In 2016, NINDS organized a conference on Alzheimer’s Disease Related Dementias (ADRDs) which focused on frontotemporal degeneration (FTD), Lewy body dementias (LBD) (including dementia with Lewy bodies (DLB)), Parkinson disease dementia (PDD), vascular contributions to cognitive impairment and dementia (VCID), mixed dementias including the associated diagnostic challenges of multiple etiology dementias (MED), and issues related to health disparities. The conference complemented the National Institute on Aging’s “Alzheimer’s Disease Research Summit 2015: Path to Treatment and Prevention.” Both conferences responded to the National Alzheimer’s Project Act that was signed into law in January 2011. The objective of the ADRD conference was to contribute to the efforts directed at preventing and effectively treating Alzheimer’s disease, including Alzheimer’s disease-related dementias, by 2025. The Alzheimer’s Disease-Related Dementias Summit solicited input from internationally recognized experts to develop prioritized recommendations to guide scientific research. This FOA is responsive to those resulting recommendations.
A major obstacle in the development of promising treatments for ADRD and also other CNS disorders is the need for well-validated targets linked to the disease process. Translating these discoveries to the clinic will depend on the quality of the target validation process plus confidence in a causative link between the modulation of a target(s) and its functional physiological consequence(s) associated with treating or preventing a disease state. In addition, partial and incomplete knowledge about the biology of the selected molecular target(s) often limit their chance to translate into successful future drug screening campaigns and drug discovery projects. This FOA provides the opportunity to address these knowledge gaps.
NIH expects that the end goals of this FOA will provide the translational research community with increased confidence in the efficacy and safety of the novel emerging target(s) to trigger the development of customized therapeutic strategies in ADRD. NIH expects the application to be composed of multi-components and multidisciplinary collaborative teams that have scientific expertise in a specific disorder within the ADRD spectrum, technical proficiency in running CNS functional assays/models plus support in statistical design and analysis. Development of the technological tools to modulate the target expression can be executed within the collaborative team or by a contract research organization.
Research Objectives and Scope
The UG3 phase (year 1- year 2) will support activities for the development of customized technology to specifically modulate the expression or activity of target candidate(s) in cells and/or tissue. Preference will be given to applications that propose target validation strategies using both in vitro human cellular model(s) and in vivo animal models. During this time, applicants will develop, in parallel, protocols to monitor the functional consequences of the target modulation in diseased-relevant in in vitro (e.g. electrophysiology in differentiated human iPSC) or in vivo (e.g., behavior, EEG in knock out/transgenic) models. Target-centric as well as phenotypic target-based validation approaches will be considered. The end of this first UG3 phase will be completed by a proof of concept study showing the feasibility of the chosen technological approach. Progress toward UH3 phase and subsequent year award(s) will be milestone-based.
The UH3 phase (up to two additional years) will carefully and reproducibly measure the positive and negative functional impacts of the target modulation in different proposed modalities across collaborating laboratories. This validation process will follow the NIH rigor and reproducibility guidelines.
Applications should include the following key components.
Selection of the target candidate, potential druggability and knowledge gaps
Comprehensive applications will initially include a target identification package that will cover the rationale and supporting experimental data in human for the target selection and its association to the ADRD disease state. Such target identification approaches include, but are not limited to, genetics, genomic, proteomic, metabolomics or other omics-based approaches, system biology, analysis of public literature-big data mining and the bioinformatic tools used to analyze large data sets. A summary of the results should include a description of the experimental protocols and statistical analyses used to assess the rigor and quality of the data linking the target candidate to the pathology of ADRD. A target identification package must be included in the Appendix (see section IV).
Drug screening and discovery efforts are out of scope for this application. Nevertheless, applicatons should address the current knowledge about the biology and potential “druggability” of the selected target and the hypothesized nature of the modulatory interaction that would either mimic or restore to normalcy the physiological abnormality observed in a disease state. Such modulatory interaction(s) could include small molecules, biologics or natural products.
