Browsing by Author "Schmidt, Manfred"

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    Autologous Ex Vivo Lentiviral Gene Therapy for Adenosine Deaminase Deficiency
    (Massachusetts Medical Society, 2021-05-27) Kohn, Donald B.; Booth, Claire; Shaw, Kit L.; Xu-Bayford, Jinhua; Garabedian, Elizabeth; Trevisan, Valentina; Carbonaro-Sarracino, Denise A.; Soni, Kajal; Terrazas, Dayna; Snell, Katie; Ikeda, Alan; Leon-Rico, Diego; Moore, Theodore B.; Buckland, Karen F.; Shah, Ami J.; Gilmour, Kimberly C.; De Oliveira, Satiro; Rivat, Christine; Crooks, Gay M.; Izotova, Natalia; Tse, John; Adams, Stuart; Shupien, Sally; Ricketts, Hilory; Davila, Alejandra; Uzowuru, Chilenwa; Icreverzi, Amalia; Barman, Provaboti; Fernandez, Beatriz Campo; Hollis, Roger P.; Coronel, Maritess; Yu, Allen; Chun, Krista M.; Casas, Christian E.; Zhang, Ruixue; Arduini, Serena; Lynn, Frances; Kudari, Mahesh; Spezzi, Andrea; Zahn, Marco; Heimke, Rene; Labik, Ivan; Parrott, Roberta; Buckley, Rebecca H.; Reeves, Lilith; Cornetta, Kenneth; Sokolic, Robert; Hershfield, Michael; Schmidt, Manfred; Candotti, Fabio; Malech, Harry L.; Thrasher, Adrian J.; Gaspar, H. Bobby; Medicine, School of Medicine
    Background: Severe combined immunodeficiency due to adenosine deaminase (ADA) deficiency (ADA-SCID) is a rare and life-threatening primary immunodeficiency. Methods: We treated 50 patients with ADA-SCID (30 in the United States and 20 in the United Kingdom) with an investigational gene therapy composed of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) transduced ex vivo with a self-inactivating lentiviral vector encoding human ADA. Data from the two U.S. studies (in which fresh and cryopreserved formulations were used) at 24 months of follow-up were analyzed alongside data from the U.K. study (in which a fresh formulation was used) at 36 months of follow-up. Results: Overall survival was 100% in all studies up to 24 and 36 months. Event-free survival (in the absence of reinitiation of enzyme-replacement therapy or rescue allogeneic hematopoietic stem-cell transplantation) was 97% (U.S. studies) and 100% (U.K. study) at 12 months; 97% and 95%, respectively, at 24 months; and 95% (U.K. study) at 36 months. Engraftment of genetically modified HSPCs persisted in 29 of 30 patients in the U.S. studies and in 19 of 20 patients in the U.K. study. Patients had sustained metabolic detoxification and normalization of ADA activity levels. Immune reconstitution was robust, with 90% of the patients in the U.S. studies and 100% of those in the U.K. study discontinuing immunoglobulin-replacement therapy by 24 months and 36 months, respectively. No evidence of monoclonal expansion, leukoproliferative complications, or emergence of replication-competent lentivirus was noted, and no events of autoimmunity or graft-versus-host disease occurred. Most adverse events were of low grade. Conclusions: Treatment of ADA-SCID with ex vivo lentiviral HSPC gene therapy resulted in high overall and event-free survival with sustained ADA expression, metabolic correction, and functional immune reconstitution.
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    From bench to bedside: preclinical evaluation of a self-inactivating gammaretroviral vector for the gene therapy of X-linked chronic granulomatous disease
    (Mary Ann Liebert, 2013-06) Stein, Stefan; Scholz, Simone; Schwäble, Joachim; Sadat, Mohammed A.; Modlich, Ute; Schultze-Strasser, Stephan; Diaz, Margarita; Chen-Wichmann, Linping; Müller-Kuller, Uta; Brendel, Christian; Fronza, Raffaele; Kaufmann, Kerstin B.; Naundorf, Sonja; Pech, Nancy K.; Travers, Jeffrey B.; Matute, Juan D.; Presson, Robert G.; Sandusky, George E.; Kunkel, Hana; Rudolf, Eva; Dillmann, Adelina; von Kalle, Christof; Kühlcke, Klaus; Baum, Christopher; Schambach, Axel; Dinauer, Mary C.; Schmidt, Manfred; Grez, Manuel; Pediatrics, School of Medicine
    Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by impaired antimicrobial activity in phagocytic cells. As a monogenic disease affecting the hematopoietic system, CGD is amenable to gene therapy. Indeed in a phase I/II clinical trial, we demonstrated a transient resolution of bacterial and fungal infections. However, the therapeutic benefit was compromised by the occurrence of clonal dominance and malignant transformation demanding alternative vectors with equal efficacy but safety-improved features. In this work we have developed and tested a self-inactivating (SIN) gammaretroviral vector (SINfes.gp91s) containing a codon-optimized transgene (gp91(phox)) under the transcriptional control of a myeloid promoter for the gene therapy of the X-linked form of CGD (X-CGD). Gene-corrected cells protected X-CGD mice from Aspergillus fumigatus challenge at low vector copy numbers. Moreover, the SINfes.gp91s vector generates substantial amounts of superoxide in human cells transplanted into immunodeficient mice. In vitro genotoxicity assays and longitudinal high-throughput integration site analysis in transplanted mice comprising primary and secondary animals for 11 months revealed a safe integration site profile with no signs of clonal dominance.