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Humanized Mouse Models Fact Sheet

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Humanized Mouse Models Fact Sheet ALZET Research Application Humanized Mouse Models The nude mouse and severe combined immunodeficiency (SCID) mouse have ALZET Pump Highlights traditionally been used as recipients for human cells or tissues because they lack host immunity and easily accept heterologous cells. The introduction of • Small size for implantation • 9 pump models for mice the non-obese diabetic (NOD)/SCID mouse led to the development of highly • Continuous and controlled immunodeficient strains, able to engraft human cells and tissues more delivery of agents efficiently, which are more appropriate for generating humanized mouse • Minimize side effects and models. experimental variables • Convenient and cost- effective dosing method The humanized mouse – a mouse carrying functional human genes, cells, • Reduced animal handling tissues, and/or organs – is now a powerful research tool for the in vivo study of and stress • Delivery rates ranging from human biology and disease. Humanized mouse models enable a better 0.11 µl/hr to 8 µl/hr understanding of disease pathways and ultimately improve the translational • Delivery durations ranging value of preclinical studies. Various humanized mouse models have been from 1 day to 6 weeks developed for the study of infectious diseases, autoimmunity, transplantation, vaccine development, cancer immunotherapy, regenerative medicine, cell development, and more. Immunodeficient Strains* ALZET® Osmotic Pumps are used extensively with immunodeficient mice, and Nude Mouse hundreds of publications attest to their research value in these species. These SCID Mouse implantable infusion pumps offer a convenient alternative to repetitive NOD/SCID Mouse injections for continuous dosing of unrestrained lab animals. Their automatic NSG Mouse operation, small size and simple design make them suitable for chronic dosing NOG Mouse studies in humanized mouse models. No researcher intervention is required during infusion, and animal handling is kept to a minimum to reduce the risk of NRG Mouse infection and stress. Read on for research summaries describing the use of *See page 4 for complete ALZET pumps in humanized mouse models. Contact us for additional descriptions information at 800.692.2990 or [email protected]. DURECT CORPORATION | 10260 BUBB ROAD | CUPERTINO CA, 95014-4166 T: 408.367.4036 F: 408.865.1406 TOLL FREE 800.692.2990 WWW.ALZET.COM | [email protected] Use of ALZET Pumps in Humanized Mouse Models Suzuki et al. Generation of engraftable hematopoietic stem cells from induced pluripotent stem cells by way of teratoma formation. Molecular Therapy 2013;21(7):1424–1431 Purpose (1) Develop an in vivo differentiation system for the generation of engraftable hematopoietic stem cells (HSCs) from induced pluripotent stem cells (iPSCs) to facilitate hematopoiesis. (2) Investigate teratomas as a suitable microenvironment for the generation of engraftable HSCs with bone marrow (BM) niche migration potential. Mouse Model Transplantation of BM cells (hiPSC-derived HSCs) of teratoma-bearing mice into irradiated NOD/SCID or NOD/SCID/ JAK3null recipient mice. Role of ALZET Continuous, SC administration of the hematopoietic cytokines, stem cell factor (SCF) and thrombopoietin (TPO), over 2 weeks in teratoma-bearing mice to stimulate differentiation of iPSCs into HSCs. Key Findings • HSCs were successfully induced by injection of iPSCs into immunodeficient mice and reproducing the HSC niche by way of teratoma formation. Co-administration of OP9 stromal cells along with hematopoietic cytokines dramatically enhanced the induction efficiency. • HSCs derived from iPSCs showed self-renewal and multi-lineage differentiation capabilities. • iPSC-derived HSCs were shown to migrate from teratomas into the BM niche following IV injection into irradiated recipients, where they are capable of long-term reconstitution of the hematolymphopoietic system. • Established an in vivo differentiation system to generate fully functional, xenotransplantable HSCs from iPSCs through teratoma formation. Gang et al. Small-molecule inhibition of CBP/catenin interactions eliminates drug-resistant clones in acute lymphoblastic leukemia. Oncogene 2013:1-10 Purpose Evaluate the efficacy of ICG-001, a novel small-molecule inhibitor of Wnt/beta catenin signaling, with or without traditional chemotherapy with nilotinib (NTB) or VDL (vincristine, dexamethasone and L-asparaginase). Mouse Model Xenograft model of primary acute lymphoblastic leukemia (ALL) in NOD/SCID gamma (NSG) mice. Role of ALZET Model 1004 used for subcutaneous administration of ICG-001 for 28 days to ensure stable plasma dosing levels. Key Findings • ICG-001 treatment in combination with chemotherapy significantly prolonged survival