Advancing Drug Testing: Genetically Diverse Mouse Models vs. Traditional Methods

Researchers typically use animal models, especially mice, to test drugs before human trials. However, these inbred mice often do not accurately simulate human diseases, particularly complex ones like diabetes and cancer. This can lead to inconsistent results. Lab-grown cell cultures, another alternative, can also fail to mimic complex diseases.

To address these issues, researchers at The Jackson Laboratory (JAX) propose a new approach. They recommend combining genetically diverse mouse models with human and mouse cells. This method aims to enhance the modeling of diseases and improve predictions regarding drug responses. Additionally, it aims to reduce reliance on traditional mouse models while maximizing scientific benefits, in line with the FDA’s Modernization Act 2.0, which encourages finding more reliable alternatives to animal testing.

In a recent interview, Prof. Nadia Rosenthal, the scientific director at JAX, explained how using genetically diverse mice can lead to improved therapies for various diseases. The FDA’s recent decision to phase out animal testing in preclinical screening responds to concerns about the effectiveness of traditional animal models in predicting human medical outcomes. The current criticism of mouse models stems from their limited ability to represent complex diseases that involve multiple genetic factors.

New alternatives for preclinical testing, such as cell-based assays and organoids, are emerging. These approaches, supported by AI analytics, aim to enhance understanding of patient responses to drug candidates while minimizing animal use. However, challenges remain in accurately predicting human responses based on these systems.

Precision medicine requires model systems reflecting the genetic diversity and complex pathologies of human diseases. Researchers at JAX are developing new genetically diverse models to better align preclinical findings with patient outcomes. This effort aims to bridge gaps between research findings and clinical results.

How can genetically diverse mouse models improve our understanding of complex human diseases in drug development?

Standing of disease mechanisms and refine drug development processes. Here is an interview with Prof. Nadia Rosenthal, who elaborates on this innovative approach.

Interview with Prof. Nadia Rosenthal, Scientific Director at The Jackson Laboratory

News Directory 3: Professor Rosenthal, thank you for joining us today. Can you tell us why traditional animal models, particularly inbred mice, have become inadequate for simulating complex human diseases?

Prof. Nadia Rosenthal: Thank you for having me. Traditionally, inbred mice have been the go-to models for preclinical testing due to their genetic uniformity, which simplifies the observation of disease phenotypes and drug responses. However, this approach has significant limitations. Many human diseases, particularly complex ones like diabetes and cancer, are influenced by a multitude of genetic factors that inbred mice simply don’t capture. This often leads to inconsistent and unreliable results, which is concerning when developing therapies intended for human use.

News Directory 3: Your team at The Jackson Laboratory is advocating for a new approach that involves genetically diverse mice. How does this differ from conventional methods?

Prof. Nadia Rosenthal: Our proposal focuses on introducing genetic diversity into mouse models. By using a range of genetically diverse mice combined with human and mouse cells, we can better replicate the complexity of human genetic variation and disease pathology. This approach helps to create a more realistic model that can produce findings more reflective of human responses, particularly in multifactorial diseases. The aim is to enhance our understanding of drug interactions and efficacy in a way that traditional models have struggled to achieve.

News Directory 3: This new strategy aligns with the FDA’s Modernization Act 2.0, which encourages alternatives to animal testing. Can you elaborate on how your research connects to this initiative?

Prof. Nadia Rosenthal: Absolutely. The FDA has recognized the need to phase out animal testing in preclinical screening, citing concerns about the effectiveness and relevance of existing animal models. Our work is in direct response to this directive. By leveraging genetically diverse mouse systems alongside innovative human cell assays and organoids, we can create more predictive and reliable models. This not only addresses ethical considerations surrounding animal testing but also enhances scientific rigor in drug development.

News Directory 3: Emerging alternatives such as cell-based assays and organoids are also gaining attention. How do these fit into your research methodology?

Prof. Nadia Rosenthal: We believe that a multidisciplinary approach is essential for the future of biomedical research. Cell-based assays and organoids allow us to model human diseases in vitro, and when used in conjunction with our genetically diverse mouse models, we can gain a more comprehensive view of disease mechanisms. Furthermore, integrating AI analytics with these models will help us sift through complexities more efficiently, providing insights that can guide therapeutic strategies.

News Directory 3: What do you hope the outcome of this research will be for the future of drug development?

Prof. Nadia Rosenthal: Our ultimate goal is to enhance the translational potential of preclinical studies. By utilizing a more sophisticated modeling system, we intend to reduce the attrition rate in drug development, which is currently unacceptably high. We hope that by providing more reliable data on drug efficacy and safety, we can expedite the process of bringing effective therapies to market, improving patient outcomes and reducing the time and resources spent on ineffective treatments.

News Directory 3: Thank you, Professor Rosenthal, for your insights into this critical area of research. It’s exciting to see how these emerging methods may change the landscape of drug discovery.

Prof. Nadia Rosenthal: Thank you for the opportunity to share our work. We are optimistic that these innovations will lead to significant advances in healthcare.

As advancements in biomedical research continue to evolve, the emphasis on ethical and effective alternative models could reshape the landscape of drug discovery and development, ensuring better outcomes for future therapies.

The introduction of genetic diversity in mouse models enhances their capability to reflect human disease complexities. While traditional inbred strains are limited in modeling diseases with multifactorial origins, genetically diverse (GeDi) mice offer a broader range of responses. These mice have improved assessments of human genetic variation and yield more clinically relevant insights into conditions like cardiovascular disease, diabetes, and infections.

Additionally, combining genetically diverse mouse models with human cell-based assays creates a more comprehensive testing framework. By analyzing human stem cell-derived systems alongside GeDi mice, researchers can identify genetic backgrounds that optimize study outcomes. This approach helps pinpoint new biomarkers and drug targets for various diseases.

Examples of insights gained from genetically diverse mouse models include studies on COVID-19. Research using GeDi mice showed a wide range of immune responses and outcomes that closely mimic the diverse reactions seen in human infections. This data underscores the importance of incorporating host genetics into understanding disease outcomes and therapeutic responses. Researchers continue to refine this method to better evaluate treatments for both acute and long COVID-19, paving the way for improved strategies in addressing future health crises.