Christof von Kalle
Affiliation: Cincinnati Children's Hospital Medical Center
- Stem cell clonality and genotoxicity in hematopoietic cells: gene activation side effects should be avoidableC von Kalle
Division of Experimental Hematology, Cincinnati Children s Hospital Research Foundation, Cincinnati, OH 45229, USA
Semin Hematol 41:303-18. 2004....
- Stem cell collection and gene transfer in Fanconi anemiaPatrick F Kelly
Fanconi Anemia Comprehensive Care Center, Divisions of Experimental Hematology and Hematology Oncology, Cincinnati Children s Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA
Mol Ther 15:211-9. 2007..Our early experience shows that stem cell collection is well tolerated in FA patients and suggests that collection be considered as early as possible in patients who are potential candidates for future gene transfer trials...
- Importance of murine study design for testing toxicity of retroviral vectors in support of phase I trialsElke Will
Division of Experimental Hematology, Cincinnati Children s Hospital Medical Center, Cincinnati, Ohio 45229, USA
Mol Ther 15:782-91. 2007....
- In vivo gene transfer into adult stem cells in unconditioned mice by in situ delivery of a lentiviral vectorD Nicole Worsham
Division of Experimental Hematology, Cincinnati Children s Hospital Medical Center, Cincinnati, OH 45249, USA
Mol Ther 14:514-24. 2006..This approach could lead to a novel application for treatment of human diseases...
- Lenti in red: progress in gene therapy for human hemoglobinopathiesChristof von Kalle
Division of Expermental Hematology, Cincinnati Children s Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA
J Clin Invest 114:889-91. 2004..While some safety concerns must be addressed, this study is an important step toward potential clinical trials of gene therapy for hemoglobinopathies...
- Vector integration is nonrandom and clustered and influences the fate of lymphopoiesis in SCID-X1 gene therapyAnnette Deichmann
Institute for Molecular Medicine and Cell Research and Department of Internal Medicine I, German Cancer Research Center, University of Freiburg, Freiburg, Germany
J Clin Invest 117:2225-32. 2007..Beyond the observed cases of insertional mutagenesis in 3 patients, these data help to elucidate the relationship between vector insertion and long-term in vivo selection of transduced cells in human patients with SCID-X1...
- Long-term clinical and molecular follow-up of large animals receiving retrovirally transduced stem and progenitor cells: no progression to clonal hematopoiesis or leukemiaHans Peter Kiem
Clinical Research Division, Fred Hutchinson Cancer Research Center, and Division of Orcology, University of Washington, Seattle, WA, USA
Mol Ther 9:389-95. 2004....
- Recurrent retroviral vector integration at the Mds1/Evi1 locus in nonhuman primate hematopoietic cellsBoris Calmels
Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, MD, USA
Blood 106:2530-3. 2005..Characterization of integration sites in this relevant preclinical model provides critical information for gene therapy risk assessment as well as identification of genes controlling hematopoiesis...
- Clonal evidence for the transduction of CD34+ cells with lymphomyeloid differentiation potential and self-renewal capacity in the SCID-X1 gene therapy trialManfred Schmidt
Department of Internal Medicine, University of Freiburg, Germany
Blood 105:2699-706. 2005..These results provide a first evidence in the setting of a clinical trial that CD34+ cells maintain both lymphomyeloid potential as well as self-renewal capacity after ex vivo manipulation...
- Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vectorH Bobby Gaspar
Molecular Immunology Unit, Institute of Child Health, University College London, London, UK
Lancet 364:2181-7. 2004..We investigated the application of somatic gene therapy by use of a gibbon-ape-leukaemia-virus pseudotyped gammaretroviral vector...
- Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1Marion G Ott
Department of Hematology Oncology, University Hospital, German Cancer Research Center, Theodor Stern Kai 7, 60590 Frankfurt, Germany
Nat Med 12:401-9. 2006....
- Hematopoietic stem cell gene transfer in a tumor-prone mouse model uncovers low genotoxicity of lentiviral vector integrationEugenio Montini
San Raffaele Telethon Institute for Gene Therapy, Via Olgettina 58, 20132, Milan, Italy
Nat Biotechnol 24:687-96. 2006..Our results validate a much-needed platform to assess vector safety and provide direct evidence that prototypical lentiviral vectors have low oncogenic potential, highlighting a major rationale for application to gene therapy...
