Persistent hematopoietic polyclonality after lentivirus-mediated gene therapy for Fabry disease
The safety and efficacy of lentivirus-mediated gene therapy was recently demonstrated in five male patients with Fabry disease—a rare X-linked lysosomal storage disorder caused by GLA gene mutations that result in multiple end-organ complications. To evaluate the risks of clonal dominance and leukem...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-03-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050123000050 |
| _version_ | 1828041959706460160 |
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| author | Amr H. Saleh Michael Rothe Dwayne L. Barber William M. McKillop Graeme Fraser Chantal F. Morel Axel Schambach Christiane Auray-Blais Michael L. West Aneal Khan Daniel H. Fowler C. Anthony Rupar Ronan Foley Jeffrey A. Medin Armand Keating |
| author_facet | Amr H. Saleh Michael Rothe Dwayne L. Barber William M. McKillop Graeme Fraser Chantal F. Morel Axel Schambach Christiane Auray-Blais Michael L. West Aneal Khan Daniel H. Fowler C. Anthony Rupar Ronan Foley Jeffrey A. Medin Armand Keating |
| author_sort | Amr H. Saleh |
| collection | DOAJ |
| description | The safety and efficacy of lentivirus-mediated gene therapy was recently demonstrated in five male patients with Fabry disease—a rare X-linked lysosomal storage disorder caused by GLA gene mutations that result in multiple end-organ complications. To evaluate the risks of clonal dominance and leukemogenesis, which have been reported in multiple gene therapy trials, we conducted a comprehensive DNA insertion site analysis of peripheral blood samples from the five patients in our gene therapy trial. We found that patients had a polyclonal integration site spectrum and did not find evidence of a dominant clone in any patient. Although we identified vector integrations near proto-oncogenes, these had low percentages of contributions to the overall pool of integrations and did not persist over time. Overall, we show that our trial of lentivirus-mediated gene therapy for Fabry disease did not lead to hematopoietic clonal dominance and likely did not elevate the risk of leukemogenic transformation. |
| first_indexed | 2024-04-10T17:23:55Z |
| format | Article |
| id | doaj.art-94ca546755434fd5983165124cd0e623 |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-04-10T17:23:55Z |
| publishDate | 2023-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-94ca546755434fd5983165124cd0e6232023-02-05T04:16:24ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012023-03-0128262271Persistent hematopoietic polyclonality after lentivirus-mediated gene therapy for Fabry diseaseAmr H. Saleh0Michael Rothe1Dwayne L. Barber2William M. McKillop3Graeme Fraser4Chantal F. Morel5Axel Schambach6Christiane Auray-Blais7Michael L. West8Aneal Khan9Daniel H. Fowler10C. Anthony Rupar11Ronan Foley12Jeffrey A. Medin13Armand Keating14University Health Network, Toronto, ON, Canada; Department of Medicine, University of Alberta, Edmonton, AB, CanadaInstitute of Experimental Hematology, Hannover Medical School, Hannover, GermanyUniversity Health Network, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, CanadaDepartment of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USADepartment of Oncology, McMaster University and Juravinski Hospital and Cancer Centre, Hamilton, ON, CanadaFred A. Litwin Family Centre in Genetic Medicine, Department of Medicine, University, Health Network, Toronto, ON, CanadaInstitute of Experimental Hematology, Hannover Medical School, Hannover, Germany; Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USADivision of Medical Genetics, Department of Pediatrics, CIUSSS de l’Estrie-CHUS, Hospital Fleurimont, Université de Sherbrooke, Sherbrooke, QC, CanadaDivision of Nephrology, Department of Medicine, Dalhousie University, Halifax, NS, CanadaDepartment of Medical Genetics, Metabolics and Pediatrics, Alberta Children’s Hospital, Cumming School of Medicine, Research Institute, University of Calgary, Calgary, AB, CanadaRapa Therapeutics, Rockville, MD, USADepartments of Pathology and Laboratory Medicine and Pediatrics, Western University, London, ON, Canada; Children’s Health Research Institute, London, ON, CanadaDepartment of Pathology and Molecular Medicine, McMaster University and Juravinski, Hospital and Cancer Centre, Hamilton, ON, CanadaDepartment of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA; Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USAUniversity Health Network, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Princess Margaret Cancer Centre, 610 University Avenue, 700U 6-325 Toronto, ON M5G 2M9, Canada; Corresponding author Armand Keating, MD, Princess Margaret Cancer Centre, 610 University Avenue, 700U 6-325 Toronto, ON M5G 2M9, Canada.The safety and efficacy of lentivirus-mediated gene therapy was recently demonstrated in five male patients with Fabry disease—a rare X-linked lysosomal storage disorder caused by GLA gene mutations that result in multiple end-organ complications. To evaluate the risks of clonal dominance and leukemogenesis, which have been reported in multiple gene therapy trials, we conducted a comprehensive DNA insertion site analysis of peripheral blood samples from the five patients in our gene therapy trial. We found that patients had a polyclonal integration site spectrum and did not find evidence of a dominant clone in any patient. Although we identified vector integrations near proto-oncogenes, these had low percentages of contributions to the overall pool of integrations and did not persist over time. Overall, we show that our trial of lentivirus-mediated gene therapy for Fabry disease did not lead to hematopoietic clonal dominance and likely did not elevate the risk of leukemogenic transformation.http://www.sciencedirect.com/science/article/pii/S2329050123000050Fabry diseaseclinical trialgene therapylentiviral integrationlentiviral safety |
| spellingShingle | Amr H. Saleh Michael Rothe Dwayne L. Barber William M. McKillop Graeme Fraser Chantal F. Morel Axel Schambach Christiane Auray-Blais Michael L. West Aneal Khan Daniel H. Fowler C. Anthony Rupar Ronan Foley Jeffrey A. Medin Armand Keating Persistent hematopoietic polyclonality after lentivirus-mediated gene therapy for Fabry disease Molecular Therapy: Methods & Clinical Development Fabry disease clinical trial gene therapy lentiviral integration lentiviral safety |
| title | Persistent hematopoietic polyclonality after lentivirus-mediated gene therapy for Fabry disease |
| title_full | Persistent hematopoietic polyclonality after lentivirus-mediated gene therapy for Fabry disease |
| title_fullStr | Persistent hematopoietic polyclonality after lentivirus-mediated gene therapy for Fabry disease |
| title_full_unstemmed | Persistent hematopoietic polyclonality after lentivirus-mediated gene therapy for Fabry disease |
| title_short | Persistent hematopoietic polyclonality after lentivirus-mediated gene therapy for Fabry disease |
| title_sort | persistent hematopoietic polyclonality after lentivirus mediated gene therapy for fabry disease |
| topic | Fabry disease clinical trial gene therapy lentiviral integration lentiviral safety |
| url | http://www.sciencedirect.com/science/article/pii/S2329050123000050 |
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