%0 Journal Article
%T Differential Secondary Reconstitution of In Vivo-Selected Human SCID-Repopulating Cells in NOD/SCID versus NOD/SCID/¦Ã chainnull Mice
%A Shanbao Cai
%A Haiyan Wang
%A Barbara Bailey
%A Jennifer R. Hartwell
%A Jayne M. Silver
%A Beth E. Juliar
%A Anthony L. Sinn
%A Arthur R. Baluyut
%A Karen E. Pollok
%J Bone Marrow Research
%D 2011
%I Hindawi Publishing Corporation
%R 10.1155/2011/252953
%X Humanized bone-marrow xenograft models that can monitor the long-term impact of gene-therapy strategies will help facilitate evaluation of clinical utility. The ability of the murine bone-marrow microenvironment in NOD/SCID versus NOD/SCID/¦Ã chainnull mice to support long-term engraftment of MGMTP140K-transduced human-hematopoietic cells following alkylator-mediated in vivo selection was investigated. Mice were transplanted with MGMTP140K-transduced CD34+ cells and transduced cells selected in vivo. At 4 months after transplantation, levels of human-cell engraftment, and MGMTP140K-transduced cells in the bone marrow of NOD/SCID versus NSG mice varied slightly in vehicle- and drug-treated mice. In secondary transplants, although equal numbers of MGMTP140K-transduced human cells were transplanted, engraftment was significantly higher in NOD/SCID/¦Ã chainnull mice compared to NOD/SCID mice at 2 months after transplantation. These data indicate that reconstitution of NOD/SCID/¦Ã chainnull mice with human-hematopoietic cells represents a more promising model in which to test for genotoxicity and efficacy of strategies that focus on manipulation of long-term repopulating cells of human origin. 1. Introduction Development of humanized hematopoietic xenograft models that can monitor both short- and long-term reconstitution of human hematopoietic stem and progenitor cells (HSCs) will be a necessity as hematopoietic stem cell gene therapy trials continue to move forward and show promise in the clinic [1¨C7]. Clearly the use of small and large animal models has been an intricate component in paving the way for these successes [8¨C24]. Adverse events, however, directly related to retroviral-mediated insertional mutagenesis in human trials, have been reported in some patients enrolled in gene-therapy clinical trials for severe combined immunodeficiency (SCID)-X1 [25, 26] and chronic granulomatous disease [7, 27]. In addition, as preclinical studies in nonhuman primates, dogs, and mice have progressed over the past decade, development of leukemias most likely linked or initiated by vector-mediated insertional mutagenesis have been reported [28¨C33]. Therefore, more investigations are needed to understand retroviral-mediated genome instability in addition to the design of new vector systems to prevent this adverse event in human gene-therapy trials. The evaluation of both short- and long-term reconstituting human HSC will be critical in addressing these issues and is the focus of the current study. In the past, in vivo experiments designed to study the engraftment and
%U http://www.hindawi.com/journals/bmr/2011/252953/