Article

Large animal models of hematopoietic stem cell gene therapy

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA.
Gene therapy (Impact Factor: 3.1). 08/2010; 17(8):939-48. DOI: 10.1038/gt.2010.47
Source: PubMed

ABSTRACT

Large animal models have been instrumental in advancing hematopoietic stem cell (HSC) gene therapy. Here we review the advantages of large animal models, their contributions to the field of HSC gene therapy and recent progress in this field. Several properties of human HSCs including their purification, their cell-cycle characteristics, their response to cytokines and the proliferative demands placed on them after transplantation are more similar in large animal models than in mice. Progress in the development and use of retroviral vectors and ex vivo transduction protocols over the last decade has led to efficient gene transfer in both dogs and nonhuman primates. Importantly, the approaches developed in these models have translated well to the clinic. Large animals continue to be useful to evaluate the efficacy and safety of gene therapy, and dogs with hematopoietic diseases have now been cured by HSC gene therapy. Nonhuman primates allow evaluation of aspects of transplantation as well as disease-specific approaches such as AIDS (acquired immunodeficiency syndrome) gene therapy that can not be modeled well in the dog. Finally, large animal models have been used to evaluate the genotoxicity of viral vectors by comparing integration sites in hematopoietic repopulating cells and monitoring clonality after transplantation.

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    • "See also Figure S5.Although the FDA considers analogous cell product data an acceptable option for preclinical studies, it requires substantial similarity between analogous animal and human products (FDA, 2013). Due to the significant differences in the innate and adaptive immune system (Mestas and Hughes, 2004), hematopoietic system homeostasis , cell surface markers, and the requirements for hematopoietic cell engraftment (Harding et al., 2013;Trobridge and Kiem, 2010), rodent models are unlikely to fulfill this FDA requirement. The NHP model will be able to overcome these inherent limitations of rodent models, especially limitations related to completely different structure and MHC binding specificity between mouse and human KIRs (Natarajan et al., 2002;Parham et al., 2010). "
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    ABSTRACT: Advances in the scalable production of blood cells from induced pluripotent stem cells (iPSCs) open prospects for the clinical translation of de novo generated blood products, and evoke the need for preclinical evaluation of their efficacy, safety, and immunogenicity in large animal models. Due to substantial similarities with humans, the outcomes of cellular therapies in non-human primate (NHP) models can be readily extrapolated to a clinical setting. However, the use of this model is hampered by relatively low efficiency of blood generation and lack of lymphoid potential in NHP-iPSC differentiation cultures. Here, we generated transgene-free iPSCs from different NHP species and showed the efficient induction of mesoderm, myeloid, and lymphoid cells from these iPSCs using a GSK3β inhibitor. Overall, our studies enable scalable production of hematopoietic progenitors from NHP-iPSCs, and lay the foundation for preclinical testing of iPSC-based therapies for blood and immune system diseases in an NHP model.
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    • "Even in the context of " humanized " mouse models, long-term engraftment of human cells has been difficult to assess and interspecies differences in homing receptors and immune modulators (e.g., cytokines) create an environment of uncertain relevance to the human clinical setting (Horn et al., 2003; Mestas and Hughes, 2004; Mezquita et al., 2008; Sykes, 2009). Studies also suggest that the histology and time course for allograft rejection in monkeys parallels humans because of similarities in major histocompatibility complex genes and immune ontogeny, while tolerance is much easier to achieve in mice (Cowan et al., 2001; Trobridge and Kiem, 2010; Gibbons and Spencer, 2011). Establishment of a functional immune system has been characterized in mice and humans as a multistage process that occurs in a unique, coordinated, sequential, and temporal sequence. "
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    • "Currently, the clinically most advanced CTX-R gene transfer strategy for myeloprotection applies MGMT point mutants resistant to the specific wild-type MGMT inhibitor O 6 -benzylguanine (BG). MutMGMT gene transfer followed by combined BG/1,3-bis(2-chloroethyl)-1nitrosourea (BCNU) or BG/temozolomide chemotherapy has proven highly efficacious for myeloprotection as well as in vivo selection in murine and several large animal models [8] [9] [10]. Furthermore, a recent clinical trial has demonstrated efficient myeloprotection and in vivo enrichment of genetically modified cells following mutMGMT gene therapy in a cohort of glioblastoma patients demonstrating progression-free survival for more than 2 years in individual patients [11]. "
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