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Magrin, E.1; Semeraro, M.2; Hebert, N.3; Kiger, L.4; Nguyen-Peyre, K.-A.4; Joseph, L.2; Miccio, A.5; Chalumeau, A.5; Magnani, A.1; Couzin, C.1; Marouene, J.2; Gabrion, A.1; Roudaut, C.1; El Nemer, W.6; Pirenne, F.3; Negre, O.7; Ribeil, J.-A.7; Brousse, V.8; De Montalembert, M.8; Asmal, M.7; Bartolucci, P.9; Cavazzana, M.10

doi: 10.1097/01.HS9.0000559976.13796.07
Poster Session I: Gene therapy, cellular immunotherapy and vaccination - Biology & translational research

1Laboratory of cell and gene therapy, Hôpital Necker-Enfants Malades

2Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, Paris

3Etablissement Français du Sang, Hôpital Henri Mondor

4INSERM-U955, EFS, Institut Mondor, Université Paris-Est, Créteil

5Laboratory of Chromatin and Gene Regulation during Development, INSERM UMR_S1163

6Laboratoire d'Excellence GR-Ex, Unité Biologie Intégrée du Globule Rouge, INSERM, Paris, France

7bluebirdbio Inc., Cambridge, MA, United States

8Service de Pédiatrie et Maladies Infectieuses, Hôpital Universitaire Necker-Enfants Malades

9Henri Mondor Hospital, APHP

10Biotherapy Department, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France

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Sickle cell disease (SCD) is one of the most prevalent inherited disorders worldwide. The ex vivo gene therapy phase 1/2 study HGB-205 conducted in France, evaluates the treatment of SCD and TDT (Transfusion Dependent Thalassemia) with LentiGlobin Drug Product (DP) containing autologous CD34+ cells transduced with the BB305 lentiviral vector encoding a human β-globin gene with a single substitution (βA-T87Q).

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We evaluated the clinical impact and the production of gene therapy-derived hemoglobin (HbAT87Q) in the 3 HGB-205 SCD patients (1204, 1207 and 1208).

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As of May 2018, the 3 patients had a follow-up of 42, 18 and 15 months respectively. HbS polymerization level was evaluated by O2 dissociation/association curves and cell morphology; membrane properties by red blood cells (RBCs) density curves, deformability under increasing osmolality and level of adherence to surfaces coated with thrombospondin (TSP). Hemoglobin contents of RBCs and reticulocytes were assessed by RP-HPLC.

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Two (1204 and 1208) of the 3 patients with SCD were free of any SCD-related treatment, with stable peripheral blood vector copy numbers and total anti-sickling haemoglobin (HbAT87Q + HbF) at 45-50% of total Hb. Both patients have less-common SCD genotypes: 1204 has a βS/βS genotype with an alpha-thalassemia trait and 1208 has a β0/βS genotype. At approximately 30 months post-infusion, patient 1204 developed vaso-occlusive pain following an episode of acute gastroenteritis; since then the patient has not had any vaso-occlusive episodes or acute chest syndrome (ACS). Patient 1208 had no episodes of vaso-occlusive crisis or ACS post LentiGlobin gene therapy. Patient 1207 had 2 episodes of ACS approximately 6 and 8 months after LentiGlobin gene therapy and re-started chronic transfusions and hydroxyurea treatment; the patient subsequently experienced 1 Grade ≥3 vaso-occlusive pain episode. Total Hb and % HbAT87Q contribution to total Hb for patients 1204, 1207 and 1208 at last visit were: 12.2, 8.4, and 10.2 g/dL, and 50.4, 4.4 and 26.4%, respectively. Dissociation and association of O2 curves for RBCs isolated from the 2 patients free of chronic transfusions (1204 and 1208) and performed 36- and 8-months post infusion, respectively, showed only a slight increase in P50 during re-oxygenation, indicating anti-sickling capability of transgenic HbAT87Q and low levels of HbS polymerization. Density curves showed an overall normal RBC hydration at multiple time points during follow-up, with dense cells contributing 0-4% compared to a mean (±SD) of 12.8% (±7.8) in untreated patients. The deformability of RBCs from the 2 patients (1204 and 1208) was lower than observed for healthy donors but higher than for untreated SCD patients. Under controlled shear stress, thrombospondin adherence was consistently lower for RBCs isolated from the 2 patients (1204 and 1208) compared to untreated patients with SCD. Slight intravascular hemolysis was observed for the 3 HGB-205 patients during follow-up, but the hemolytic levels improved compared to baseline. RP-HPLC analysis of total RBCs isolated at last visit showed an increase in βA-T87Q and a decrease in βS in comparison to reticulocytes, indicating an improved survival of RBCs expressing more anti-sickling β-globin transgene. A longer follow-up and data on deformability, distribution of fetal Hb and additional adhesion markers will be presented.

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Further investigations are needed to better define the sickle cell disease phenotype which could most benefit from a gene therapy approach.

Copyright © 2019 The Authors. Published by Wolters Kluwer Health Inc., on behalf of the European Hematology Association.