Part 1. Overview Information

Key Dates

All applications are due by 5:00 PM local time of applicant organization. 

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide, except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts).

Conformance to all requirements (both in the How to Apply - Application Guide and the NOFO) is required and strictly enforced. Applicants must read and follow all application instructions in the How to Apply - Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the How to Apply - Application Guide, follow the program-specific instructions.

Applications that do not comply with these instructions may be delayed or not accepted for review.

There are several options available to submit your application through Grants.gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

1. Use the NIH ASSIST system to prepare, submit and track your application online.
2. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants.gov and eRA Commons to track your application. Check with your institutional officials regarding availability.
   
   
3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.



Table of Contents
Part 1. Overview Information
Key Dates
Part 2. Full Text of Announcement
Section I. Notice of Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Background

Goal 1 of the National Plan to Address Alzheimer’s Disease is to prevent and effectively treat Alzheimer's disease (AD) and Alzheimer’s disease-related dementias (ADRD) by 2025. ADRD are defined as Frontotemporal Dementia (FTD), Vascular Contributions to Cognitive Impairment and Dementia (VCID), Lewy Body Dementias (LBD) and Multiple Etiology Dementias (MED). Starting in 2012, the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS) have held research summits to assess the needs and set AD/ADRD research implementation milestones. The NINDS ADRD Summit in 2022 resulted in the currently proposed ADRD research priorities for advancing the state-of-the-science toward meeting Goal 1 of the National Plan. This Notice of Funding Opportunity Announcement (NOFO) is responsive to those resulting recommendations and to other implementation milestones in the National Plan.

The broad applicability of targeted and programmable genome editing approaches, including, but not limited to those based on CRISPR-Cas9, raise the possibility of a fundamentally new way to treat a variety of genetic diseases, including some ADRD. However, many challenges need to be overcome before such techniques could be widely used in the clinic. To realize the potential of genome editing technology for ADRD, and to address these challenges, this NOFO is soliciting applications for the translation of genome editing technology for ADRD.

Research Objectives and Scope

This Notice of Funding Opportunity (NOFO) is to encourage applications for the translation of new genome editing technologies for the development of treatments for ADRD. The end goals of this NOFO are to provide the translational research community increased confidence in the efficacy and safety of novel genome editing technologies for ADRD. It is expected that applications will be composed of multidisciplinary collaborative teams that have scientific expertise in a specific disorder within the ADRD spectrum, technical proficiency genome editing technologies used in CNS functional assays/models, plus support in statistical design and analysis.

This NOFO will support the identification and optimization of a genome editing reagent lead culminating in the selection of an optimized clinical candidate therapeutic for ADRD. This is a milestone-driven Cooperative Agreement Program involving participation of NIH program staff in the development of the project plan and monitoring of research progress. Projects will be funded through the U01 cooperative agreement award mechanism, which involves NINDS Scientific/Research staff's participation in developing the project plan, monitoring research progress, and establishing appropriate milestones.

Projects should propose a strong scientific rationale, and a relevant, rigorous, convincing approach for identifying one or more genome editing agent(s). Applications should outline the parameters to be optimized and quantitatively specified, so that at the end of the funding period, a candidate can be identified that has sufficient bioactivity, stability, manufacturability, bioavailability, in vivo efficacy, with defined minimal and optimal doses, and other favorable properties consistent with the desired clinical application.

This NOFO invites applications from interdisciplinary Research Teams to integrate:

• Identification and optimization of genome editing therapeutic lead(s) using ADRD-related in vitro and/or animal model(s) to improve in vivo editing efficiency, biodistribution, dose range, and safety profiles such as off-target effects and/or immune responses for the intended route of administration.
• Optimization of delivery system(s), process development, Chemistry, Manufacturing, and Control (CMC) related activities (e.g., master and working cell banks development, purification development, CMC analytical development, final formulation development) intended for future IND-enabling studies.
• Development of a regulatory strategy to facilitate early-stage interactions (e.g. INTERACT and/or pre-IND meetings) with the regulatory agency.
• Approaches that are unlikely to be blocked by any legal (e.g., intellectual property) constraints to pursuing the proposed agent(s) and using the proposed assays and models for research purposes and/or commercial development.

