Effective Multi-lineage Engraftment in a Mouse Model of Fanconi Anemia Using Non-genotoxic Antibody-Based Conditioning
| Autor: | Anthony E. Boitano, Rahul Palchaudhuri, Hans-Peter Kiem, David T. Scadden, Meera A. Srikanthan, Christina Ironside, Olivier Humbert, Kevin G. Haworth, Bruce R. Blazar, Yogendra S. Rajawat, Michael P. Cooke |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
lcsh:QH426-470 medicine.medical_treatment Article CD117 03 medical and health sciences 0302 clinical medicine Fanconi anemia Genetics medicine Autologous transplantation lcsh:QH573-671 Molecular Biology Chemotherapy saporin lcsh:Cytology business.industry medicine.disease Fanconi anemia gene therapy FANCA 3. Good health Transplantation lcsh:Genetics Haematopoiesis 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Cancer research Molecular Medicine non-genotoxic conditioning Bone marrow Stem cell business |
| Zdroj: | Molecular Therapy: Methods & Clinical Development, Vol 17, Iss, Pp 455-464 (2020) Molecular Therapy. Methods & Clinical Development |
| ISSN: | 2329-0501 |
| Popis: | Conditioning chemotherapy is used to deplete hematopoietic stem cells in the recipient’s marrow, facilitating donor cell engraftment. Although effective, a major issue with chemotherapy is the systemic genotoxicity that increases the risk for secondary malignancies. Antibody conjugates targeting hematopoietic cells are an emerging non-genotoxic method of opening the marrow niche and promoting engraftment of transplanted cells while maintaining intact marrow cellularity. Specifically, this platform would be useful in diseases associated with DNA damage or cancer predisposition, such as dyskeratosis congenita, Schwachman-Diamond syndrome, and Fanconi anemia (FA). Our approach utilizes antibody-drug conjugates (ADC) as an alternative conditioning regimen in an FA mouse model of autologous transplantation. Antibodies targeting either CD45 or CD117 were conjugated to saporin (SAP), a ribosomal toxin. FANCA knockout mice were conditioned with either CD45-SAP or CD117-SAP prior to receiving whole marrow from a heterozygous healthy donor. Bone marrow and peripheral blood analysis revealed equivalent levels of donor engraftment, with minimal toxicity in ADC-treated groups as compared with cyclophosphamide-treated controls. Our findings suggest ADCs may be an effective conditioning strategy in stem cell transplantation not only for diseases where traditional chemotherapy is not tolerated, but also more broadly for the field of blood and marrow transplantation. |
| Databáze: | OpenAIRE |
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