Gene therapy of Fanconi anemia: preclinical efficacy using lentiviral vectors
| Autor: | Francesco Galimi, Inder M Verma, Cynthia Chen, Timothy Lax, Markus Grompe, Yoshiyuki Kanazawa, Meenakshi Noll |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
DNA Repair
Genetic enhancement Genetic Vectors Immunology Cell Cycle Proteins Biology Transfection Polymerase Chain Reaction Biochemistry Mice FANCF Fanconi anemia FANCG hemic and lymphatic diseases FANCD2 medicine Animals Bone Marrow Transplantation Mice Knockout Fanconi Anemia Complementation Group A Protein Fanconi Anemia Complementation Group C Protein Lentivirus Nuclear Proteins Proteins Genetic Therapy Cell Biology Hematology Hematopoietic Stem Cells medicine.disease Fanconi Anemia Complementation Group Proteins FANCA DNA-Binding Proteins Disease Models Animal Transplantation Isogeneic Leukemia Fanconi Anemia medicine.anatomical_structure Mutation Bone marrow |
| Zdroj: | Blood. 100:2732-2736 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2002-04-1245 |
| Popis: | Fanconi anemia (FA) is an inherited cancer susceptibility syndrome caused by mutations in a DNA repair pathway including at least 6 genes(FANCA, FANCC, FANCD2, FANCE, FANCF, and FANCG). The clinical course of the disease is dominated by progressive, life-threatening bone marrow failure and high incidence of acute myelogenous leukemia and solid tumors. Allogeneic bone marrow transplantation (BMT) is a therapeutic option but requires HLA-matched donors. Gene therapy holds great promise for FA, but previous attempts to use retroviral vectors in humans have proven ineffective given the impaired proliferation potential of human FA hematopoietic progenitors (HPCs). In this work, we show that using lentiviral vectors efficient genetic correction can be achieved in quiescent hematopoietic progenitors from Fanca−/− andFancc−/−mice. Long-term repopulating HPCs were transduced by a single exposure of unfractionated bone marrow mononuclear cells to lentivectors carrying the normal gene. Notably, no cell purification or cytokine prestimulation was necessary. Resistance to DNA- damaging agents was fully restored by lentiviral transduction, allowing for in vivo selection of the corrected cells with nonablative doses of cyclophosphamide. This study strongly supports the use of lentiviral vectors for FA gene therapy in humans. |
| Databáze: | OpenAIRE |
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