Notice of Special Interest (NOSI): Pre-Clinical Research on Gene Therapies for Rare Genetic Neurodevelopmental Disorders
Notice Number:

Key Dates

Release Date:

April 28, 2023

First Available Due Date:
June 05, 2023
Expiration Date:
September 08, 2026

Related Announcements

NOT-MH-23-235 Notice of Special Interest (NOSI): NIMH Planning Grants for Natural History Studies of Rare Genetic Neurodevelopmental Disorders

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

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

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

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

Issued by

National Institute of Mental Health (NIMH)


The National Institute of Mental Health (NIMH) is issuing this Notice of Special Interest (NOSI) to highlight interest in pre-clinical research aimed at developing novel approaches for somatic cell gene therapies to treat neurodevelopmental disorders with prominent cognitive, social and/or affective impairment.


Considerable recent progress has been made in both the discovery of gene mutations that are causal and highly penetrant for neurodevelopmental disorders as well as molecular strategies that can be used to restore proper gene function. The confluence of this progress has opened the possibility of significant advancement toward the production of gene therapies to treat severe neurodevelopmental disorders. A key step towards such treatments is preclinical data obtained from cell-based and/or animal experimental systems that would permit an assessment of whether a candidate gene therapy may be reasonably effective and safe for initial testing in humans. This NOSI encourages research specifically focused on obtaining such data, thereby filling a critical gap in the pre-clinical-to-clinical pipeline of gene therapy development for neurodevelopmental disorders.

Research Objectives

NIMH is encouraging research to establish, optimize, and evaluate technologies and assays needed for the clinical development of somatic cell gene therapies (e.g., gene replacement, gene addition, gene editing, gene silencing) to treat rare neurodevelopmental disorders with prominent cognitive, social and/or affective impairment. Applicants may utilize novel genome targeting technologies (e.g., as developed through the Somatic Cell Genome Editing Program) and/or brain access and delivery systems (e.g., as developed through the BRAIN Initiative Armamentarium). A range of cell-based assays (e.g., using induced pluripotent stem cells), small animal or large animal assays may be appropriate to pre-clinically test the utility of the candidate therapeutic approaches. Projects should focus on further development and rigorous characterization of the technology and/or assay(s) for utilization and adoption in anticipated regulatory submissions and clinical trials.

It is expected that technologies and assays under investigation will target genomic loci that are determined to be causal and highly penetrant for neurodevelopmental disorders based on criteria consistent with recommendations in the National Advisory Mental Health Council’s Genomics Workgroup Report. NIMH is interested in supporting neglected rare disorders and strongly encourages applications focused on targets that are not the subject of ongoing therapeutic development by industry. In addition, the age of onset, progression, and severity (e.g., involvement of severe intractable epilepsy, profound intellectual disability and/or neurodegeneration) of the targeted disorder should have a risk/benefit ratio that justifies the novel gene therapeutic approach. Successful investigations will likely focus on pathogenic mutations whose relevant genetic mechanism is understood, whose targeting payload can be efficiently packaged into a delivery vector, and which are amenable to gene replacement, addition, editing or silencing strategies.

Investigations will be conducted in available pre-clinical experimental systems (e.g., cell-based and/or animal) that will be used to demonstrate genetic rescue. Investigators considering animal neurobehavioral approaches as part of a research strategy should adhere to NIMH guidelines in NOT-MH-19-053. Detailed analysis of this rescue would characterize the conditions of effective therapeutic delivery, including the bioavailability, bioactivity, cell-type requirements, and needed dosages of gene-targeting reagents along with assessment of adverse effects. Quantitative and comparative analysis of phenotypic reversal would also identify pre-clinical biosignatures most likely to translate into effective clinical biomarkers, which could subsequently be tracked in natural history studies of relevant patient populations in preparation for clinical trials. NIMH, through its therapeutics discovery research programs, provides multiple therapeutics pipeline funding opportunities through which early and mid-stage pre-clinical development can be supported. Candidate gene therapies that demonstrate utility by these measures could then be moved forward to the clinic, either through direct partnership with industry, involvement in the Bespoke Gene Therapy Consortium (BGTC) or by entry into the NIH-supported Neurotherapeutics Network for Biologics, which aims to provide the expertise and infrastructure that is needed to enable the submission of Investigational New Drug (IND) applications for candidate neurotherapeutic biologics within a five-year timeframe.

Examples of specific research areas of interest include, but are not limited to:

  • Testing and optimization of delivery systems and payloads for specific access or gene/cell-type targeting requirements. Note that optimization of certain delivery systems (e.g., adeno-associated viruses) may be most appropriate for the BGTC program.
  • Technologies for tracking and monitoring of gene targeting therapeutics in vivo, which may include in utero or postnatal delivery.
  • Cell and/or animal-based assays demonstrating the temporal, cell-type or circuit-level requirements for phenotypic rescue with outcome measures at the molecular, cellular, circuit and/or behavioral levels.
  • Comparative animal-based assays for the analysis of the translatability of putative rescue biosignatures between smaller and larger brains (e.g., as aligned with NIMH priorities on research using genetically modified nonhuman primates; see NOT-MH-22-010).
  • Cell and/or animal-based assays for testing how robustness of phenotypic rescue is affected by genetic background.
  • Cell and/or animal-based assays for evaluating the pharmacodynamic and pharmacokinetic properties of a gene therapy delivery system and targeting payload, including dose range specificity, sensitivity, activity, and functionality.
  • Toxicological assays applicable for assessing safety of gene targeting approaches, including assessment of adverse effects, e.g., cytotoxicity, immunogenicity, genotoxicity, mutagenicity and tumorigenicity potential. Such projects may be most appropriate for the Neurotherapeutic Network for Biologics program.

Research Topics of Low Priority:

  • Research directed at genomic modification of the human germline.
  • Research premised on candidate risk genes that are not identified by well-powered, statistically significant disease association.
  • A focus on rare disorders where cognitive, social and/or affective impairment is infrequently or minimally involved, such as disorders principally affecting motor, sensory organ or craniofacial function (which are under the purview of other NIH institutes).
  • Research on therapeutic development that is currently well-supported pre-clinically or clinically by industry.
  • Animal studies that rely mainly or exclusively on behavioral analysis rather than underlying cellular and/or circuit biology to validate the utility of the candidate intervention (e.g., genetically modified animals as a model of mental illness based on purported face validity and interpretation of behaviors as symptoms).

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 notice of funding opportunities.

Application and Submission Information

This notice applies to due dates on or after June 5, 2023 and subsequent receipt dates through September 8, 2026.

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

Applications for this initiative must be submitted using the following opportunities or their subsequent reissued equivalents.

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

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-23-236 (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.


Please direct all inquiries to the contacts in Section VII of the listed notice of funding opportunity with the following additions/substitutions:

Scientific/Research Contact(s)