Activities Appropriate for this NOFO include, but are not limited to:

• Optimization of the gene editing agent, such as improvement of editing efficiency, specificity, bioavailability, and suitability for human testing, etc. 
• Specific examples include: optimize selectivity/specificity by selection of the best promoter or viral serotype for delivery of gene editing agent and ideal sequence of guide RNAs to hone its specificity, optimization of delivery systems  to achieve an acceptable stability in half-life in vivo, minimizing a predicted or previously encountered toxicity, optimization of acceptable level of production, optimization for better suitability for the route of administration
• Characterization of identity and properties of delivery vehicles
• Assessment of in vitro proof of concept (POC) studies
• Assessment of in vivo proof of concept (POC) studies, such as determination of dose range, dosing regimen, route of administration, and ideal time and duration of treatment. This includes but is not limited to assessment of efficacy and/or target correction, correlations between in vitro and in vivo activities, bioavailability at the site of action, and blood-brain-barrier penetration
• Studies to support independent replication, appropriate powering, or an assessment of efficacy in additional animal models if necessary to gain higher level of confidence for translatability to humans, along with the model in which the leads were shown to have efficacy.
• Optimization of production (e.g., expression levels, purification yield, purity, yield of vector)
• Process development for scale-up manufacturing
• Stage-appropriate bioanalytical assay development and optimization in compliance with regulatory requirements
• Optimization of delivery systems and special formulations (such as, liposomes, nanoparticles, etc.)
• Development of regulatory strategy and stage-appropriate interactions with regulatory agency
• Validation of target engagement assays, including experiments using human specimens, are within the scope of this NOFO. However, these activities are restricted to the purpose of supporting the proposed development of a therapy.

Applications Not Responsive to the NOFO:

• Applications not focused on AD/ADRD
• Developing animal models (supported by NINDS through in PAR21-123)
• Basic research of disease mechanisms
• Early activities such as target identification
• Development of risk, detection, diagnostic, prognostic, efficacy prediction biomarkers
• Applications lacking milestones
• Studies only focused on  identifying, validating, or qualifying a target engagement marker and other bioanalytical assays
• Only screening activities to identify new therapeutic leads
• Nonclinical studies of disease mechanism or therapeutic mechanism of action studies
• Studies for ex vivo genome editing therapeutic development
• Development of diagnostics or diagnostic devices
• Clinical research and clinical trials involving human subjects, except those in scope using human samples to validate target engagement assays

Milestones:

Annual milestones must be proposed to reflect progress of the overall integrated Program. The milestones proposed will be evaluated by scientific peer review and NIH Program staff may contact the applicant to discuss the proposed milestones and any changes suggested by the scientific review panel or Program Staff. A final set of approved milestones will be specified in the Notice of Award.

NIH program staff and leadership will conduct an annual administrative review of progress toward the milestones. Additional meetings with NIH program staff will be arranged on a frequency appropriate for the development stage of the Project, as determined by NIH. If justified, future year milestones may be revised based on data and information obtained during the previous grant period. The administrative reviews will be based on:

1. Successful achievement of milestones
2. The overall feasibility of Program advancement, considering data that may not have been captured in milestones
3. Ethical considerations

Rigor and Transparency

NINDS, as part of NIH, strives for rigor and transparency in all research it funds. For this reason, NINDS explicitly emphasizes the NIH application instructions related to rigor and transparency (https://grants.nih.gov/policy/reproducibility/guidance.htm) and provides additional guidance to the scientific community (https://www.ninds.nih.gov/Funding/grant_policy). For example, the biological rationale for the proposed experiments must be based on rigorous and robust supporting data, which means that data should be collected via methods that minimize the risk of bias and be reported in a transparent manner. If previously published or preliminary studies do not meet these standards, applicants should address how the current study design addresses the deficiencies in rigor and transparency. Proposed experiments should likewise be designed in a manner that minimizes the risk of bias and ensures validity of experimental results.

Pre-application Consultation

As an U01 cooperative agreement, implementation will involve the participation of NINDS Program staff in the planning and execution of the therapy-directed projects. Applicants and their multidisciplinary team are strongly encouraged to consult with NINDS Scientific/Research staff when planning an application. Early contact provides an opportunity for NINDS Scientific/Research staff to provide further guidance on program scope, goals, developing appropriate milestones, and budget.

See Section VIII. Other Information for award authorities and regulations.

Section II. Award Information

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this NOFO.

Section III. Eligibility Information

1. Eligible Applicants

All organizations administering an eligible parent award may apply for a supplement under this NOFO.

