Browsing by Author "Baum, Christopher"

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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.
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    Preclinical safety and efficacy of an anti–HIV-1 lentiviral vector containing a short hairpin RNA to CCR5 and the C46 fusion inhibitor
    (Nature Publishing Group, 2014-02-12) Wolstein, Orit; Boyd, Maureen; Millington, Michelle; Impey, Helen; Boyer, Joshua; Howe, Annett; Delebecque, Frederic; Cornetta, Kenneth; Rothe, Michael; Baum, Christopher; Nicolson, Tamara; Koldej, Rachel; Zhang, Jane; Keech, Naomi; Camba Colón, Joanna; Breton, Louis; Bartlett, Jeffrey; An, Dong Sung; Chen, Irvin SY; Burke, Bryan; Symonds, Geoff P.; Department of Medical & Molecular Genetics, IU School of Medicine
    Gene transfer has therapeutic potential for treating HIV-1 infection by generating cells that are resistant to the virus. We have engineered a novel self-inactivating lentiviral vector, LVsh5/C46, using two viral-entry inhibitors to block early steps of HIV-1 cycle. The LVsh5/C46 vector encodes a short hairpin RNA (shRNA) for downregulation of CCR5, in combination with the HIV-1 fusion inhibitor, C46. We demonstrate here the effective delivery of LVsh5/C46 to human T cell lines, peripheral blood mononuclear cells, primary CD4+ T lymphocytes, and CD34+ hematopoietic stem/progenitor cells (HSPC). CCR5-targeted shRNA (sh5) and C46 peptide were stably expressed in the target cells and were able to effectively protect gene-modified cells against infection with CCR5- and CXCR4-tropic strains of HIV-1. LVsh5/C46 treatment was nontoxic as assessed by cell growth and viability, was noninflammatory, and had no adverse effect on HSPC differentiation. LVsh5/C46 could be produced at a scale sufficient for clinical development and resulted in active viral particles with very low mutagenic potential and the absence of replication-competent lentivirus. Based on these in vitro results, plus additional in vivo safety and efficacy data, LVsh5/C46 is now being tested in a phase 1/2 clinical trial for the treatment of HIV-1 disease.