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Issued by

National Institute of Mental Health (NIMH)

Purpose

NIMH is issuing this Notice to alert the research community to the current NIMH priorities for the use of genetically modified non-human primates (NHP) in research relevant to higher order brain function and/or mental illness.

Unique Opportunities Afforded by NHP Genetic Models

The application of genetic engineering technologies has contributed significantly to advances in molecular, cellular and integrative neuroscience. Despite this progress, understanding of higher order brain function and complex behaviors such as cognition, social processing, emotion regulation, as well as pathological mechanisms of mental illnesses, has been lagging. This is partly due to functional and structural differences between human brains and those of the most commonly studied model organisms, such as rodents. Compared to rodents, non-human primates (NHP) are physiologically and phylogenetically closer to humans. For example, social interactions significantly modulate NHP cognitive functions, particularly in the contexts of observational learning and social facilitation, whereby the presence of a conspecific can influence the behavioral actions of another. These types of similarities with humans make NHP more suitable experimental systems to probe the behavioral output of cortical and subcortical networks in these complex cognitive functions. Additionally, NHP studies provide an important avenue for testing mechanistic hypotheses derived from the non-human primate literature to determine their relevance to findings from human studies and for pre-clinical testing of novel therapeutic strategies, including those for mental illnesses.

Mechanistic studies of NHP have become more attainable with rapid advances in tool development for specific targeting of genes, cells, and circuits, allowing greater precision in exploring mechanisms of cognitive, social, and emotional behavior across species. These methods have also been applied in NHP to study individual genes that have been associated with disease risk. Furthermore, these approaches offer potential to advance genetically based therapies. NIMH provides this Notice to outline priorities for applicants considering the development or use of genetically modified NHP in research relevant to mental illnesses.

Responsible Use of NHPs

Although genetically modified NHPs hold the promising potential for use in translational neuroscience, the specific rationale for their use must be sufficiently justified and the welfare of the NHP subjects must be a priority. Compliance with the Public Health Service (PHS) Policy on Humane Care and Use of Laboratory Animals (Policy) is an absolute requirement. All institutions are required to comply, as applicable, with the Animal Welfare Act, and other Federal statutes and regulations relating to animals. NIMH advises investigators to carefully consider the ethical and efficient use of NHP resources following these principles:

• Clear scientific justification as to when and why a NHP model is necessary and the best choice of species to address the scientific question with respect to neurobiological system specialization.
• Evidence that previously used model systems have not been successful in addressing the question of interest.
• Rationale as to how the NHP experimental system is expected to address the question of interest more effectively.
• Minimizing the number of animals to obtain valid results used in a study through data sharing efforts, collaborations and multi-disciplinary approaches.
• Obtaining data through multiple levels of analysis from the same cohort of animals.
• Applying rigorous and reproducible designs, controls, and statistical power for realistic and meaningful effect sizes to maximize confidence in experimental outcomes.
• Consideration of development or use of automated systems for tracking and analyzing behavior to assess normal variations in species-specific behavior.
• Assuring appropriate scientific and veterinary expertise to address health and welfare concerns induced by the mutation(s) and maintain a dialog with relevant stakeholders regarding ethical considerations for NHP research.
• Minimizing discomfort, distress, and pain when consistent with sound scientific practices.
• Ensuring proposed research is not unnecessarily duplicative.

Genetic Modification Approaches in Basic and Translationally Relevant Research

As basic science studies remain an important component of the NIMH Strategic Plan, NIMH aims to support the use of genomic engineering in NHP to elucidate fundamental principles of higher order brain function and behavior, provided that investigators adhere to the expectations for responsible use of NHPs as described above. This can include basic studies of evolutionary specializations purported to be unique to and shared between humans and NHPs.

Distinct from this are studies aiming to leverage the increasing wealth of information pertaining to genetic loci associated with risk for mental illness by characterizing the involvement of disease-associated genes or effects of gene variants in NHP brain function and behavior. However, the shared genetic complexity of mental illnesses where many genes increase risk for the same disorder and the same gene may increase risk for many disorders creates fundamental challenges in inferring pathophysiological mechanisms for diagnostic categories. As detailed in NOT-MH-19-053, this is incommensurable with the creation of “models of disease.” This is also true for highly penetrant single gene and structural genetic mutations in rare neurodevelopmental disorders where genetic background influences the type and severity of disease.

NIMH prioritizes NHP studies predicated on the rigorous standards of gene discovery described in the NAMHC Genomics Workgroup Report, along with NIMH guidance on follow-up experimentation. While an increasing number of loss-of-function variants implicate dosage sensitivity for an increasing number of genes, scientific considerations dictate that substantial prior evidence be in place before introducing such variants into NHP. This evidence can include functional data in other model organisms or cell-based assays, reference data addressing the conservation of gene expression and cell-type involvement between NHP and humans, and penetrance of the variant in the general population. Such evidence is expected to serve as the foundation for specific hypotheses that necessitate testing in NHP.

Genetically engineered NHPs may be particularly useful in providing a bridge to test the translational relevance of hypotheses generated in other experimental systems, including rodent and human cellular models. In considering the utility and significance of such approaches, consideration should be given to the strength of available evidence and the importance of the added information regarding translatability that might be gained from any proposed NHP experiments.

Finally, the use of NHPs for pre-clinical testing of small molecules, biologics, or devices as part of therapeutics development should be predicated on a substantial proof-of-concept in other paradigms. NHP studies should also be sufficiently justified as required prior to clinical trials to address issues associated with delivery and distribution of candidate therapeutics in the larger NHP brain, as well as targeting issues, potential adverse effects, and other impacts on brain function. Information on current NIMH priorities may be found on NIMH Strategic Plan website that is updated annually and research topic of low priority can be found in DNBBS branch and program pages. The following are examples of studies encouraged by NIMH.

• Development and application of new genetic modification techniques in NHP experimental systems to advance understanding of neural bases of cognitive, social, arousal, positive and negative valence systems, and their development and interaction across the lifespan.
• Collaborative, interdisciplinary studies that span levels of analysis, from behavioral to neural, and those that employ causal experimental designs to probe functions of neural circuits that subserve the core aspects of the above-mentioned behavioral domains are of particular interest.
• Studies that propose to use genetically modified NHPs to investigate the role of genes, including psychiatric risk genes, and their mutations in basic molecular, cellular and systems-level processes
• Studies that propose to test hypotheses regarding pathophysiological processes underlying mental illnesses.
• Studies using genetically modified NHPs to address the developmental time course and/or sex differences of mental health relevant functional domains or pathophysiological processes.
• Studies that leverage resources developed and supported through the NIH BRAIN Initiative and NIH Blueprint for Neuroscience Research with a goal to generate cell- and circuit-specific genetically modified NHPs to expand understanding of connectivity of cortical and subcortical networks and to reveal their functional and behavioral readout.
• Studies that propose new technology development that will be applied to further understanding of the neural circuits that subserve cognitive, social, and affective functions. Applicants should also consider submitting to NIH BRAIN Initiative FOAs (e.g., RFA-DA-21-006, or reissues) for projects focusing on NHP genetic tool and technology development.
• Bridging preclinical stage studies to advance genetically based therapies to the clinic where the use of NHPs is required to address issues associated with delivery and distribution of gene-based therapies as well as assessment of target engagement, adverse effects, and impacts on brain function.

Program Directors/ Principal Investigators planning to submit applications concerning the use of genetically modified NHPs are strongly encouraged to contact NIMH scientific program staff early when developing their projects to ascertain that their proposed study is aligned with NIMH priorities.

Inquiries

Please direct all inquiries to:

Email: [email protected]