- Chance or necessity? Insertional mutagenesis in gene therapy and its consequencesChristopher Baum
Department of Hematology and Oncology, Hannover Medical School, Hannover, Germany
Mol Ther 9:5-13. 2004..Based on these considerations, we propose approaches to risk prediction and prevention...
- A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiencySalima Hacein-Bey-Abina
N Engl J Med 348:255-6. 2003
- Side effects of retroviral gene transfer into hematopoietic stem cellsChristopher Baum
Department of Hematology and Oncology, Hannover Medical School, Hannover, Germany
Blood 101:2099-114. 2003....
- Murine leukemia induced by retroviral gene markingZhixiong Li
Heinrich Pette Institute, D 20251 Hamburg, Germany
Science 296:497. 2002
- Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patientsSteven J Howe
Centre for Immunodeficiency, Molecular Immunology Unit, UCL Institute of Child Health, University College London, London, United Kingdom
J Clin Invest 118:3143-50. 2008....
- Pharmacologically regulated in vivo selection in a large animalTobias Neff
Divisions of Hematology and Oncology, Department of Medicine, University of Washington, Seattle, WA 89195, USA
Blood 100:2026-31. 2002..Cell growth switches could greatly enhance the efficacy and applicability of gene and cell therapy...
- Lentiviral vectors pseudotyped with murine ecotropic envelope: increased biosafety and convenience in preclinical researchAxel Schambach
Department of Hematology, Hemostaseology and Oncology, Hannover Medical School, Germany
Exp Hematol 34:588-92. 2006..However, this method has found little acceptance, despite potential advantages...
- Polyclonal long-term repopulating stem cell clones in a primate modelManfred Schmidt
Department I of Internal Medicine and the Institute for Molecular Medicine and Cell Research, University of Freiburg, Germany
Blood 100:2737-43. 2002..Our study provides direct molecular evidence for a polyclonal, multilineage, and sustained contribution of individual stem cells to primate hematopoiesis...
- A hybrid vector for ligand-directed tumor targeting and molecular imagingAmin Hajitou
Department of Genitourinary Medical Oncology, The University of Texas M D Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
Cell 125:385-98. 2006..This new class of targeted hybrid viral particles will enable a wide range of applications in biology and medicine...
- Lentiviral vector transduction of NOD/SCID repopulating cells results in multiple vector integrations per transduced cell: risk of insertional mutagenesisNiels Bjarne Woods
Department for Molecular Medicine and Gene Therapy, Institute of Laboratory Medicine, Lund University, Sweden
Blood 101:1284-9. 2003..While this is efficient in terms of transduction and transgene expression, it may increase the risk of insertional mutagenesis...
- Cell-culture assays reveal the importance of retroviral vector design for insertional genotoxicityUte Modlich
Department of Experimental Hematology, Hannover Medical School, Carl Neuberg Strasse 1, D 30625 Hannover, Germany
Blood 108:2545-53. 2006..Additional modifications of SIN vectors may further increase safety. Improved cell-culture assays will likely play an important role in the evaluation of insertional mutagenesis...
- Methylguanine methyltransferase-mediated in vivo selection and chemoprotection of allogeneic stem cells in a large-animal modelTobias Neff
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109 1024, USA
J Clin Invest 112:1581-8. 2003....
- Genetic marking as an approach to studying in vivo hematopoiesis: progress in the non-human primate modelPatricia A Shi
Molecular Hematopoiesis Section, Hematology Branch, NHLBI, NIH, 9000 Rockville Pike, Bethesda, Maryland, MD 20892, USA
Oncogene 21:3274-83. 2002..These approaches will have significant impact in studying various aspects of stem cell biology including the phenomenon of stem cell plasticity...
- Molecular evidence of lentiviral vector-mediated gene transfer into human self-renewing, multi-potent, long-term NOD/SCID repopulating hematopoietic cellsLaurie Ailles
Laboratory for Gene Transfer and Therapy, University of Torino Medical School, Candiolo, Italy
Mol Ther 6:615-26. 2002..Our findings are relevant for the design of clinical protocols that exploit this system to reach significant engraftment by genetically modified HSC in the absence of in vivo selection or strong conditioning regimens...
