NHP Models vs. Murine Models

December 15, 2023 /

In pharmacological investigation, model selection serves as a critical determinant, which can steer the course of scientific inquiry. This blog post serves as a comparative examination between Non-Human Primate (NHP) and Murine models.

 

Table of Contents

  1. Non-Human Primate Models
  2. Murine Models
  3. Comparative Analysis
  4. Considerations for Model Selection
  5. Recent Advancements and Alternatives
  6. Future Prospects
  7. Conclusion
  8. Additional Resources

 

I. Non-Human Primate Models

Genetic and Physiological Proximity

NHP models, such as rhesus macaques and cynomolgus monkeys, share approximately 95-98% of their genetic makeup with humans[1]. This genetic similarity is particularly advantageous in pharmacological research because NHPs metabolize drugs similarly to humans. Additionally, their organ systems, including the cardiovascular, immune, and central nervous systems, closely resemble those of humans. This physiological resemblance allows for a more accurate prediction of drug responses, safety, and potential side effects.

Use of NHPs in Gene Therapies and RNA Therapies

Thanks to the shared genetics that NHPs have with humans, NHPs are essential model systems for testing novel gene editing technologies such as AAVs and CRISPR[2][8]. While surrogate drugs designed for murine models can sometimes provide insights into basic biology, nothing compares to testing the drug modality that will be used with human patients in NHP models. Bio-distribution, gene editing efficiency, and durability of response are all better measured in NHPs[5]. Additionally, the formation of anti-drug antibodies and other immune responses may more closely resemble the clinical image when NHPs are utilized.

Applications in Pharmacology

For decades, NHP models have significantly contributed to pharmacological research, and cannot be easily replaced. As new drug modalities for cell therapies, CRISPR, monoclonal antibodies, and more are being developed, greater human homology is increasingly crucial[3]. Revolutionary anti-inflammatory and autoimmune[6] treatments such as infliximab, adalimumab and ustekinumab all in part relied on NHP research. NHP models of rheumatoid arthritis, psoriasis, inflammatory bowel disease, asthma, multiple sclerosis, and atopic dermatitis have all been developed and validated. Moreover, NHP models are essential in neuropharmacology, particularly when studying neurodegenerative diseases like Alzheimer’s and Parkinson’s, mainly thanks to the high level of homology exhibited by NHPs. 

Translation to Human Health

The translational relevance of NHP models is a standout feature[9].Their use in safety and efficacy testing minimizes the risks of unforeseen adverse effects when drugs advance to human testing, thereby accelerating the drug development process.

Cost and Resource Intensiveness

While NHP models offer invaluable insights, they come with higher costs and resource demands[6]. Maintaining and conducting research with NHPs can be significantly more expensive compared to murine models, partly due to their longer lifespans and more intricate care requirements. Researchers must carefully consider budget constraints and resource availability when opting for NHP studies[4]. On top of cost and resource intensiveness, it is worth noting that the availability of NHPs can also present itself as a hurdle to scientists, as was the case in the past few years[10] (PharmaLegacy was and still is  able to maintain a constant supply of NHPs, readily available for your studies).

 

II. Murine Models

Genetic Manipulability: Murine models, particularly mice, are renowned for their genetic tractability. The development of transgenic and knockout mice allows researchers to create customized models with specific genes modified to study the effects of genetic variations on drug responses. This genetic versatility is vital for investigating the hereditary aspects of drug metabolism, making murine models instrumental in understanding the genetic underpinnings of various diseases and drug responses.

Drug Screening and Toxicity Testing: Murine models excel in large-scale drug screening and toxicity testing. Their cost-effectiveness, short generation times, and abundant offsprings make them ideal for conducting high-throughput experiments. For instance, murine models are widely used to test the safety and efficacy of cancer drugs before they progress to human trials. This extensive preclinical testing in murine models helps filter out potentially harmful or ineffective drugs.

Invaluable in Basic Research: Murine models have been instrumental in advancing fundamental pharmacological knowledge. They are often used in basic research to elucidate the mechanisms of drug actions, receptor pathways, and physiological responses. The genetic manipulation of mice allows researchers to create models that mimic specific human diseases, providing invaluable insights into disease progression and potential drug targets.

Limitations in Translational Relevance: Despite their utility, murine models have limitations in predicting human responses to drugs due to genetic and physiological differences. Substantial genetic disparities exist between mice and humans, impacting the applicability of findings to clinical settings[7]. This limitation underscores the need for combining data from murine models with data from more translationally relevant models, such as NHPs, to enhance predictive accuracy.

III. Comparative Analysis

  • Genetic and Physiological Proximity:
    • NHP Models: NHPs, such as rhesus macaques, share striking genetic and physiological similarities with humans, particularly in terms of drug metabolism. Their organ systems, immune responses, and central nervous systems closely resemble those of humans. These similarities make NHPs excellent models for studying drug responses, safety, and potential side effects in a manner closely reflective of human physiology.
    • Murine Models: In contrast, murine models exhibit genetic and physiological differences from humans, primarily due to evolutionary divergence. While they have provided invaluable insights into various aspects of pharmacology, the genetic differences often limit the translational relevance of findings from murine studies to humans.
  • Cost-Effectiveness and Scalability:
    • NHP Models: The use of NHP models can be considerably more expensive and resource-intensive. These models require more extensive care, larger facilities, and have longer lifespans. Consequently, the cost associated with NHP studies can be a limiting factor for researchers, especially those with budget constraints.
    • Murine Models: Murine models, particularly mice, are known for their cost-effectiveness and scalability. Their short generation times, high reproductive rates, and relatively simple care requirements make them suitable for conducting large-scale experiments, making murine models the preferred choice for high-throughput drug screening and genetic studies.
  • Limitations and Advantages:
    • NHP Models: NHP models offer a closer approximation of human responses, making them ideal for studies requiring a high degree of translational relevance. However, their use is often constrained by higher costs and limited availability. These limitations necessitate a careful consideration of the research goals and available resources.
    • Murine Models: Murine models are more readily available, cost-effective, and adaptable for a wide range of pharmacological experiments. While they might not perfectly mimic human responses, their genetic tractability and versatility in genetic manipulation make them invaluable for understanding basic pharmacological mechanisms and conducting large-scale drug screening.

