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Novel Assays to Address Translational Gaps in Treatment Development


Lois Winsky, Ph.D.
Division of Neuroscience and Basic Behavioral Science


This initiative addresses a translational gap in therapeutic discovery and development that exists between the preclinical screening pipeline and early experimental medicine studies in humans. Support would be provided for collaborative teams focused on developing, evaluating, and optimizing clinically meaningful and biologically-based measures that tap into functional domains to inform therapeutic development. Studies would evaluate the alignment or divergence of measures across preclinical screening and into healthy humans. Ideally, the initiative would illuminate the types of preclinical data and approaches that may be useful (or not useful) in predicting effects in humans based on biological conservation of signaling pathways and circuits, and provide tools needed to test novel therapeutic targets or mechanisms in animals and in humans.


The NIMH recently initiated new requirements for Institute-supported clinical trials such that new pharmacological and device clinical trials must adopt an experimental medicine -based approach. In this framework, dose is optimized for safety, target engagement, and target physiological effect prior to rigorous hypothesis testing trials in patients. Ideally, patient enrollment is based on physiological measures that reflect deficits in key functional domains in trials where the novel therapeutic targets the same physiology and domains. Thus, even negative trials will provide meaningful scientific information. Complementary to this effort, the Research Domains Criteria (RDoC) project was developed as a framework for conducting clinical research with a focus on biologically-anchored domains, many of which are disrupted across current diagnostic (DSM) disorders, or are differentially disrupted within an existing DSM disorder. This confluence of new trial designs and domain-focused research has the potential to reveal biological targets to advance treatment development for mental disorders, and provides stronger evidence to reject hypotheses proposing links between specific molecular targets and effects in humans. However, while 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 predicting effects in patients with mental disorders.

The goal of this initiative is to support the development of assays to address translational gaps in treatment development for mental disorders. Assay development efforts will focus on quantitative measures of physiology/circuit activity relevant domains of function that are potential treatment targets (e.g., working memory, attention, anhedonia, etc.). The initiative will 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.

Support would be provided for cooperative planning and prioritization of measure development and evaluation. Successful research groups would provide a strong rationale for the initial selection of measures to be evaluated and/or developed based on: a) links to specific biology; b) the ability to evaluate measures across preclinical and clinical platforms; c) the expectation that measures will be robust and reliable; and, d) the ability to modify the measure to test conservation of mechanism between the preclinical species and humans.

The breadth of projects could include:

  • Develop and test assays or measures that tap into fundamental, basic physiological functions that are disrupted within or across mental disorders, such as aspects of sensory integration or arousal, which can be measured in animals and humans (e.g., via spectral EEG analyses, MEG, sleep architecture). Innovative measures would be encouraged.
  • Develop and test highly tractable task-based assays that may serve as proxies of circuit activity linked to a functional domain (e.g., gain control, striatal circuits mediating reward contingency coding and effortful behavior, lactate and CO2 signaling pathways, fear potentiated circuits, attentional control and other components of cognition). Researchers are encouraged to combine behavioral and physiological measures, such as tracking changes in local field potentials or EEG oscillation patterns during performance of a task, in their studies.

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 control 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.

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