara, Nabil
Dalle, Bruno
Gourmel, Bernard
Socie, Gerard
Chretien, Stany
Cartier, Nathalie
Aubourg, Patrick
Fischer, Alain
Cornetta, Kenneth
Galacteros, Frederic
Beuzard, Yves
Gluckman, Eliane
Bushman, Frederick
Hacein-Bey-Abina, Salima
Leboulch, Philippe
[J]. NATURE, 2010, 467 (7313) : 318 - U94
[8] CHAO A, 1984, SCAND J STAT, V11, P265
[9] EATON WA, 1976, BLOOD, V47, P621
[10] Individual red blood cell fetal hemoglobin quantification allows to determine protective thresholds in sickle cell disease
Hebert, Nicolas
Rakotoson, Marie Georgine
Bodivit, Gwellaouen
Audureau, Etienne
Bencheikh, Laura
Kiger, Laurent
Oubaya, Nadia
Pakdaman, Sadaf
Sakka, Mehdi
Di Liberto, Gaetana
Chadebech, Philippe
Vingert, Benoit
Pirenne, France
Galacteros, Frederic
Cambot, Marie
Bartolucci, Pablo
[J]. AMERICAN JOURNAL OF HEMATOLOGY, 2020, 95 (11) : 1235 - 1245

← 1 2 3 4 →