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Local Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)

Federal Government

• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

Non-domestic (non-U.S.) Entities (Foreign Organizations) are not eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed. 

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the How to Apply - Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications for additional information. 

• System for Award Management (SAM) – Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code – Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
  • Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.
• eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.gov registration; all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov – Applicants must have an active SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account.  PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with their organization to develop an application for support. Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the How to Apply - Application Guide.

2. Cost Sharing

This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement Section 1.2 Definition of Terms.

3. Additional Information on Eligibility

Number of Applications

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time, per NIH Grants Policy Statement Section 2.3.7.4 Submission of Resubmission Application. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NIH Grants Policy Statement 2.3.9.4 Similar, Essentially Identical, or Identical Applications).

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity to do otherwise. Conformance to the requirements in the How to Apply - Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

All page limitations described in the How to Apply – Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the How to Apply – Application Guide and should be used for preparing an application to this NOFO.

All instructions in the How to Apply - Application Guide must be followed.

All instructions in the How to Apply - Application Guide must be followed.

All instructions in the How to Apply - Application Guide must be followed.

Other attachments

Intellectual Property (Required, 1 Page Maximum):

Applicants should describe any constraints of which they are aware that could impede their use of compounds, assays, or models for research purposes and/or clinical development (e.g., certain restrictions under transfer or sharing agreements, applicants' previous or present intellectual property (IP) filings and publications, compounds with similar structures that are under patent and/or on the market, etc.) and how these issues would be addressed. If the applicant has filed pertinent patents, the applicant should indicate filing dates, the type of patent, and application status.

Team Management Plan (Required, 1 Page Maximum)

Genome editing therapy development is a complex and time-consuming undertaking, and NINDS expects applicants to form multidisciplinary teams that may consist of preclinical and clinical scientists, PK experts, CMC experts, regulatory experts, statisticians, project manager, and other academic/industry experts relevant to the therapeutic modality and disorder. This multidisciplinary team should establish a desired TPP (see details in Section IV-Research Strategy), define the attributes of a successful genome editing candidate for the intended clinical indication, identify gaps that need to be filled during this funding period, and design the details of the plans and experiments to execute the research strategy. Engaging a team that includes members experienced in the IND process will help identify issues, strategize solutions and options, plan details of studies and set a realistic timeline. Describe how the team, including consultants, has already been engaged and a plan as to how they will continue working together over the course of the project (e.g., recurring team meetings, review and report of data across disciplines, decision-making, participate in meetings with NINDS, communication, etc.).

All instructions in the How to Apply - Application Guide must be followed.

R&R or Modular Budget

All instructions in the How to Apply - Application Guide must be followed.

R&R Subaward Budget

All instructions in the How to Apply - Application Guide must be followed.

All instructions in the How to Apply - Application Guide must be followed.

All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions:

Specific Aims:

This section should provide a concise description of the aims for the project.

The Research Strategy must include the following sections:

Significance:

Describe the impact of the science proposed in relation to the state of the field. Applicants should include a brief statement of the therapeutic hypothesis that includes: the projected patient reduction of symptoms, slowing disease progression, side effects, dose administration, and regimen, and sustainability of effect.

Discuss how the therapy would be an improvement over currently available therapy. Describe the target clinical population and how treatment would be most efficacious at different stages of disease (therapeutic window). Describe how the target patient population may be identified (e.g., based on the pathogenic variant and other common disease characteristics and clinical manifestations).

Describe the current state of knowledge of the etiology, clinical characteristics, and prevalence of the proposed disease indication.

Discuss the evidence and provide any POC data that altering (editing) target activity as proposed will give the desired clinical outcomes and is appropriate for the identified genetic disease.

Discuss the disease-relevance of in vitro or in vivo models that are proposed or that have been used and whether the endpoints measured, and levels of activity observed are likely to be clinically relevant.

Applicants must provide a Target Product Profile (TPP) that summarizes the minimal/ideal profile of the final product and shows the ultimate goals of the proposed gene editing development effort, such as disease indication, patient population, delivery mode, treatment duration, treatment regimen, and standards for clinical efficacy  (https://neuroscienceblueprint.nih.gov/sites/default/files/documents/tpp-worksheet_508c.pdf).