- Stable differentiation and clonality of murine long-term hematopoiesis after extended reduced-intensity selection for MGMT P140K transgene expressionClaudia R Ball
National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany
Blood 110:1779-87. 2007....
- Hot spots of retroviral integration in human CD34+ hematopoietic cellsClaudia Cattoglio
Italian Institute of Technology, Unit of Molecular Neuroscience, Istituto Scientifico H San Raffaele, Milan, Italy
Blood 110:1770-8. 2007..The lower propensity of LV vectors for integrating in potentially dangerous regions of the human genome may be a factor determining a better safety profile for gene therapy applications...
- Ex vivo treatment of proliferating human cord blood stem cells with stroma-derived factor-1 enhances their ability to engraft NOD/SCID miceHanno Glimm
Terry Fox Laboratory, British Columbia Cancer Agency, University of British Columbia, Vancouver, Canada
Blood 99:3454-7. 2002..These results suggest new strategies for improving the engraftment activity of HSCs stimulated to proliferate ex vivo...
- Gammaretrovirus-mediated correction of SCID-X1 is associated with skewed vector integration site distribution in vivoKerstin Schwarzwaelder
National Center for Tumor Diseases, German Cancer Research Center, Heidelberg, Germany
J Clin Invest 117:2241-9. 2007....
- Adeno-associated virus vector genomes persist as episomal chromatin in primate muscleMagalie Penaud-Budloo
INSERM UMR 649, CHU Hotel Dieu, 44035 Nantes, France
J Virol 82:7875-85. 2008..Because of this unique context, our data, which provide important insight into in situ vector biology, are highly relevant from a clinical standpoint...
- Effective gene therapy with nonintegrating lentiviral vectorsRafael J Yáñez-Muñoz
Molecular Immunology Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK
Nat Med 12:348-53. 2006..For therapeutic application to postmitotic tissues, this system substantially reduces the risk of insertional mutagenesis...
- Oncogenesis following delivery of a nonprimate lentiviral gene therapy vector to fetal and neonatal miceMike Themis
Gene Therapy Research Group, Section of Cell and Molecular Biology, Imperial College London, UK
Mol Ther 12:763-71. 2005..This system may provide a highly sensitive model to investigate integrating vector safety prior to clinical application...
- Selective survival of peripheral blood lymphocytes in children with HIV-1 following delivery of an anti-HIV gene to bone marrow CD34(+) cellsGreg M Podsakoff
Childrens Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA 90027, USA
Mol Ther 12:77-86. 2005..These findings indicate that there was a selective survival advantage for PBMC containing the huM10 gene during the time of increased HIV-1 load...
- Retrovirally transduced muscle-derived cells contribute to hematopoiesis at very low levels in the nonhuman primate modelChunji Gao
Molecular and Clinical Hematology Branch, National Institute of Diabetes and Digestive and Kidney Disorders, National Institutes of Health, Bethesda, Maryland 20892, USA
Mol Ther 8:974-80. 2003..These results demonstrate that harvesting disparate organs for cellular therapy is currently highly inefficient at best...
- Gene therapy targeting hematopoietic cells: better not leave it to chanceChristopher Baum
Department of Hematology and Oncology, Hannover Medical School, Hannover, Germany
Acta Haematol 110:107-9. 2003..Interestingly, correction of genetic disorders by homologous gene repair in defined stem cell clones is on the horizon, but far from being available for clinical use...
- Effect of chronic cytokine therapy on clonal dynamics in nonhuman primatesKen Kuramoto
Molecular Hematopoiesis Section, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
Blood 103:4070-7. 2004..These relevant large animal studies are reassuring regarding clinical applications of cytokines and provide new insights into their mechanisms of action...
- Efficient characterization of retro-, lenti-, and foamyvector-transduced cell populations by high-accuracy insertion site sequencingManfred Schmidt
Department I of Internal Medicine, University of Freiburg, 79106 Freiburg, Germany
Ann N Y Acad Sci 996:112-21. 2003....
