Nonhuman Primate Models in Biomedical Research State of the Science and Future Needs (2023) / Chapter Skim
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5 Future Needs and Opportunities for Nonhuman Primate Models in Biomedical Research
5 Future Needs and Opportunities for Nonhuman Primate Models in Biomedical Research
Pages 147-184
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From page 147... ...
For now, however, given the need for continued use of NHPs in NIH-supported biomedical research, it is critical to ensure that these animal models are used as effectively as possible, particularly given the ongoing shortage of NHPs available for research, as highlighted in Chapter 3. Research should be conducted humanely with respect to the well-being of the animals under study and at the highest level of scientific integrity and rigor.
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From page 148... ...
However, treatments shown to clear plaques in mouse models failed to benefit human patients in clinical trials, indicating that these animal models were not fully recapitulating the human condition. Therefore, NHP models in which Alzheimer's disease phenotypes are induced and three-dimensional human brain organoids are being pursued as complementary models for nonclinical drug testing (Arnsten et al., 2019; Beckman et al., 2019, 2021; King, 2018)
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From page 149... ...
. In the context of the unanticipated need for NHP models for COVID-19 research, NHP resources were conserved for COVID-19 research at a cost to progress in other important research domains (NIH, 2022d)
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Given that NHPs are likely to remain a limited and high-cost resource -- even with further investments in domestic breeding to address current shortages -- advances in new approach methodologies offer the potential benefit of helping to reduce costs and mitigate future NHP shortages. In anticipation of this, attention is needed to the development of a strategy for the advancement of new approach methodologies that can be used in conjunction with NHP models to optimize the application of NHP research and to answer pressing biomedical research questions in the future.
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The committee understands the continued emphasis of policy makers on the development and implementation of new approach methodologies with the potential to reduce reliance on NHPs and other animal models. Critically, however, policy needs to be informed by the state of the science.
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From page 152... ...
Policy actions may also catalyze the continued development of new approach methodologies with the potential to reduce reliance on NHPs. In response to a congressional directive to accelerate efforts to identify and implement nonanimal alternatives for biomedical research,3 NIH launched a new working group on Novel Alternative Methods under the auspices of the NIH Advisory Committee to the Director (ACD)
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From page 153... ...
. Certain infectious diseases have a pathogenic mechanism seen only in primate species, and the COVID-19, Zika, Ebola, and other recent epidemics demonstrate the importance of NHP models to understanding novel diseases and testing the safety and efficacy of vaccines and therapeutics.
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From page 154... ...
Examples include requiring protease-activated receptors that mediate platelet activation and monoclonal antibodies. As a a primate- result of their specificity, therapeutics developed using mice or other nonprimate models may specific miss their intended target in humans, necessitating studies in NHPs.
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From page 155... ...
• Brain injury and new methods for promoting recovery of function following stroke and spinal cord injury • Addiction and substance abuse • Social/behavioral effects on health • New approaches to preventing and treating neurodevelopmental disorders • New methods for preventing blindness and restoring vision • Human immunodeficiency virus • Coronaviruses • Viruses targeted for eradication, such as measles and polio viruses • Filoviruses, such as Ebola • Tuberculosis • Malaria • The next novel pandemic virus • G enetic disorders with a high level of sequence identity or homology between NHPs and humans (e.g., colorectal cancer, retinitis pigmentosa, epidermolysis bullosa) • Gene therapy • Gene editing • Monogenic and polygenic diseases • Genetic modification of NHPs to model diseases caused by specific gene polymorphisms • Immunotherapies • Gene therapies • Cellular therapies • Medical countermeasures against radiation, chemical, or biological hazards • Fertility • Endometriosis • Polycystic ovarian syndrome • Cardiovascular disease • Type 2 diabetes • Kidney disease • Depression • Dementia • Osteoporosis • Anemia • Osteoarthritis • Sarcopenia • Multimorbidity patterns of aging • Determinants of frailty and resilience • Naturally occurring cancers, such as breast, colon, cervical, and lymphoma cancers
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From page 156... ...
FUTURE NEEDS FOR SPECIFIC NHP SPECIES While multiple macaque species continue to be used in and contribute knowledge to different domains of biomedical research (e.g., neuroscience, infectious disease) , rhesus macaques (Macaca mulatta)
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From page 157... ...
; expansion of this service and designation of NIH staff to support that effort would improve transparency regarding the availability of scarce NHP resources and allow their more efficient utilization. Increasing Use of Data-Driven Noninvasive or Minimally Invasive Technologies This section describes noninvasive or minimally invasive technologies with the potential to enhance biomedical research conducted using NHP models.
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From page 158... ...
. Use of digital biomarkers enables the collection of objective, quantifiable, and clinically relevant measures of physiological and behavioral response to disease progression or therapeutic intervention (Motahari-Nezhad et al., 2021; Traverso et al., 2015)
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From page 159... ...
Digital biomarker technologies have the potential to provide a more holistic assessment and view of NHPs because they offer continuous monitoring instead of the snapshot derived from traditional assessments. Continuous collection of digital biomarkers has the potential to enhance current NHP approaches by providing unbiased longitudinal monitoring of behavioral and physiological function for various research domains, from aging to neurological diseases to safety testing.
