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Related Announcements

NOT-MH-23-236 Notice of Special Interest (NOSI): Pre-Clinical Research on Gene Therapies for Rare Genetic Neurodevelopmental Disorders

NOT-OD-23-105 Notice to Extend Parent R01/R03/R21 Parent Notices of Funding Opportunity

PA-20-183 Research Project Grant (Parent R01 Clinical Trial Required)

PA-20-184 Research Project Grant (Parent R01 Basic Experimental Studies with Humans Required)

PA-20-185 NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)

Issued by

National Institute of Mental Health (NIMH)

Purpose

The National Institute of Mental Health (NIMH) is issuing this Notice to highlight its interest in supporting planning grants to conduct retrospective natural history studies that explore the prevalence of disabling psychiatric symptoms and disruptions in function in patients (birth to 25 years of age) with rare genetic neurodevelopmental disorders (NDD). The principal goal of these studies is to assess the time of onset and severity of these symptoms, identify appropriate outcome measures, and establish potential timepoints for intervention. Additionally, the planning grants should focus on identifying potential quantitative clinical functional measures or biomarkers that could be used as prognostics and/or measures of change in future clinical trials. These retrospective natural history studies are expected to enable future prospective longitudinal studies (see Food and Drug Administration’s (FDA's) guidance on natural history studies for rare disorders).

Background

Genetic studies have led to the identification of thousands of rare, penetrant, recurrent mutations in genes that are associated with NDDs. Individual mutations in particular genes can lead to a range of psychiatric symptoms, including attentional deficits, social deficits, cognitive dysfunction, emotional dysregulation, anxiety, depression, and psychosis. Importantly, phenotypic outcomes may be affected by variable penetrance in which some individuals with a given mutation express only a subset of the typical symptoms. There are challenges in understanding the genetic, environmental and lifestyle factors that relate the progression of genetic mutations to disease phenotypes. Natural history studies are essential for identifying the onset and progression of severe mental illness in rare NDDs, and include these specific goals:

• to identify relevant clinical functional measures for use in future clinical trials.
• to identify biomarkers, see FDA's biomarker definition, a biomarker is a defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or biological responses to an exposure or intervention, including therapeutic interventions. Biomarkers may include molecular, histologic, radiographic, or physiologic characteristics. A biomarker is not a measure of how an individual feels, functions, or survives. Categories of biomarkers include susceptibility/risk biomarker; diagnostic biomarker; monitoring biomarker; prognostic biomarker; predictive biomarker; response biomarker; safety biomarker.
• to progress toward establishing clinical trials of novel gene-based or other course-altering treatments for NDDs.

This NOSI encourages planning grants to conduct retrospective natural history studies of rare genetic neurodevelopmental disorders. These studies are intended to enable future prospective natural history studies to further define the trajectory of psychiatric symptoms, clinical functional measures and biomarkers, and to address unmet needs for therapeutic development relevant to psychiatry.

Research Objectives

Applications must include a clear rationale for selecting rare genetic disorder(s) of interest and psychiatric symptoms/clinical deficits most disabling for patients and families (see the description of patient-focused drug development at an FDA website). Data collection should include clinical deficits associated with psychiatric symptoms and how they associate with other non-psychiatric clinical deficits.

Criteria for the selection of appropriate NDDs and genetic variants

The following criteria should be considered for selecting genes, genetic variants and associated disorders for natural history studies:

• There is expected to be strong evidence for the association of rare variants with a NDD. This must include statistical significance, with appropriate multiple test correction for genome-wide tests, following the guidelines of the NIMH Report of the National Advisory Mental Health Council Workgroup on Genomics. Pathogenic variants can include gain-of-function or loss-of-function mutations, as well as copy number variants that have large effect sizes for psychiatric traits.
• Clinical evidence for rare variants includes strong evidence for pathogenicity in association with NDD disorders and severe mental illness following ClinGen curations and American College of Medical Genetics and Genomic (ACMG) guidelines.
• Rare genetic disorders must have a therapeutically actionable/tractable genetic target or have known genetic mechanism(s) that can be reasonably expected to be accessed by gene-based, small molecule-based, or other therapeutic strategies.
• Diseases that have rapid progression of severe symptoms (e.g., severe intractable epilepsy, profound intellectual disability) and have a risk/benefit ratio that justifies a novel gene-based therapy approach.

