Nonhuman Primate Models in Biomedical Research State of the Science and Future Needs (2023) / Chapter Skim
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4 The Landscape of New Approach Methodologies
4 The Landscape of New Approach Methodologies
Pages 113-146
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New approach methodologies have been used to answer diverse questions of biomedical relevance, and ongoing research efforts continue to explore their potential to • improve the translatability of nonclinical research by providing data that optimally reproduce the human condition; • extend current knowledge of human diseases and provide opportunities to gain additional insights, as well as identify knowledge gaps; • address shortages in the supply of NHPs by reducing the numbers required for bio medical research; and • replace the use of NHPs in biomedical research. In the context of this report, the term "new approach methodology" encompasses in vitro and in silico technologies and approaches that can be used to complement NHP studies or reduce reliance on NHPs in biomedical research (see Box 1-2 in Chapter 1)
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While there are examples discussed later in this chapter showing the potential for new approach methodologies to reduce reliance on NHPs, in vitro and in silico models are often used in ways that are complementary to NHP studies and that can help to answer different kinds of scientific questions, including those that cannot be answered using NHP models. It is important to note that scientists conducting research are always expected to seek out nonanimal or non-NHP methods wherever feasible, and to determine that research using NHPs is the most appropriate (or only)
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is key to successful adoption of a new approach methodology by scientists and organizations (Eckert et al., 2020; Marx et al., 2020; van der Zalm et al., 2022)
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. Benchmarking has several ben Towards qualification of the performance of a new approach methodology 1.
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NEW APPROACH METHODOLOGIES WITH THE POTENTIAL TO COMPLEMENT OR REDUCE RELIANCE ON NHP MODELS IN BIOMEDICAL RESEARCH This section describes new approach methodologies with the potential to complement or reduce reliance on NHP models in biomedical research. These examples are intended to be illustrative and do not represent a comprehensive cataloging of all possible new approach methodologies.
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human cell culture models with great potential to complement NHP research and, in some cases, reduce reliance on NHPs. In Vitro Immunoassays In vitro immunoassays that use cultured human cells, such as assays that predict the risk of cytokine release syndrome,2 provide a clear example of how in vitro models can address a question related to human safety (Finco et al., 2014)
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. Compared with 2D cell culture models, human organoids are in general more complex and, in many cases, more physiologically relevant because they preserve or reconstitute the cell-type diversity of the organs in vivo.
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The real power of MPS technology lies in the capacity of singular organ chips to reveal not only drug effects or biological response on primary human organs but also secondary effects stemming from organ–organ interactions. Therefore, multiorgan MPS are being designed to be as physiologically realistic as possible by connecting individual organ chips in a modular fashion (Ronaldson et al., 2022; Sung et al., 2019)
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Ultimately, the goal of multiorgan MPS efforts is not to build a perfect replicate of the human body but to provide a predictive model that is superior to animal models, including NHPs. Cultured Tissue Slice Models Cultured human tissue explants,4 such as precision-cut-tissue slices (PCTS)
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Examples Demonstrating Potential to Complement or Reduce Reliance on NHP Models This section provides examples of the application of 2D and 3D human cellular models in research areas in which NHPs are commonly used. These examples include research
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Note that these examples are intended to be illustrative and do not represent a comprehensive cataloging of ways in which these models have complemented NHP research or reduced reliance on NHPs. Note also that, while the examples focus primarily on human cell culture models, animal cell–based models have a role in informing the development of and building confidence in human cell–based MPS, as well as in assisting in the interpretation of existing animal model data and refining the use of future animal models (NASEM, 2021)
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, a finding that has been replicated in many animal models, including NHP models. Human brain organoids are also being applied to study human immunodeficiency virus (HIV)
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. Induced pluripotent stem cells (iPSCs)
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showed that a MPS could recapitulate antibodymediated lung toxicities observed in cynomolgus macaques, demonstrating the value of the model for evaluating translation of animal findings to human cellular models, and raising the potential for a reduction in reliance on NHP-based safety assessments. Other Applications of In Vitro Cell Culture Models As emphasized earlier in this chapter, the usefulness of new approach methodologies extends beyond opportunities to reduce reliance on NHPs; 2D and 3D cell culture models have many valuable applications, particularly when good animal models for human disease are lacking.