of mice engrafted with primary ALL: a mean survival time (MST) of 100 days was seen in mice treated with ICG-001 plus chemotherapy, compared to 85 days MST for chemotherapy only-treated mice, 37.5 days MST for ICG-001 only treated mice, and 34 days MST for saline control-treated mice. • Selective inhibition of CBP/catenin signaling with ICG-001 prevents self-renewal of drug-resistant leukemia- initiating cells by forced differentiation, thereby sensitizing them to chemotherapy. • This approach represents a promising therapeutic strategy for specifically eradicating drug-resistant leukemia- initiating cells. Klug et al. Low-dose irradiation programs macrophage differentiation to an iNOS+/M1 phenotype that orchestrates effective T cell immunotherapy. Cancer Cell 2013;24:589–602. Purpose Evaluate the effect of low-dose irradiation (LDI) as adjuvant for improving the efficacy of adoptive T cell therapy or tumor vaccination on various xenograft tumor models. Mouse Model Human melanoma (MeWo) xenograft model in NOD/SCID gamma (NSG) mice and NOD/SCID mice for cancer immunotherapy; RIP1-Tag5 (RT5) pancreatic tumor xenograft model in NOD/SCID mice. Role of ALZET Model 2002 used for subcutaneous administration of the selective iNOS inhibitor 1400W over 2 weeks to evaluate the effect of iNOS inhibition on vascular normalization, activation, and T cell recruitment into RT5 tumors. Key Findings • iNOS inhibition by 1400W treatment eliminated NO secretion in irradiated and CD8TC-treated tumors and completely inhibited vascular cell adhesion protein-1 expression. • LDI programs the differentiation of iNOS+ M1 macrophages which induce CTL recruitment and killing within solid tumors by inducing endothelial activation and TH1 chemokine expression, as well as by suppressing the production of angiogenic, immunosuppressive, and tumor growth factors. • iNOS+ macrophages are required to mediate effector T cell recruitment into tumors for successful tumor immune rejection through an NO-dependent mechanism. • Adoptive transfer of iNOS-expressing macrophages is a promising strategy to improve the efficacy of cancer immunotherapy. DURECT CORPORATION | 10260 BUBB ROAD | CUPERTINO CA, 95014-4166 T: 408.367.4036 F: 408.865.1406 TOLL FREE 800.692.2990 WWW.ALZET.COM | [email protected] Use of ALZET Pumps in Humanized Mouse Models Krause et al. Differential regulation of myeloid leukemias by the bone marrow microenvironment. Nature Med 2013;19:1513–1517 Purpose Evaluate the effect of human parathyroid hormone (PTH) for modulation of the bone marrow microenvironment to eliminate persistent and drug resistant leukemia stem cells (LSC) in chronic myelogenous leukemia (CML) and acute myeloid leukemia (AML). Mouse Model Xenograft model of chronic myelogenous leukemia in NOD/SCID IL-2 receptor γ deficient (NSG) mice. Role of ALZET 14-day ALZET pumps used for SC administration of human PTH (1–34) for 18 weeks (PTH treatment started 4 weeks prior to xenotransplantation and continued for 14 weeks thereafter, with pump replacement every two weeks). Key Findings • PTH treatment caused a 15-fold decrease in LSCs in wild type mice with CML-like myeloproliferative neoplasia and significantly reduced engraftment of primary human CML cells in NSG mice. • The beneficial effect of PTH in CML is mediated via suppressive effects of TGF-β. • Study suggests that targeting the hematopoietic microenvironment through PTH may render it hostile for CML cells, indicating that alteration of the tumor microenvironment is a potentially complementary approach to tumor cell-specific therapy. Chandramohan et al. Recombinant anti-podoplanin (NZ-1) immunotoxin for the treatment of malignant brain tumors. Int J Cancer. 2013;132(10) Purpose Evaluate the intracranial efficacy of an anti-podoplanin immunotoxin (NZ-1-(scdsFv)-PE38KDEL) in the meduloblastoma tumor model. Mouse Model Intracranial meduloblastoma xenograft model in NOD/SCID gamma (NSG) mice. Role of ALZET Model 1003D used for administration (3 days) of an anti-podoplanin immunotoxin directly into the brain tumor site to bypass the blood-brain barrier. Key Findings • The podoplanin tumor antigen is overexpressed in several glioblastoma and medulloblastoma xenograft cells. • Recombinant immunotoxin was highly efficacious against CNS tumors expressing podoplanin, increasing survival by 41% in tumor bearing mice compared to controls. • Podoplanin is a suitable candidate for targeted therapy of malignant brain tumors. Examples of Humanized Mouse Models Available BLT humanized (hBLT) mouse PBMC humanized (hPBMC) mouse • Modification of the SCID-Hu model • NSG mice engrafted with human peripheral blood • NOD/SCID mice engrafted with human liver and thymus mononuclear cells (hPBMC) tissues, along with autologous CD34+ HSCs • Perfect for short-term experiments where T cell engraftment • Robust
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