Approach:

Plans should include, but are not limited to:

Describe how proposed experiments will address considerations for preclinical studies and expound how the genome editing product and its individual components will be evaluated to assess its manufacturability, delivery, activity, efficacy, safety, and potential risks associated with in vivo administration of the product.

Describe and offer evidence for the feasibility of the proposed experiments, the advantages of any new methodologies, the potential pitfalls, and alternative approaches for the project and how these might impact overall progress.

Describe experiments such as demonstration of in vivo efficacy, target engagement with dose-response, bioavailability at the site of action (including brain penetration), and pharmacokinetic-pharmacodynamics relationships.

Discuss how the genome editing based therapeutic proposed is expected to alter the activity of the putative target as intended and/or produces desired outcomes in disease models, with sufficient detail to allow reviewers to evaluate the rigor of the experimental design. Explain the choice of models, assays, and endpoints for these studies and how activity in relevant human cells for the genome editing-based therapeutic will be confirmed.

Describe the in vivo (animal model) efficacy study design in detail, including the power analysis and associated assumptions for the determination of sample size, statistical handling of the data (such as criteria for data inclusion or exclusion), procedures used for blinding and randomization, and whether studies were replicated and consideration of sex as a biological variable (SBV) and the authentication of reagents.

Summarize the evidence that validates the editing target from cellular or animal models and/or related clinical studies. Provide a summary of the rationale for the selection of the target, the level of agreement in the field regarding the target's role in disease pathogenesis, and clinical relevance of the target.

Studies using animal models presented to justify the choice of genome editing based therapeutic must be sufficiently powered, controlled, and replicated to lend a high degree of confidence in the results.

Describe how the research design will maximize the reliability and replicability of the findings. Describe the essential assays (in vitro and in vivo) that will be used to optimize the genome editing agent(s) (e.g., the dynamic range, variability, specificity).

Explain how the project offers an approach to treating the patient population as proposed in the Target Product Profile (TPP).

NINDS urges investigators to follow the NIH guidance for rigor and transparency in grant applications (https://grants.nih.gov/policy/reproducibility/guidance.htm) and additionally recommends the research practices described at https://www.ninds.nih.gov/Funding/grant_policy.

Milestones:

Milestones are required and should be well-described, quantifiable, and scientifically justified to allow Program Staff to assess progress for the proposed project. One or more milestone(s) should be used for each key objective. For each milestone provide details on methods, assumptions, experimental designs, and data analysis plans (if the results are quantitatively measured). Specify the quantitative criteria for measuring success and related rationale. Quantitative criteria should be robust and be consistent with the state-of-the-art in the field. The quantitative criteria for success in the milestones will also be used for making go/no-go decisions and this should be specified. Specify the timeline for each milestone. There should be at least one milestone each year.

Include an outline of milestones that lays out each step in the critical path of the project.

Include a table with yearly milestones and quantitative successes (Go-No Go criteria).

Describe plans for data analysis and interpretation of outcomes, including what effect size would be considered minimally acceptable and clinically relevant (i.e., what constitutes a Go-No go decision for advancement future clinical trials).

Letters of Support:

Statements of individual and institutional commitment, as appropriate to the Research Project, should be included in this section.

Letters of support should be included and should not be generic, but instead indicate what has been contributed so far and what they expect to provide during the project to allow an evaluation of team engagement (see below). Indicate the willingness of the PD/PI(s) and key personnel to operate under the cooperative agreement terms and conditions outlined in section VI.2. Of the NOFO. Note: Multi-PI plans should not duplicate information from the multi-PI plan.

Resource Sharing Plan:

Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the How to Apply - Application Guide. 

Other Plan(s):

All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions:

• All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the How to Apply - Application Guide.

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the How to Apply - Application Guide, with the following additional instructions:

If you answered “Yes” to the question “Are Human Subjects Involved?” on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the How to Apply - Application Guide must be followed.

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start). All instructions in the How to Apply - Application Guide must be followed.

All instructions in the How to Apply - Application Guide must be followed.

3. Unique Entity Identifier and System for Award Management (SAM)

See Part 2. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

Part I. contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time.  If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the How to Apply – Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement Section 7.9.1 Selected Items of Cost.

Applications must be submitted electronically following the instructions described in the How to Apply - Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply – Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile form. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this NOFO for information on registration requirements.

