In Vivo Selection and Chemoprotection After Drug Resistance Gene Therapy in a Nonmyeloablative Allogeneic Transplantation Setting in Dogs
| Autor: | Tobias Neff, Sabine Gerull, Hans-Peter Kiem, Laura J. Peterson, Brian C. Beard |
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| Rok vydání: | 2007 |
| Předmět: |
Allogeneic transplantation
Methyltransferase Genetic enhancement Genetic Vectors Drug Resistance Drug resistance Biology Dogs Graft Enhancement Immunologic In vivo Genetics Animals Transplantation Homologous Molecular Biology DNA Primers Transplantation Chimera Base Sequence Lentivirus Chemoprotection Genetic Therapy Carmustine Transplantation Immunology Cancer research Molecular Medicine Stem cell Stem Cell Transplantation |
| Zdroj: | Human Gene Therapy. 18:451-456 |
| ISSN: | 1557-7422 1043-0342 |
| DOI: | 10.1089/hum.2006.039 |
| Popis: | We have previously demonstrated successful in vivo selection, chemoprotection, and modulation of donor chimerism in dogs that received myeloablative allogeneic stem cell transplantation with cells expressing the P140K mutant of the DNA repair enzyme methylguanine methyltransferase (MGMTP140K). Here, we wished to investigate whether in vivo selection, chemoprotection, and modulation of donor chimerism could also be achieved after nonmyeloablative transplantation, which could allow for less toxic transplantation regimens for patients with malignant and genetic diseases. Three dogs received a nonmyeloablative conditioning regimen and infusion of allogeneic stem cells transduced with MGMTP140K. All three dogs had stable gene marking and donor chimerism before receiving a course of O(6) -benzylguanine (O(6) BG)/1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) between days 210 and 589 after transplantation. One to four doses led to a marked increase in gene marking in all dogs. Furthermore, the transduced cells conferred chemoprotection and prevented severe neutropenia. Our results suggest that drug resistance gene therapy is feasible and safe in the nonmyeloablative transplantation setting. |
| Databáze: | OpenAIRE |
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