Humanized Mouse Models

ALZET Research Alert - September 2014

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The development of highly Immunodefficient mice, which support human cell and tissue growth, are indispensable for generating humanized mouse models. The humanized mouse – a mouse carrying functional human genes, cells, tissues, and/or organs – is a powerful research tool for the in vivo study of human biology and disease. Humanized mouse models enable a better understanding of disease pathways and ultimately improve the translational value of preclinical studies.

ALZET® Osmotic Pumps are used extensively with immunodefficient mice. Their automatic operation, small size and simple design make them suitable for implantation in humanized mice. These small, infusion pumps are a convenient alternative to repetitive injections for continuous dosing of unrestrained laboratory animals. Once implanted, no researcher intervention is required during infusion, reducing the risk of infection and stress associated with frequent animal handling. Read on for select research on the use of ALZET pumps in humanized mouse models. Contact us for additional information at 800.692.2990 or alzet@durect.com.

Recombinant anti-podoplanin (NZ-1) immunotoxin for the treatment of malignant brain tumors
  Purpose of study: Evaluate the intracranial efficacy of an anti-podoplanin immunotoxin in the meduloblastoma tumor model
  Mouse Model: Intracranial meduloblastoma xenograft model in NOD/SCID gamma (NSG) mice
  Role of ALZET pumps: (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
IntJCancer 2013;132(10)
 
Small-molecule inhibition of CBP/catenin interactions eliminates drug-resistant clones in acute lymphoblastic leukemia
  Purpose of study: 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 pumps: 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.
Oncogene 2013:1-10
 
Low-dose irradiation programs macrophage differentiation to an iNOS+/M1 phenotype that orchestrates effective T cell immunotherapy
  Purpose of study: 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 pumps: 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.
Cancer Cell 2013;24:589-602
 
Differential regulation of myeloid leukemias by the bone marrow microenvironment
  Purpose of study: 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 pumps: 14-day ALZET pumps used for subcutaneous 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.
Natute Medicine 2013;19:1513-1517
 
Generation of engraftable hematopoietic stem cells from induced pluripotent stem cells by way of teratoma formation
  Purpose of study: (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 pumps: 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 reproduced 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 multilineage differentiation capabilities
• iPSC-derived HSCs were shown to migrate from teratomas into the BM niche following intravenous 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.
Molecular Therapy 2013;21(7):1424-1431

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What researchers are saying...

"Utilizing continuous minipump administration enhances the knockdown to 63% of control." (p. 619) This compared with 40% by twice daily administration. "The results of the present study confirm the utility of osmotic minipump administration of antisense oligonucleotides." (p. 621) Falk et al., Pharmacol Biochem Behav 2002;72:617-622.