In Vivo Selection and Chemoprotection After Drug Resistance Gene Therapy in a Nonmyeloablative Allogeneic Transplantation Setting in Dogs

S Gerull, BC Beard, LJ Peterson, T Neff… - Human gene …, 2007 - liebertpub.com
S Gerull, BC Beard, LJ Peterson, T Neff, HP Kiem
Human gene therapy, 2007liebertpub.com
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 …
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 O6 -benzylguanine (O6 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.
Mary Ann Liebert