The scientific community has widely accepted the potential of gene therapy, which has led to gene therapies receiving increased attention from policymakers, innovators, and others. In recent years, there has been rapid development among companies focused on the research and development (R&D) of gene therapy products, and those providing CRO or CDMO services for the related R&D of gene therapy products, have achieved rapid development in recent years.
In the progress of gene therapy research, there have been cases of death due to strong immune response on test patients after receiving gene therapy. In 1999, the first case of death associated with clinical trials of gene therapy occurred. Jesse Gelsinger, an ornithine transcarbamylase (OTC) deficiency patient, developed a severe immune response after the injection of the adenoviral vector carrying the corrected gene, causing multiple organ failure and leading to his death. A thorough understanding of the currently available gene therapy methods is critical for successfully developing new gene therapy strategies and projects- there are gene augmentation, gene silencing/inhibition, genome editing and gene suicide. At present, effective safety evaluations are of vital importance in the process of R&D for gene therapy products.
Gene Therapy as a Direct Treatment Option
The concept of gene therapy is to replace, edit or suppress disease-causing genes to effectively treat diseases caused by gene differences. Compared with the development of traditional drugs, the mechanism of action of gene therapy products is clearer and more precise, and usually being confirmed in the early stages of research. Therefore, in the pre-clinical research and development stage, the safety of gene therapy is of greater concern to researchers and regulatory authorities than its effectiveness.
Risks of Gene Therapy: Cytokine Storm
At present, the risks of gene therapy include severe immune response (such as cytokine storm), neurotoxicity, and insertional mutagenesis (tumorigenicity). Among them, severe immune response is the most common adverse reaction that may be life-threatening to patients in the short term. There are currently two main strategies to reduce the occurrence of severe immune response during gene therapy. The first strategy aims to minimize the immunogenicity of viral vectors in the stages of selection, design, and construction - this may sacrifice the effectiveness of some products. Another approach is to combine the adenoviral vector with other drugs (such as antibody drugs) to lower the incidence and severity of adverse reactions.
BRGSF Immunodeficiency Mouse Model
BRGSF mice are one of the most adapted immunodeficient mice with highly effective technology to study human immune responses. Compared with the commonly used N*G mice, BRGSF mice completely lack lymphocytes and the function of macrophages is inhibited, and the development of myeloid cells (especially DC) is also impaired due to the knockout of Flk2 gene. Thus, BRGSF mice are more effective for the establishment of tumor-bearing cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models as well as an ideal option for researching the pharmacological and pharmacodynamic properties of anti-tumor drugs.
Figure 1. The Features of BRGSF Mice
Applications in CAR T-Cell Therapy Research
BRGSF mice also have unique advantages in the field of gene therapy, exemplified in the popular field of chimeric antigen receptor (CAR) T-cell treatments. Unlike the N*G mice on NOD background (complement C5-/-), BRGSF mice on the BALB/c background preserve their complement cascades and retain in vivo complement-dependent cytotoxicity (CDC) mechanisms. Based on these characteristics, we can develop or search for drugs that use CDC to eliminate residual CAR T-cells after treatment, thereby reducing the toxic side effects of CAR T-cell treatment. For example, Valton J., et al constructed a CubiCAR-T cell for multiple myeloma treatment: the constructed CAR contained CD20 epitopes, and the CAR-T cell was removed on demand by injecting monoclonal anti-CD20 antibody (Rituximab) (Valton J., et al., 2018).
Model Advantages for the Human Immune System
In addition, BRGSF mice are ideal for reconstructing human immune system (HIS), demonstrated by the BRGSF-HIS model. Compared with other HIS models, BRGSF-HIS has three major advantages:
In addition, Flt3-L treatment can promote the development of human myeloid compartment (especially DCs), and the model can be used to study myeloid compartment development.
As mentioned above, the most prevalent life-threatening adverse reaction of gene therapy is severe immune system reaction known as a cytokine storm, which is thought to occur due to the adenoviral vector used. To help prevent or reduce the occurrence of such adverse reactions, the gene therapy product may be tested and observed in mice with humanized immune system before clinical trials. In the past, researchers have used wild-type mice or mouse models with low level of humanization of the immune system to perform such safety verification tests. The verification results were far from the clinical results, and the data from such studies were not ideal. The degree of humanization of BRGSF-HIS mice is remarkably high and research has also confirmed that it has a rapid and significant immune response to human antigens - providing a powerful tool for evaluating the safety of potential gene therapies. While other humanized mouse models typically survive under 4 months, the BRGSF-HIS model has a longer survival time and is more suitable for research that requires long-term observation. BRGSF-HIS is also one of the best choices for the efficacy evaluation of gene therapy for human immune system related diseases.
In addition to BRGSF mice, Cyagen’s drug screening and evaluation mouse model platform can also provide you with a series of immune checkpoint humanized mice, inflammation and allergy humanized mice, humanized reporter mice, humanized PK/PD mice, to accelerate your research in immunotherapy!
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