Mice are commonly used as models of human disease, helping scientists to understand the workings of complex pathologies and develop safe and efficacious drugs. It is now possible to create a range of genetically engineered mouse models, including humanized, knock-in and knock-out models, that can be used to further advance our understanding and treatment of human diseases.Technology Networks recently spoke with Dr. Marvin Ouyang, Cyagens executive vice president and chief scientific officer, to learn more about humanized mice and the applications they can benefit. In this interview Dr. Ouyang also explains how humanized mice can be generated and highlights some of Cyagens capabilities in this area.Anna MacDonald (AM): What are humanized mice?Dr. Marvin Ouyang (MO): A humanized mouse model is a broad term referring to a mouse engrafted with functional human genes, cells, or tissues. This type of model is usually used as a powerful in vivo model for preclinical study of human diseases and drug discovery. Humanized mouse models have become an important animal model for identifying how human genes impact development and disease.AM: Why are humanized mice a popular research tool?MO: The predominant goal of all biomedical research is to overcome human diseases. Due to medical ethics, we cannot initially test drugs with uncertain effects in the human body. Therefore, evaluating the drug safety and efficacy through animal models has become the best alternative. Mouse models have since become irreplaceable for the study of gene function and pathogenesis and have also accelerated the process of drug screening. Humanized mice widely serve as models in translational medicine, playing an important role in biological research and drug discovery, including regenerative medicine, transplantation, and immunology.
AM: What applications can humanized mice particularly benefit?MO: Humanized mice are important tools for preclinical research that enable researchers to conduct translationally relevant studies. They benefit a wide range of research fields, including:
AM: Can you tell us more about the use of humanized mice in cancer research?MO: Humanized mice can be applied to the study of T-cell editing as an evaluation method to optimize the efficacy and safety of TCR/CAR regulation and expand the scope of cancer treatment. Optimized mechanisms for introducing tumor-specific TCRs into T cells through the transgenic (TG) method have been investigated in humanized mouse models. There is one primary concern regarding the safety of TG TCR therapy, which is the potential for mispairing between the TG TCR and the endogenous TCR, causing off-target specificity and thereby increasing cytotoxicity. After destroying endogenous TCRa and TCRb genes with the ZFN method, researchers found that the Hu-PBL-SCID model transplanted with a source of wt-1-positive leukemia edited TG T cells could express only WT-1 tumor-specific TCRs.Humanized mice can also serve as evaluation tools for immune checkpoint inhibitors. At present, two immune checkpoint monoclonal antibodies have been successfully developed in the clinic, anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) monoclonal antibody and anti-programmed cell death-1 (anti-PD-1) monoclonal antibody. Both CTLA-4 and anti-PD-1 monoclonal antibody treatments have demonstrated efficacy in combating melanoma, but not all patients respond to both CTLA-4 and anti-PD-1 therapy. Therefore, humanized mice transplanted with tumors can reveal the interaction mechanism between blocking and immune system and evaluate the efficacy and efficiency of immunomodulators. Recent studies have shown that the combined administration of anti-hcd137 and anti-PD-1 monoclonal antibodies has a significant antitumor effect in RAG2 IL2RG mice transplanted with human colorectal HT-29 cancer cells and heterologous human peripheral blood mononuclear cells (PBMCs), or in mice transplanted with gastric cancer tissue from patients and autologous PBMCs.
AM: Can you explain the different ways that humanized mice can be generated?MO: There are two primary methods of generating humanized mouse models, described below.1) Transplantation of human cells or tissues into immunodeficient miceConventional humanized mouse models were established by transplanting human cells or tissues into immunodeficient mice. Due to the merits of high efficiency, economy, and relatively simple operation process, this method has been widely used as a preclinical experimental animal model in the research of human infectious diseases, cancer, regenerative medicine, transplantation, allergy, and immunity.2) Insertion of human genes into the mouse genome using transgenic/gene targeting/gene editing technologyGenetically modified humanized mouse models have been widely applied in the research of human gene function, tumor immune drug development, infectious diseases, preclinical evaluation of drugs and more. For example, by humanizing mouse genes related to immune checkpoints such as CTLA4 and PD1, humanized mice that can interact with anti-CTLA4 and PD1 humanized antibodies can be constructed which provide an effective tool for preclinical screening and evaluation of antibody drugs.AM: What are the advantages of using humanized mouse models for antibody production?MO: With the rapid advancement of humanized antibody production, the use of genetic modification to develop mice that produce human antibodies has become an important facet of antibody drug development research. A humanized mouse expressing human antibody can be obtained through multiple rounds of gene targeting, respectively replacing the homologous mouse region with the human antibody heavy chain/light chain variable region. After being stimulated by the corresponding antigen, the humanized mouse can produce an antibody containing a humanized variable region portion against the antigen along with the constant region of a mouse antibody. Studies have shown that human antibodies obtained through humanized mouse screening have a more effective affinity and activity compared with human antibodies obtained by in vitro DNA recombination methods.AM: What factors should researchers consider when choosing between CRISPR/Cas or embryonic stem (ES) cell targeting methods?MO: CRISPR, which stands for clustered regularly interspaced short palindromic repeats, works alongside Cas proteins to form the CRISPR-Cas complex a biological technology originally derived from a prokaryotic adaptive immunity system. Although CRISPR is known for advantages such as high efficiency, rapid turnaround, convenient process, low cost, and successful application to different species; the disadvantages include the unpredictable and uncontrollable off-target risks, fragment size limitations, and ongoing patent disputes often making it unsuitable for complex genetic modification projects.
ES cell mediatedgenetargeting technology widely regarded as the Gold Standard of the industry provides accurate gene changes without off-target effects, enablingcomplex genetic modification.
Since the beginnings of gene editing research, the ability to accurately modify large genomic regions has remained a primary driver of innovation in the field. Although gene editing technologies have been continuously refined, the size of the modifiable region is still constrained depending on the methods used.
Developing (humanized) mouse models with large genomic modifications has proven to be a challenging task for many institutional cores and companies. Research of whole gene replacements used in gene replacement therapy often pushes the limits of gene editing technologies. Large fragment knock-ins (LFKIs) similarly limited are used to develop humanized mouse models.AM: Can you tell us more about Cyagens humanized mouse generation capabilities and the advantages they offer researchers?MO: While either CRISPR/Cas9 editing or ESC-mediated gene targeting may be used to develop humanized knock-in (KI) mouse models, each method offers its own benefits for model development. TheCyagen TurboKnockoutgene targeting service brings together the advantages of each method to provide complex gene modeling in C57BL/6 or BALB/c mouse models including LFKIs up to 300 kb on an accelerated timeline. TurboKnockout delivers research-ready humanization mouse models in as fast as 6 months.Compared to CRISPR/Cas9-based gene engineering, TurboKnockoutprovides accurate genetic changes without off-target effects, is free of patent disputes, and is the technology of choice for drug development projects requiring freedom to operate.Dr. Marvin Ouyang was speaking to Anna MacDonald, Science Writer for Technology Networks.
See the rest here:
Humanized Mice: Generation, Advantages and Applications - Technology Networks
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