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The importance of the cynomolgus macaque’s origin in drug safety assessment

17 September 2024

Cynomolgus macaques are the most commonly used non-human primate species for drug safety assessment. However, recent supply shortages  have brought increased attention to the genetic differences between cynomolgus macaques of varying geographic origins. It is important to examine the relevance of geographic origin for cynomolgus macaques used in regulatory toxicology studies.

Geographic origins and genetic differences

Cynomolgus macaques have a natural habitat spanning Southeast Asia and were introduced to the island of Mauritius 400 years ago. Today, animals for research originate from various facilities across Southeast Asia, China and Mauritius. Studies have identified four distinct subpopulations based on genetic analysis: Asia mainland, Asia island, Philippine and Mauritius.

The Asia mainland subpopulation, from Indochina, has high genetic diversity due to introgression with rhesus macaques. The Asia island subpopulation, including Indonesia and Malaysia, likely represents the origin of the species, whereas the Philippine subpopulation has been isolated for around 1 million years. Lastly, The Mauritius subpopulation has limited genetic diversity due to a strong founder effect from the small, introduced population.

Additional genetic analysis has revealed differences in allelic diversity, expected and observed heterozygosity, and inbreeding coefficients among subpopulations. For example, the Mauritius subpopulation exhibited the lowest allelic diversity and highest inbreeding coefficient in one study, while the Asia mainland subpopulation showed the highest diversity. Studies of major histocompatibility complex , or MHC, genes also found more restricted polymorphism in Philippine and Mauritius subpopulations compared to Asia mainland.

Relevance for drug safety assessment

While biological differences between among subpopulations have been reported, few studies have systematically examined the impact on regulatory toxicology. Recent publications conclude that cynomolgus macaques from all origins are suitable but emphasize the importance of maintaining consistency in geographic origin within a study.

Differences have been noted in immune response, background pathology findings, and incidence of adverse effects. For example, one study found a higher incidence of mononuclear infiltrates in the kidney, liver, and brain of Mauritius-origin animals compared to Asian origin. However, Asian-origin animals showed a higher incidence in the GI tract. Another study reported developmental and degenerative findings were more common in Mauritius animals.

Although differences exist, the overall conclusion is that robust pre-study screening and use of concomitant controls enables the use of any subpopulation. Data from the four subpopulations should be analyzed separately. Combining data could mask important differences linked to geographic origin.

Best practices for study design

When designing toxicology studies using cynomolgus macaques, researchers should take care to document the geographic origin of all animals. Animals in both control and treatment groups should originate from the same subpopulation. While mixing origins within a subpopulation is acceptable, different subpopulations should not be mixed in the same study arms.

Researchers should also be aware that animals from the Mauritius subpopulation may show more uniform responses due to genetic homogeneity. Asian-origin animals have greater diversity and may show a wider range of responses. Study design, group sizes, and statistical power should account for this.

For ongoing analysis of biological and toxicological differences, a global database separating data by origin would be invaluable. Data from new studies should be contributed following publication to enable continuous re-evaluation of geographic origin as a variable.

In summary, geographic origin must be considered when designing studies with cynomolgus macaques. While animals from any origin can be utilized, consistency in origin within a study is critical. Ongoing analysis of genetic and biological differences will further inform best practices for optimizing the use of this valuable research model.

Explore our insights on maintaining data integrity and optimizing this key preclinical model in this recording of our JSOT 2024 presentation on cynomolgus macaques.