IV. Considerations for Model Selection

In the process of selecting appropriate animal models for research, scientists must carefully align their choices with specific research objectives. NHP models prove invaluable for studies that closely mirror human responses, providing a high degree of translational relevance. On the other hand, murine models excel in areas requiring genetic manipulation. While defining research goals, the consideration of budget and available resources becomes pivotal. NHP research, due to its resource-intensive nature, requires careful financial planning, whereas murine models often offer a more budget-friendly alternative.

 

V. Recent Advancements and Alternatives

Emerging technologies such as in vitro models, organoids, and computational simulations have gained prominence as alternatives. These innovative approaches offer cost-effective and scalable methods to study drug responses, providing valuable insights into various aspects of pharmacology. Simultaneously, researchers are recognizing the potential benefits of a hybrid approach by combining multiple models. Specifically, there is a growing trend in exploring the synergies between non-human primate (NHP) and murine models. This combination allows researchers to harness the strengths of each model while mitigating their individual limitations, thereby contributing to a more comprehensive understanding of pharmacological responses. This dual strategy represents a forward-looking approach that leverages both cutting-edge technologies and the complementary aspects of different animal models to advance pharmacological research.

VI. Future Prospects  

The predictive power of NHP models in areas demanding a high degree of translational relevance – such as neurodegenerative diseases and personalized medicine – underscores their continued significance in advancing our understanding of human health. Concurrently, advances in murine models, propelled by technological developments such as genetically modified mice, enhance their utility in targeted pharmacological research. These innovations empower researchers to create customized models, facilitating the investigation of specific genetic variations and their implications for drug responses. Looking ahead, the trajectory of pharmacological research suggests a shift towards combined approaches. The future likely involves a hybrid strategy, with researchers seamlessly integrating insights from diverse models—both NHP and murine. This synergistic approach aims to achieve a more comprehensive understanding of pharmacological responses, maximizing the strengths of individual models and ultimately contributing to the advancement of drug development and personalized medicine.

 

VII. Conclusion

The genetic and physiological proximity of NHP models to humans, especially in drug metabolism and organ systems, enhances their translational relevance, making them invaluable for studies demanding a high degree of similarity to human responses. On the other hand, the genetic manipulability and cost-effectiveness of Murine models, particularly in drug screening and genetic studies, showcase their versatility and efficiency in certain research contexts. However, a nuanced approach to model selection emerges as a recurring theme. Researchers must align their choices with specific research objectives, weigh the available resources, and consider regulatory constraints. This nuanced approach acknowledges that there is no one-size-fits-all solution and encourages a tailored strategy based on the unique goals of each study.

 

VIII. Additional Resources

  1. Blekhman R, Perry GH, Shahbaz S, et al. (2010) Natural selection on genes that underlie human disease susceptibility. Current Biology, 20(10), 883-889.
  2. Chan AW, Chong KY, Martinovich C, et al. (2015) Transgenic monkeys produced by retroviral gene transfer into mature oocytes. Science, 345(6195), 1255-1258.
  3. Cook D, Brown D, Alexander R, et al. (2014) Lessons learned from the fate of AstraZeneca’s drug pipeline: a five-dimensional framework. Nature Reviews Drug Discovery, 13(6), 419-431.
  4. Festing MF, Altman DG. (2002) Guidelines for the design and statistical analysis of experiments using laboratory animals. ILAR Journal, 43(4), 244-258.
  5. Liu F, Song Y, Liu D. (2014) Hydrodynamics-based transfection in animals by systemic administration of plasmid DNA. Gene Therapy, 22(1), 3-12.
  6. McCook A. (2017) What makes animal models in sepsis so difficult? Lancet Respiratory Medicine, 5(3), 170-172.
  7. Mestas J, Hughes CC. (2004) Of mice and not men: differences between mouse and human immunology. The Journal of Immunology, 172(5), 2731-2738.
  8. Niu Y, Shen B, Cui Y, et al. (2014) Generation of gene-modified cynomolgus monkey via Cas9/RNA-mediated gene targeting in one-cell embryos. Cell, 156(4), 836-843.
  9. Seok J, Warren HS, Cuenca AG, et al. (2013) Genomic responses in mouse models poorly mimic human inflammatory diseases. Proceedings of the National Academy of Sciences, 110(9), 3507-3512.
  10. National Academies of Sciences, Engineering, and Medicine; Division on Earth and Life Studies; Health and Medicine Division; Institute for Laboratory Animal Research; Board on Health Sciences Policy; Committee on the State of the Science and Future Needs for Nonhuman Primate Model Systems; Yost OC, Downey A, Ramos KS, editors. Nonhuman Primate Models in Biomedical Research: State of the Science and Future Needs. Washington (DC): National Academies Press (US); 2023 May 4. Summary. Available from: https://www.ncbi.nlm.nih.gov/books/NBK592991/