Titre
Clinical efficacy of gene-modified stem cells in adenosine deaminase-deficient immunodeficiency.
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Shaw, K.L.
Auteure/Auteur
Garabedian, E.
Auteure/Auteur
Mishra, S.
Auteure/Auteur
Barman, P.
Auteure/Auteur
Davila, A.
Auteure/Auteur
Carbonaro, D.
Auteure/Auteur
Shupien, S.
Auteure/Auteur
Silvin, C.
Auteure/Auteur
Geiger, S.
Auteure/Auteur
Nowicki, B.
Auteure/Auteur
Smogorzewska, E.M.
Auteure/Auteur
Brown, B.
Auteure/Auteur
Wang, X.
Auteure/Auteur
de Oliveira, S.
Auteure/Auteur
Choi, Y.
Auteure/Auteur
Ikeda, A.
Auteure/Auteur
Terrazas, D.
Auteure/Auteur
Fu, P.Y.
Auteure/Auteur
Yu, A.
Auteure/Auteur
Fernandez, B.C.
Auteure/Auteur
Cooper, A.R.
Auteure/Auteur
Engel, B.
Auteure/Auteur
Podsakoff, G.
Auteure/Auteur
Balamurugan, A.
Auteure/Auteur
Anderson, S.
Auteure/Auteur
Muul, L.
Auteure/Auteur
Jagadeesh, G.J.
Auteure/Auteur
Kapoor, N.
Auteure/Auteur
Tse, J.
Auteure/Auteur
Moore, T.B.
Auteure/Auteur
Purdy, K.
Auteure/Auteur
Rishi, R.
Auteure/Auteur
Mohan, K.
Auteure/Auteur
Skoda-Smith, S.
Auteure/Auteur
Buchbinder, D.
Auteure/Auteur
Abraham, R.S.
Auteure/Auteur
Scharenberg, A.
Auteure/Auteur
Yang, O.O.
Auteure/Auteur
Cornetta, K.
Auteure/Auteur
Gjertson, D.
Auteure/Auteur
Hershfield, M.
Auteure/Auteur
Sokolic, R.
Auteure/Auteur
Candotti, F.
Auteure/Auteur
Kohn, D.B.
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
ISSN
1558-8238
Statut éditorial
Publié
Date de publication
2017-05-01
Volume
127
Numéro
5
Première page
1689
Dernière page/numéro d’article
1699
Peer-reviewed
Oui
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Publication Status: ppublish
Résumé
Autologous hematopoietic stem cell transplantation (HSCT) of gene-modified cells is an alternative to enzyme replacement therapy (ERT) and allogeneic HSCT that has shown clinical benefit for adenosine deaminase-deficient (ADA-deficient) SCID when combined with reduced intensity conditioning (RIC) and ERT cessation. Clinical safety and therapeutic efficacy were evaluated in a phase II study.
Ten subjects with confirmed ADA-deficient SCID and no available matched sibling or family donor were enrolled between 2009 and 2012 and received transplantation with autologous hematopoietic CD34+ cells that were modified with the human ADA cDNA (MND-ADA) γ-retroviral vector after conditioning with busulfan (90 mg/m2) and ERT cessation. Subjects were followed from 33 to 84 months at the time of data analysis. Safety of the procedure was assessed by recording the number of adverse events. Efficacy was assessed by measuring engraftment of gene-modified hematopoietic stem/progenitor cells, ADA gene expression, and immune reconstitution.
With the exception of the oldest subject (15 years old at enrollment), all subjects remained off ERT with normalized peripheral blood mononuclear cell (PBMC) ADA activity, improved lymphocyte numbers, and normal proliferative responses to mitogens. Three of nine subjects were able to discontinue intravenous immunoglobulin replacement therapy. The MND-ADA vector was persistently detected in PBMCs (vector copy number [VCN] = 0.1-2.6) and granulocytes (VCN = 0.01-0.3) through the most recent visits at the time of this writing. No patient has developed a leukoproliferative disorder or other vector-related clinical complication since transplant.
These results demonstrate clinical therapeutic efficacy from gene therapy for ADA-deficient SCID, with an excellent clinical safety profile.
ClinicalTrials.gov NCT00794508.
Food and Drug Administration Office of Orphan Product Development award, RO1 FD003005; NHLBI awards, PO1 HL73104 and Z01 HG000122; UCLA Clinical and Translational Science Institute awards, UL1RR033176 and UL1TR000124.
Ten subjects with confirmed ADA-deficient SCID and no available matched sibling or family donor were enrolled between 2009 and 2012 and received transplantation with autologous hematopoietic CD34+ cells that were modified with the human ADA cDNA (MND-ADA) γ-retroviral vector after conditioning with busulfan (90 mg/m2) and ERT cessation. Subjects were followed from 33 to 84 months at the time of data analysis. Safety of the procedure was assessed by recording the number of adverse events. Efficacy was assessed by measuring engraftment of gene-modified hematopoietic stem/progenitor cells, ADA gene expression, and immune reconstitution.
With the exception of the oldest subject (15 years old at enrollment), all subjects remained off ERT with normalized peripheral blood mononuclear cell (PBMC) ADA activity, improved lymphocyte numbers, and normal proliferative responses to mitogens. Three of nine subjects were able to discontinue intravenous immunoglobulin replacement therapy. The MND-ADA vector was persistently detected in PBMCs (vector copy number [VCN] = 0.1-2.6) and granulocytes (VCN = 0.01-0.3) through the most recent visits at the time of this writing. No patient has developed a leukoproliferative disorder or other vector-related clinical complication since transplant.
These results demonstrate clinical therapeutic efficacy from gene therapy for ADA-deficient SCID, with an excellent clinical safety profile.
ClinicalTrials.gov NCT00794508.
Food and Drug Administration Office of Orphan Product Development award, RO1 FD003005; NHLBI awards, PO1 HL73104 and Z01 HG000122; UCLA Clinical and Translational Science Institute awards, UL1RR033176 and UL1TR000124.
PID Serval
serval:BIB_116142C43273
PMID
Open Access
Oui
Date de création
2017-05-22T13:56:19.440Z
Date de création dans IRIS
2025-05-20T19:30:27Z