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

被引：75

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

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