基因治疗,免疫缺陷小鼠 z-bo 2020-10-26 323

　　Since 2017, the field of gene therapy has been in favor of policy, capital attention, and the scientific community is very optimistic. Whether it is a company that focuses on the research and development of one or several gene therapy products, or a company that provides CRO or CDMO services for the research and development of gene therapy products, they have achieved rapid development in recent years.

　　In the course of the development of gene therapy, there have been cases of death due to strong immune response caused by the test patients receiving gene therapy (such as the first death case in 1999-American OTC deficiency patient Jesse, injected with normal gene fragments Adenovirus triggers a severe immune response, causing multiple organ failure and death). At present, in the process of research and development and marketing application of gene therapy products, the safety evaluation is very important. In addition, the treatment idea of gene therapy is to replace, edit or suppress disease-causing genes to treat diseases caused by gene defects. Therefore, compared with the development of traditional drugs, the mechanism of action of gene therapy products is clearer and more precise. It has been confirmed at the early stage of research and development. Therefore, in the pre-clinical research and development stage, the safety assessment of gene therapy is more concerned by researchers and regulatory authorities than the effectiveness assessment of gene therapy.

　　The current risks of gene therapy include severe immune reactions (such as cytokine storm), neurotoxicity, and insertional mutations (tumorigenicity). Among them, severe immune reactions are the most common adverse reactions that may threaten the life of patients in the short term. In order to reduce the occurrence of severe immune response in the process of gene therapy, there are currently two main strategies. One is to minimize the immunogenicity of viral vectors in the selection, design, and construction of viral vectors, but this approach may sacrifice the effectiveness of some products. Sex; another strategy is to combine with other drugs (such as antibody drugs) to reduce the incidence and severity of adverse reactions.

　　BRGSF mice are a kind of immunodeficiency mice with the most mature technology and the greatest degree of immunodeficiency. Compared with the current common N*G mice, the immune cells of BRGSF mice not only completely lack lymphocytes, but also myeloid cells ( For example, the function of macrophages is also severely lacking, so it is more effective for the establishment of tumor CDX and PDX models, which is suitable for the pharmacological and pharmacodynamic research of anti-tumor drugs.

　　In the field of gene therapy, BRGSF mice also have their unique advantages. For example, in the current popular CAR-T treatment field, unlike the NOD background of N*G mice (complement C5-/-), BRGSF mice have a BALB/c background, and their complement cascades are retained and exist in the body. Complement-dependent cytotoxicity (CDC) mechanism, so we can develop or find drugs that use CDC mechanism to eliminate residual CAR-T cells after treatment, thereby reducing the toxic side effects of CAR-T treatment.

　　In addition, BRGSF mice are very suitable for the reconstruction of the human immune system (HIS), that is, the BRGSF-HIS model. Compared with other HIS model mice, BRGSF-HIS has three major advantages:

　　1) It can promote the development of human myeloid cells;

　　2) Long survival period (> 1 year) after HIS;

　　3) The subgroups of the immune components after reconstitution are more complete and the ratio is closer to that of humans. It can be said that BRGSF-HIS is currently the closest mouse model to the human immune system.

　　As mentioned earlier, the most common adverse reaction of gene therapy is severe immune system reaction. If the gene therapy product can be tested and observed in mice with humanized immune system before clinical trials of gene therapy products, the severe immune system can be further reduced. Reactions such as cytokine storms lead to adverse reactions and even deaths. In the past, some researchers used wild-type mice or mouse models with a low degree of humanization of the immune system for such safety verification. The verification results were far from the clinical results, and the results were not ideal. The degree of humanization of BRGSF-HIS mice is very high. Our research has also confirmed that it has a rapid and significant immune response to human antigens. This provides a powerful tool for verifying the safety evaluation of gene therapy, and BRGSF- The HIS model has a long survival time (other humanized models<4 months), which is very suitable for research that requires long-term observation. Finally, BRGSF-HIS is also one of the best choices for the evaluation of the effect of gene therapy for diseases related to the human immune system.