- Comparison of three retroviral vector systems for transduction of nonobese diabetic/severe combined immunodeficiency mice repopulating human CD34+ cord blood cellsCordula Leurs
Klinik für Pädiatrische Hämatologie und Onkologie, Zentrum fur Kinderheilkunde, Heinrich Heine Universitat, 40225 Dusseldorf, Germany
Hum Gene Ther 14:509-19. 2003..These data demonstrate that vectors based on FVs warrant further investigation and development for medical use...
- LMO2 and gene therapy for severe combined immunodeficiencyAlain Fischer
N Engl J Med 350:2526-7; author reply 2526-7. 2004
- Low-dose total body irradiation causes clonal fluctuation of primate hematopoietic stem and progenitor cellsMikko O Laukkanen
Molecular Hematopoiesis Section, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bldg 10, Rm 7C103, 9000 Rockville Pike, Bethesda, MD 20892, USA
Blood 105:1010-5. 2005..The results indicate that even low-dose irradiation affects hematopoietic clonal dynamics and have implications for design of conditioning regimens for transplantation purposes...
- Clonality analysis after retroviral-mediated gene transfer to CD34+ cells from the cord blood of ADA-deficient SCID neonatesManfred Schmidt
Department I of Internal Medicine, University of Freiburg, Freiburg, Germany
Nat Med 9:463-8. 2003....
- Distinct genomic integration of MLV and SIV vectors in primate hematopoietic stem and progenitor cellsPeiman Hematti
Hematology Branch, National Institutes of Health Bethesda, Maryland, USA
PLoS Biol 2:e423. 2004..These integration patterns suggest different mechanisms for integration as well as distinct safety implications for MLV versus SIV vectors...
- Evidence of similar effects of short-term culture on the initial repopulating activity of mobilized peripheral blood transplants assessed in NOD/SCID-beta2microglobulin(null) mice and in autografted patientsHanno Glimm
Department of Internal Medicine I, Institute of Molecular Medicine and Cell Research, Albert Ludwigs University, Freiburg, Germany
Exp Hematol 33:20-5. 2005....
- Failure of SCID-X1 gene therapy in older patientsAdrian J Thrasher
Molecular Immunology Unit, Institute of Child Health, London, United Kingdom
Blood 105:4255-7. 2005..In particular, there is likely to be a limitation to initiation of normal thymopoiesis, and we therefore suggest that intervention for these patients should be considered as early as possible...
- Leukemias following retroviral transfer of multidrug resistance 1 (MDR1) are driven by combinatorial insertional mutagenesisUte Modlich
Department of Hematology, Hemostaseology and Oncology, Institute of Cellular and Molecular Pathology, Hannover Medical School, Germany
Blood 105:4235-46. 2005..On the basis of these findings, we suggest the use of preclinical dose-escalation studies to define a therapeutic index for retroviral transgene delivery...
- Efficient marking of human cells with rapid but transient repopulating activity in autografted recipientsHanno Glimm
Department of Internal Medicine I, Albert Ludwigs University, Freiburg, Germany
Blood 106:893-8. 2005..Eighty percent of inserts were located within or near genes, 2 near CXCR4. These findings provide direct evidence of cells with rapid but transient repopulating activity in patients and demonstrate their efficient transduction in vitro...
- The impact of low-dose busulfan on clonal dynamics in nonhuman primatesKen Kuramoto
Molecular Hematopoiesis Section, Hematology Branch, Natiomal Heart, Lung and Blood Institute NIH, Bldg 10, Rm 7C103, 9000 Rockville Pike, Bethesda, MD 20892, USA
Blood 104:1273-80. 2004..period of suppression of many clones suggests that transplanted HSCs may have a marked competitive advantage if they can engraft and proliferate during this time period, and supports the use of this agent in nonmyeloablative regimens..
- Gene therapy: therapeutic gene causing lymphomaNiels Bjarne Woods
Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037, USA
Nature 440:1123. 2006..Gene-therapy trials for X-SCID, which have been based on the assumption that IL2RG is minimally oncogenic, may therefore pose some risk to patients...