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. Advantages and Limitations of In Vitro Models Significant advances have been made in deriving and culturing human cells, tissues, and organs from stem cells to study basic biology and certain disease-related cellular pathologies.
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However, results from studies using in vitro models can inform improvements in the design of experiments using NHPs to reduce reliance on these animal models, such as with drug screening, as discussed earlier in this chapter. In Silico Models Over the years, researchers have attempted to use a wide array of quantitative and computational methods to model the properties of biological systems, including their response to perturbations, with greater or lesser degrees of success.
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The AI/ML models thus trained could be used to evaluate thousands of structurally defined compounds in order to identify candidates that might be more effective than existing compounds or might have fewer side effects. Yet while this methodology can speed drug development by guiding the search for new agents and help design and reduce reliance on NHP studies, it does not obviate the need for in vitro or in vivo testing.
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influence cellular or organismal phenotypes in the same way. Instead, the hope is that by incorporating higher-order associations among genes, RNAs, proteins, and metabolites, together with mechanistic models, AI/ML models can be developed to better predict human responses relative to those in animal models, thus helping to improve the translational relevance of data from NHP studies.
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. In NHP research, a fragmented knowledge landscape, lack of data harmonization, lack of data digitization and digitalization, and limited access to NHP and human data of sufficient quality and quantity can result in poor system training and overfitting, which in turn leads to poor-quality model performance.
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Finally, advancing the use of AI/ML models to complement and reduce reliance on NHP models will require a strong commitment to open science and data sharing -- including the sharing of training data sets, computational models, and software code. The value of any such AI/ML model will be strongly driven by the data used to train and validate it, while the community's confidence in the model's results will depend on the transparency and understanding of the model so it can be tested and validated (Haibe-Kains et al., 2020)
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Taken together with the efforts already implemented at the FDA, this new law encourages the application of new approach methodologies and documents policy efforts to facilitate their use as they are qualified and/or validated. New FDA guidance with direct relevance to the reliance on NHPs for conducting nonclinical toxicity assessments is included in Nonclinical Considerations for Mitigating Nonhuman Primate Supply Constraints Arising from the COVID-19 Pandemic (FDA, 2022c)
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Additionally, the inclusion of experts in new approach methodologies in the review process for NIH research proposals involving NHP models (including review of the consideration of alternatives in the vertebrate animals section of the proposal) could help identify opportunities for collaborative research that might complement the proposed NHP study or reduce the need for NHPs.
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CONCLUSIONS In its examination of new approach methodologies, the committee identified numerous ways in which in vitro and in silico models are being used to complement NHP research, but few concrete examples of a demonstrated role for those models in reducing reliance on NHPs. While references to replacement of NHPs are aspirational at this time, the committee envisions the potential for new approach methodologies to reduce reliance on NHPs in the future, especially as technology and science continue to advance, and as investments are made in the development of fit-for-purpose model systems and in their validation and qualification.
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Conclusion 4-5: Efforts to reduce reliance on nonhuman primates (NHPs) in bio medical research will require investment in opportunities to facilitate direct interac tion and collaborative research among investigators using NHP models and those developing in vitro and in silico approaches to expand the applicability of new approach methodologies to research questions for which NHPs are currently needed.
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2019. Human induced pluripotent stem cells: Clinical signifi cance and applications in neurologic diseases.
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2022c. Nonclinical considerations for mitigating nonhuman primate supply constraints arising from the CO VID-19 pandemic.
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2018. Disease modeling using 3D organoids derived from human induced pluripotent stem cells.
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2020. Genomic integrity of human induced pluripotent stem cells across nine studies in the NHLBI NextGen program.
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2018. Modeling cancer using patient-derived induced pluripotent stem cells to understand development of childhood malignancies.
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2019. Research and therapy with induced pluripotent stem cells (iPSCs)
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2017. Nonhuman primate models of Zika virus infection, immunity, and therapeutic development.
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2017. Biomarker discovery by modeling Behçet's disease with patient-specific human induced pluripotent stem cells.
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2020. In vitro models of neuromuscular junctions and their potential for novel drug discovery and development.
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2012. Induced pluripotent stem cells: Past, present, and future.
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