Gene Transfer into Hematopoietic Stem Cells of Nonhuman Primates

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Abstract
Nonhuman primates provide an appropriate preclinical large-animal model to test the efficacy of bone marrow gene therapy procedures. Successful retroviral vector-mediated gene transfer into monkey pluripotent hematopoietic stem cells (PHSC) has closed the gap between gene transfer experiments in mouse models and clinical application of bone marrow gene therapy. After initial bone marrow transplant failures, ex vivo bone marrow culture conditions were found that sufficiently supported maintenance of the long-term repopulating ability of genetically modified autologous monkey grafts. The efficiency of gene transfer into primate PHSC has, however, remained at least one order of magnitude lower than has been achieved in mice. Similar gene transfer efficiencies have been obtained with total bone marrow grafts, CD34+ bone marrow grafts, and mobilized peripheral blood progenitor cell grafts; however, various attempts to increase the transduction efficiency have been without significant success. Primate PHSC seem to require quite different culture conditions for their maintenance and transduction than mouse PHSC, in particular regarding hematopoietic growth factor addition. In contrast to observations in other species, some form of conditioning appeared essential for engraftment of transduced PHSC in monkeys. Although it has been shown that mouse retroviruses can replicate in monkeys and are capable of inducing neoplasms, experiments in monkeys have sufficiently confirmed the safety of current gene transfer procedures to allow their clinical application. Preclinical bone marrow gene transfer experiments in non-human primates have been of great value for the development of gene therapy procedures in humans. They have demonstrated the efficacy and safety of retroviral vector-mediated gene transfer into primate pluripotent hematopoietic stem cells (PHSC). Although gene transfer efficiency into monkey PHSC has remained disappointingly low, various studies have provided reasonable experimental support to assume that gene transfer into human PHSC could lead to long-term expression of the introduced sequences in mature cells at levels sufficient to gain clinical benefit. As a direct result, numerous clinical gene therapy and gene marking studies are now in progress.