Novel target candidates include, but are not limited to, proteins, lipids, sugar, or nucleic acids. Those targets can commonly be used for a target-centric drug discovery approach but could also be proposed to develop future phenotypic assay(s) and drug discovery strategies. Target(s) for future phenotypic assay(s) and drug screening could include, but are not limited to, indirect read out of the target activity via an engineered reporting system, molecular and metabolic pathways, or cellular and physiological tissue functions. The validation strategy of the “phenotypic target(s)” should demonstrate that its modulation leads to the normalization or impairment of the functional read outs selected to represent respectively the disease or control states in in vitro or in vivo models.
The expected direction and efficacy of the target modulation leading to a therapeutic effect or mimicking a disease state should be discussed to justify the choice of the target validation approaches. In the absence of a strong hypothesis, the application could propose a comprehensive and un-biased target validation strategy that would test both the inhibition and activation of the target in a dose dependent manner.
The application should address and discuss the knowledge gap(s) about the biological function of the target(s) related to the pathophysiology of the ADRD disease state and its therapeutic application. The following describes some examples of questions related to the expected effectiveness of the translational ability of the validation approach. Are the target’s mechanism of action and physiological consequences well understood at different system organizational levels (molecular, metabolic, cellular, tissue, neuronal network and behavior)? How is the target selected and expressed when multiple uncharacterized isoforms or genetic variants are present? Which degree of modulation is expected to reach target-related maximal therapeutic effect(s) while minimizing negative safety side-effect(s)? Does the prevention or mimicking of a disease state require the co-influence of environmental insults and aging process?
Target validation approaches
Comprehensive target validation is a low-throughput process that involves more than a single method or assay. It depends on convergent evidence collected from a variety of studies. Therefore, preference will be given to applications proposing a comprehensive target validation strategy with different but complementary tools and multi-disciplinary in vitro assays and in vivo models. The functional validation strategy should include the technical approaches to be used to modulate the target expression or activity under different modalities and the functional assays/models to monitor their physiological impacts.
First, the selection and description of the target validation tool(s) should be outlined. Examples of tools to modulate the expression of the target or pathway include, but are not limited to, the state-of-the-art gene manipulation methods for genome editing, silencing, knocking out, or knocking in. Examples of tools used to modulate the activity of the target or pathway are antibodies, chemical genomics or pharmacology if specific small molecules or peptides have been previously identified and characterized.
Second, the application should include a description of the models and functional read out(s) selected to monitor the physiological consequences of the modulation of the target expression or activity on cellular, ex vivo or in vivo systems. For in vitro, proposed cellular models should include highly differentiated and organized CNS 2D or 3D cultures in order to replicate some of the relevant disease physiological processes. The use of transformed, immature, immortalized or cancerous cell lines is out of scope. Examples of acceptable cellular models with relevance to the disease mechanism(s) are highly differentiated CNS cultures derived from human induced pluripotent stem cells (iPSCs) or from animals generated with engineered genetic modifications (transgenic, knockout/in, viral infection…). This later example could also represent the main sources for the in vivo animal models. Other animal models using pharmacological and surgical modifications can be also proposed as long as a solid case can be made for their relevance to certain aspects of the disease mechanism(s) or phenotypic exhibition. Examples of physiological read outs include, but are not limited to, measurements of activity of molecular pathway(s), organelle and cellular functions, synaptic and channel electrophysiology, structural and functional imaging, neuronal network activity and animal behaviors, anatomy and safety profiles.
Third, the application should include a description of the different experimental modalities that should be tested in the UH3 phase. Those should include parameters that can achieve comprehensive validation and inform future therapeutic approaches on the optimal level of target tuning or engagement to obtain maximal therapeutic efficacy and minimal adverse effects. Examples of modalities include, but are not limited to, testing a different range of expression levels of the target, time window of modulation, age of onset, various isoforms or genetic variants, or environmental conditions.