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From page 160... ...
Computational Methods, Including AI/ML and Computer Vision AI/ML methods and applications are described in Chapter 4 in the context of approaches for complementing or reducing reliance on NHP models. AI/ML can also assist with the analysis of NHP experimental data to obtain information on and insight into the systems being studied.
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From page 161... ...
. For example, combining digital biomarker data collected continuously from freely moving animals in their home environment with AI/ML extraction (such as computer vision)
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From page 162... ...
Nonetheless, these findings suggest that the best NHP models for studying human health are NHPs living in social contexts -- and preferably specific types of social contexts that include full access to partners in stable relationships. Similarly, research has shown that providing NHPs with control over their environment by training them to participate actively in research studies, such that they are cooperative during drug administration or blood sampling reduces stress, decreases the variability of research data, and more accurately models diabetes in a macaque model (Graham et al., 2012)
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From page 163... ...
Collaborative approaches could provide an opportunity for, and reduce barriers to, incorporating novel technologies, including new approach methodologies, into research using NHPs. Regardless of whether collaborations would be established within a single research institution or across multiple facilities where NHPs are being used, plans for each upcoming NHP study would be shared among participating researchers so additional samples could be taken or data collected from the same NHP cohort for use by multiple research groups.
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From page 164... ...
has supported collaboration in nonhuman primate (NHP) research through the multicenter Nonhuman Primate Transplantation Tolerance Cooperative Study Group program.
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From page 165... ...
. For these reasons, it is important to promote data sharing opportunities by developing and maintaining a robust infrastructure that can accommodate the large quantities and types of data generated within the diverse NHP research ecosystem, including all relevant metadata (e.g., genetic characteristics and origins of the animals, clinical data, how the animals were housed and handled [Pomerantz et al., 2022]
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From page 166... ...
. These data are made available via the California NPRC colony records, allowing researchers to select animals based on early temperament and physiology, and also serving as a valuable resource for the identification and characterization of naturally occurring animal models, most recently yielding a naturally occurring macaque model for the study of autism (Myers et al., 2021)
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From page 167... ...
Development of Genetic and Genotype–Phenotype Resources Progress has been made in the genomic sequencing of select NHP species commonly used in research, including rhesus macaques (Gibbs et al., 2007) , vervets (Warren et al., 2015)
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From page 168... ...
Much work remains, however, before the characterization of NHP models is as extensive as that of murine models, which benefit from an International Mouse Phenotyping Consortium (IMPC) .11 The IMPC is focused on systematically characterizing mouse strains and models using a standardized battery of methods aimed at revealing disease manifestations across multiple body systems (Muñoz-Fuentes et al., 2018)
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. NIA's Nonhuman Primate Tissue Bank serves as a repository of tissue for researchers conducting aging studies funded by NIH or other government institutions at no cost to the researchers (NIA, 2022)
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From page 170... ...
Systems for tracking animal use for scientific purposes in the European Union, such as the ALURES Statistical EU Database,14,15 provide useful models for investment in data infrastructure and support openness in animal research. Importantly, such investments will also be integral to future efforts to reduce reliance on NHPs by enabling accurate measurement of the impact of such measures as changes in policy and implementation of nonanimal models.
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From page 171... ...
Conclusion 5-3: Addressing the challenges posed for the national research infrastruc ture by a persistent lack of nonhuman primates (NHPs) will require a commitment and comprehensive national effort focused on expanding domestic NHP resources.
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From page 172... ...
Examples of successful cooperative efforts from the community of NIH-funded NHP researchers -- including collabora tive working groups; data-sharing resources for clinical and clinical pathology data, gene expression profiling, and genotype data; and biospecimen repositories -- can serve as models for broader adoption. Conclusion 5-7: A system for consistent reporting is needed to adequately capture the life, scientific, and medical history, including experimental treatments and pro cedures, of individual nonhuman primates (NHPs)
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2019. Association of primate veterinarians' guidelines for laparoscopic repro ductive manipulation of female nonhuman primates in biomedical research.
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2021a. Improving rigor and reproducibility in nonhuman primate research.
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2015. Endoscopy and endosurgery in nonhuman primates.
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2020. Opportunities and limitations of genetically modified nonhuman primate models for neuroscience research.
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2021. Nonhuman primate models of Zika virus infection and disease during pregnancy.
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2021. Nonhuman primate models for SARS-CoV-2 research: Infrastructure needs for pandemic preparedness.
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2017. An overview of nonhuman primates in aging research.
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2020. Validation of animal models and tools for biomedical research: Session VI -- Validation of nonhuman primate models for preclinical research.
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2022. Improving transparency -- A call to include social housing information in biomedical research articles involving nonhuman primates.
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2021. Nonhuman primates at the intersection of aging biology, chronic disease, and health: An introduction to the American Journal of Primatology special issue on aging, cognitive decline, and neuropathology in nonhuman primates.
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2022. Nonhuman primates' tissue banks: Resources for all model organism research.
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2022. Multi-site proficiency testing for validation and standardization of assays to detect specific pathogen-free viruses, coro naviruses, and other agents in nonhuman primates.
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