October 13, 2021
National Institute of Mental Health (NIMH)
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:
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.
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.