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Novel Assays to Address Translational Gaps in Treatment Development


Susan Koester, Ph.D. 
Division of Neuroscience and Basic Behavioral Science


This initiative would address a translational gap in therapeutic discovery and development that exists between the preclinical screening pipeline and early experimental medicine studies in humans. NIMH continues to encourage research focused on developing, evaluating, and optimizing clinically meaningful and biologically-based measures of physiology or circuit activity that tap into functional domains to inform therapeutic development. Studies under this initiative would evaluate the alignment or divergence of measures from preclinical screening to healthy humans. Ideally, the initiative would encourage research that illuminates the types of preclinical data and approaches that may be useful (or not useful) in predicting effects of novel therapeutic candidates in humans based on biological conservation of signaling pathways and circuits.  The initiative would also provide translational tools needed to test novel therapeutic targets or mechanisms in animals and in humans.    


While NIMH efforts in clinical neuroscience emphasize biological mechanisms, preclinical studies have lagged in adopting this approach within the early-stage therapeutic development pipeline, relying on measures that have little or untested value for assessing the effects of novel treatments on biological targets, circuits, or domains of function in human subjects. The goal of this initiative is to continue supporting the development of assays to address translational gaps in treatment development for mental disorders.  Assay development efforts will focus on quantitative, non-invasive measures of physiology/circuit activity that are relevant to domains of function (e.g., working memory, attention, anhedonia) that are potential treatment targets. The initiative would support partnerships among basic and clinical neuroscientists who are committed to advancing the discovery of translational physiological measures across preclinical development and into humans as tools for target validation and therapeutic development. 

Expected outcomes include the identification of tractable measures for further development as tools for assessing the biology of the therapeutic target or approach in preclinical and early phase clinical studies. Data will also identify measures demonstrating differences in performance between preclinical species and humans, thus establishing a firm basis for limiting speculative extrapolations of preclinical findings. Although only studies in preclinical species and in healthy humans would be supported by this initiative, the emphasis is on developing measures that will ultimately be useful in selection or evaluation of novel therapeutic mechanisms in patients with mental disorders.