By Kiave Yune Ho Wang Yin, PhD

Infectious diseases such as human immunodeficiency virus (HIV) and hepatitis B (HBV) can have severe implications for liver health, and in the worst cases, cause death. While symptoms vary from condition to condition, infectious diseases have one thing in common—their transmissibility. Such conditions are therefore able to affect millions of lives across the globe. HIV alone was responsible for an estimated 650,000 deaths in 2021, for example, while HBV affects approximately 296 million people and contributes to around 820,000 deaths per year.

Developing new drugs to combat these infectious diseases is crucial, but the process is fraught with challenges. One major obstacle is the selection of an appropriate mouse model that facilitates the translation of preclinical study findings into successful clinical trials. In particular, existing models struggle to determine efficacy, drug toxicity, and drug-drug interactions, all of which are crucial to develop safe and efficacious drugs. Furthermore, having the right facilities to run compliant studies on infectious diseases is essential—something which many organizations do not have.

Humanized in vivo mouse models, with either humanized immune systems or humanized livers, offer the potential for more human-relevant preclinical findings. In this article, we delve into the different types of models available, their role in developing more efficacious treatments, and the benefits of partnering with a company that can provide the necessary facilities and services to streamline the drug development process.

Why use humanized mouse models for infectious diseases?

When developing treatments for infectious diseases, it is crucial to consider the roles of the liver and immune system, as they significantly influence the pathophysiology of infectious diseases. For example, HIV targets human CD4⁺ circulating lymphocytes, which can directly impact liver health. Secondly, the liver influences drug activity by either metabolizing prodrugs into active metabolites or deactivating active drugs.

Failing to account for liver interactions during drug development can lead to missed key parameters that affect treatment efficacy, such as dosage, treatment, pharmacokinetic (PK), and pharmacodynamic (PD) data. Not having this data to factor into your analysis makes it challenging to choose the best preclinical candidate for progression, as the full picture of its safety and efficacy is unavailable. Subsequently, it squanders valuable time, money, and resources.

Further complicating preclinical animal studies, toxicity may be incorrectly detected if a less human-relevant model is used. Drugs might trigger highly dangerous side effects in human studies, for example, or they may cause a misleading reaction in mice, leading to the dismissal of a drug that would actually be safe for human use.

Humanized mouse models can bridge this gap by providing more relevant results. As the mice recapitulate human organs and the immune system, better insights into drug efficacy, safety, and interactions with human biology are unlocked.

Consider the liver for more relevant results

The humanized liver mouse model is a powerful tool in drug development for infectious diseases. To create the model, human liver cells are transplanted into mice that lack a functional liver or have liver damage. Subsequently, the mice gain a fully functional human liver, thereby offering a highly predictive model that is ideal for studying HBV.

Humanized liver mouse models allow researchers to study the complete life cycle of HBV and the effects of antiviral therapies on infected liver cells. Data generated using these models is therefore more human-relevant, allowing researchers to better predict clinical outcomes.

Humanized liver mouse models have many applications, including:

• Preclinical toxicity testing
• Drug metabolism analysis to identify all human-generated drug candidate metabolites
• Drug-drug interaction studies
• Metabolic research

The immune system plays a crucial role

As well as the liver, the immune system is also highly important in many infectious diseases such as HIV and HBV. Since many drug candidates target the immune system, preclinical models must therefore account for the interactions between the immune system, the disease, and potential treatments for maximum relevancy.

The humanized immune system mouse model is an invaluable tool in this regard. In this model, the mice are engrafted with CD34+ cells (undifferentiated cells) derived from cord blood to generate a fully functional human immune system. What’s more, the mice can undergo hydrodynamic gene delivery (or boosting) to enable customized human immune systems with enhanced differentiation of cells.

Compared to traditional preclinical models, humanized mice offer several benefits:

• The absence of graft versus host disease (GvHD) reactions
• Stable humanization for the animal’s lifetime
• Presence of all immune cell types—myeloid cells, T cells, B cells, and NK cells

Owing to the advantages of humanized mouse models, they can enhance multiple study areas. For example, immune-targeted studies, drug efficacy evaluations, and drug safety assessments can all be investigated using humanized mice.

It takes a village: How a partner can support your studies

Studying infectious diseases involves adhering to stringent safety regulations to eliminate contamination risks, protect personnel involved in running experiments, and prevent transmission—all while maintaining biocontainment and security. Biosafety levels (BSL) play a vital part in ensuring compliance, with BSL-2 and BSL-3 being particularly relevant for infectious disease research.

BSL-2 labs are designed for handling bacteria, viruses, and organisms associated with human diseases. These labs require biological safety cabinets and autoclaves as barriers. BSL-3 labs, on the other hand, are intended for handling indigenous or exotic agents that can cause potentially lethal diseases, such as HIV or HBV. Access to BSL-3 labs is limited, and personnel require medical surveillance for their safety.

Implementing BSL-compliant labs, however, can be notoriously challenging. Notably, labs take up valuable building space. But to be certified, they must be situated in specific areas of the building, which can be expensive and time-consuming to achieve. Additionally, maintaining BSL compliance entails a high burden, including staff training, extensive administration, liability risks, and high operational costs.

Working with a partner, rather than just a mouse model supplier, can alleviate these challenges and allow labs to confidently investigate treatments in humanized mouse models. It’s important to seek a partner that offers both BSL-2 and BSL-3 facilities, as they can run the experiments on your behalf—thereby eliminating the need for your own in-house facilities.

Partnering with a company experienced in handling infectious disease research using humanized mouse models offers numerous advantages, including:

• Reduced personnel burden (with no training or liability)
• Increased confidence in the safety of experiments
• Potential cost savings compared to investing in your own BSL-2/3 spaces and getting certification

Deeper insights for better treatments

New treatments are urgently needed to reduce the number of deaths worldwide caused by infectious diseases such as HIV and HBV. More relevant preclinical models are essential for developing efficacious treatments, as they enable better translation of results into clinical studies.

The humanized liver mouse model improves and enables studies for toxicity, drug metabolism, and drug-drug interactions. Meanwhile, the humanized immune system mouse model provides deeper insights into disease mechanisms and immune interactions.

For labs lacking the necessary BSL-2 or BSL-3 facilities, working with a partner can remove barriers to successfully running preclinical studies. By leveraging the insights gained from humanized mouse models, researchers can be more confident in their results and advance the most promising treatments into clinical studies—ultimately helping to get effective treatments to patients more rapidly.

Kiave Yune Ho Wang Yin, PhD, is chief business officer at TransCure bioServices.

The post Overcoming the Challenges of Infectious Disease Studies: The Use of Advanced Animal Models in Studying HIV and HBV appeared first on GEN - Genetic Engineering and Biotechnology News.

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