All projects will be milestone-driven with clear go/no-go criteria that are quantifiable. Prior to funding an application, the Program Official will contact the applicant to discuss the proposed UG3 and UH3 milestones and any changes suggested by NIH staff or the NIH review panel. The Program Official and the applicant will negotiate and agree on a set of approved UG3 milestones which will be specified in the Notice of Award. These milestones will be the basis for judging the successful completion of the work proposed in the UG3 stage and progress towards interim milestones in the UH3 stage. An administrative review will be conducted by NIH program staff to decide which projects will advance from the UG3 phase to the UH3 phase. Only UG3 projects that meet their milestones will have an opportunity to move to the UH3 phase.
UG3 milestones guidelines:
- Demonstrate that the team members work and communicate cohesively and collaboratively to respect the timelines and deliveries of the UG3 phase. PD(s)/PI(s) will organize a kick off meeting at the beginning of the project to facilitate and coordinate the collaboration. This event will be followed with emails communications and bi-annual virtual conferences to monitor progress toward the milestones.
- Demonstrate that the technical approaches and tools selected to modulate the expression or activity of the target(s) are set up and ready for the next UH3 steps.
- Demonstrate that the in vitro and/or in vivo models are set up and ready for the next UH3 phase.
- Demonstrate that the functional read out methods are set up and ready to measure the physiological consequences of the target modulations in different models.
- For each technical approach, demonstrate feasibility and the integration of each component (# 1-4) in a proof of concept experiment:
1. The implementation of the modulatory tools in the in vitro and/or in vivo models should show that the expression or activity levels of the target(s) are measurable and significantly different between the “control” and the “disease” biological samples. The degree and the direction of the target modulation should be consistent with the proposed validation and disease hypothesis. Power analysis should address reproducibility and significance of the results.
2. Modulation of the target(s) expression or activity in in vitro and/or in vivo models should translate into measurable functional or physiological differences between the “control” and the “disease” biological samples. The degree and the direction of the functional read out modulations should be consistent with the proposed validation and disease hypothesis. Power analysis should address reproducibility and significance of the results.
Before moving to the next UH3 phase, the Program Official and the applicant will negotiate and agree on a final set of UG3 specific-milestones which will be specified in the Notice of Award. UH3 milestones will be the basis for judging progress towards and completion of interim milestones in the UH3 stage.
UH3 milestones guidelines:
- For each technical proposed modality to be tested, provide the expected measurable outcomes on the target expression or activity levels and their functional or physiological consequences in the in vitro or in vivo models between the “control” and the “disease” biological samples. Power analysis should address reproducibility and significance of the results.
Collaborative interactions between interdisciplinary teams are a critical aspect of this FOA. Successful target validation applications will require extensive collaboration among experts. The later would include, but are not limited to, specialists in assay biology and development, CNS cellular models, tissue engineering, ADRD pathophysiology, animal models and behaviors, histopathology, electrophysiology, drug discovery and translational research, bioinformatics and biostatistics. Development of the technological tools to modulate the target expression can be executed within the collaborative team or via a contract research organization. The application should describe how the collaboration between this interdisciplinary team would work in the UG3 and UH3 phases of the grant.
Applicants are encouraged to leverage existing NINDS resources for disorders within the ADRD spectrum. Such resources may include cellular or DNA samples from NINDS BioSEND or other existing biospecimen and data repositories. Human ADRD iPSC resources targeting Frontotemporal Degeneration and Lewy Body Dementia are available through the NINDS Human and Cell Repository (NHCDR). Studies are also encouraged that leverage the resources of cell banks supported through other Federal or private funds.
The following types of studies are non-responsive and will not be reviewed:
- Clinical trials or basic experimental studies in humans
- Target identification, genome-wide ‘omics profiling studies
- Validation of biomarkers
- Assay development for high-throughput drug screening.
- Development or use of transformed, immature, immortalized or cancerous cell lines as physiological cellular CNS disease models.
Deadline: May 6, 2019 (letters of intent due 30 days prior to deadline)
Filed Under: Funding Opportunities