Criteria for the conduct of the natural history study

The research team should propose a retrospective natural history study to review patient charts and medical records, using electronic health record (EHR) as well as other existing resources (when applicable), such as registries, collected from sites that have higher incidences of these disorders in their practices. Use of commercial entities with expertise in data collection and harmonization from medical chart EHR/other resources is encouraged to enable rigorous mining and merging of data. Once the data merging and analysis are completed, a literature review will be conducted to assess quantitative clinical functional measures that could be used as prognostic and/or measures of clinical change associated with psychiatric deficits. During the literature search it would be helpful to identify limits of the quantitative measures in relationship with the population (e.g., age-related effects, floor/ceiling effects, data loss). Ideally, the biomarkers identified should be able to be processed/analyzed in near real time at subject-level, including at least one CNS measure. It is expected that both psychiatric and non-psychiatric measures of symptoms and clinical deficits are included in the data collection and analysis as part of the study. These data will inform which measures are useful in therapeutic development for addressing the disease symptoms.

Additional criteria for the conduct of the retrospective natural history study should include the following:

• A multidisciplinary team engaging representatives from patient advocacy group(s), clinicians who provide services for rare genetic disorder of focus, and various experts in: psychiatric symptom assessment, central nervous system (CNS) biomarker data acquisition, analysis of other quantitative measures that may correlate with psychiatric symptoms/clinical function, patient chart reviews, data mining from registries, and EHR data mining.
• Access to comprehensive longitudinal medical, clinical, lab, behavioral, and family data. When available, demographic, socio-economic, ancestry, and environmental data for the disorders of interest should be included.
• Engagement with well-organized patient advocacy organizations to actively participate on this planning grant.

Criteria that are encouraged (but not required) include:

• Evidence of a proof-of-concept study using in vivo and/or in in vitro experimental systems supporting a targetable genetic mechanism to demonstrate genetic rescue.
• Pre-clinical studies with established pharmacodynamic/pharmacokinetic (PD/PK) parameters of gene targeting delivery-payload reagents (e.g., bioavailability, bioactivity, cell/tissue specificity in dose ranging studies), particularly in larger animals.
• Preclinical biomarkers/biosignatures suggesting translational measures to inform the types of clinical biomarkers to incorporate into the NH study.

Research topics of low priority include:

• A focus on rare disorders where cognitive, social and/or affective impairment is infrequently or minimally involved, such as disorders principally affecting motor, sensory or craniofacial function (which are under the purview of other NIH institutes).
• Research premised on 'candidate' risk genes that are not identified by statistically significant disease association.
• Research on therapeutic development that is currently well-supported pre-clinically or clinically by industry.

Timeline, outcome, and mechanism

The timeline for R01 planning grants is three years in duration. The main outcome of this research is to establish a plan for a future, more focused prospective natural history study for further assessing these disabling psychiatric symptoms/clinical deficits to determine points of intervention. Additionally, the future study would test the quantitative measures identified for utility as prognostic measures or to monitor clinical status over time. Ultimately, the research should provide the needed framework for conducting future treatment development studies. Multiple Principal Investigator (MPI) applications are encouraged. Applicants are strongly encouraged to contact NIMH scientific program staff early when developing their projects to ascertain that the proposed study is aligned with NIMH priorities and relevant programs and/or funding opportunity announcements.

Application and Submission Information

This notice applies to due dates on or after June 5, 2023 and subsequent receipt dates through September 7, 2026.

Submit applications for this initiative using one of the following notice of funding opportunity (NOFO) or any reissues of these announcement through the expiration date of this notice.

• PA-20-183 Research Project Grant (Parent R01 Clinical Trial Required)
• PA-20-184 Research Project Grant (Parent R01 Basic Experimental Studies with Humans Required)
• PA-20-185 NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)

All instructions in the SF424 (R&R) Application Guide and the notice of funding opportunity used for submission must be followed, with the following additions:

• For funding consideration, applicants must include NOT-MH-23-235 (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.

Inquiries

Please direct all inquiries to the Scientific/Research, Peer Review, and Financial/Grants Management contacts in Section VII of the listed notice of funding opportunity.

Margaret Grabb, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-443-3563
Email: mgrabb@mail.nih.gov