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the How to Apply - Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by NINDS, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Recipients or subrecipients must submit any information related to violations of federal criminal law involving fraud, bribery, or gratuity violations potentially affecting the federal award. See Mandatory Disclosures, 2 CFR 200.113 and NIH Grants Policy Statement Section 4.1.35.

Send written disclosures to the NIH Chief Grants Management Officer listed on the Notice of Award for the IC that funded the award and to the HHS Office of Inspector Grant Self Disclosure Program at grantdisclosures@oig.hhs.gov. 

Applicants are required to follow the instructions for post-submission materials, as described in the policy

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process.  Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

Overall Impact

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Scored Review Criteria

Reviewers will consider each of the review criteria below in the determination of scientific merit and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Specific to this NOFO:

How strong is the evidence supporting the choice of therapeutic intervention for the identified genetic disease?

Will the parameters proposed for optimization result in a candidate consistent with the requirements stated in the TPP?

Is understanding of the pathogenic variant and its consequences adequate to form the basis for the proposed therapeutic approach?

How well do the POC data (in vitro and/or in vivo models) support the therapeutic hypothesis for the patient population and establish a potential clinical significance for the potential therapeutic intervention?

How robust is the data provided in support of the target for the intended disease? Does preliminary data for genome editing agent(s) show efficacy and target engagement, and does it provide sufficient experimental and statistical rigor?

For the key experiments, how well did the application explain assumptions for power analysis, describe statistical analysis methods and criteria for data inclusion or exclusion, and detail the procedures of how blinding and randomization were conducted?

Are the starting agent(s) sufficiently profiled so that all the parameters needed to be optimized to achieve the desired candidate profile specified? Will the parameters proposed for optimization result in a candidate consistent with the requirements stated in the TPP?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance, and organizational structure appropriate for the project?

Specific to this NOFO:

Has a multidisciplinary team been engaged, including expertise in preclinical, clinical, PK, CMC, regulatory, statistics, and any other experts relevant to the therapeutic modality and disorder? Is there any expertise lacking? Based on the team management plan and letters of support descriptions of how the members have already contributed to the design and proposed implementation of the project and how they will continue working together over the course of the project, does the team seem capable and sufficiently engaged to successfully complete the activities needed to obtain an optimized therapeutic candidate?

Innovation

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

Specific to this NOFO:

Are plans with all necessary steps to optimize the genome editing agent(s), in order to obtain a candidate, clearly spelled out? Can all the proposed parameters be optimized within the funding period?

Are there sound rationales for the choice of model(s), and advancement criteria?

How well characterized are the essential assays (in vitro and in vivo) that will be used to optimize the genome editing agent(s) (e.g., the dynamic range, variability, specificity)?

How rigorous are the experimental design and methodological approaches? For key critical experiments (such as an in vivo demonstration of efficacy and target engagement with a dose response), does the application have the following:

• A primary, secondary, exploratory endpoint (when applicable), and an explanation as to why they were chosen
• Appropriate controls
• An explanation of assumptions and reference to supporting data for power analyses
• A description of planned data analyses and data handling rules such as criteria for data inclusion or exclusion
• A detailed description of the procedures of how blinding and randomization will be implemented
• Minimal requirement of the purity of the reagents
• Plan for replication

Is there support for the activity in relevant human cells for the genome editing-based therapeutic?

If there is anticipated toxicity based on the proposed therapeutic target, is there a plan for stage appropriate preliminarily evaluation of toxicity?

Environment

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment, and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

Additional Review Criteria

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

Milestones and Timelines:

Are milestones robust and associated with clear, quantitative criteria for success that allow go/no-go decisions? If a criterion is not to be used for go/no-go decisions, is it justifiable?

Are the timelines proposed for achieving the milestones realistic and inclusive of necessary steps, but also efficient without unnecessary steps?

Are there any gaps in the proposed milestones?

Team Management Plan:

To what extent is the proposed Team Management Plan appropriate to support the research proposed within this application?

Protections for Human Subjects

For research that involves human subjects but does not involve one of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Individuals Across the Lifespan

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following three points: (1) a complete description of all proposed procedures including the species, strains, ages, sex, and total numbers of animals to be used; (2) justifications that the species is appropriate for the proposed research and why the research goals cannot be accomplished using an alternative non-animal model; and (3) interventions including analgesia, anesthesia, sedation, palliative care, and humane endpoints that will be used to limit any unavoidable discomfort, distress, pain and injury in the conduct of scientifically valuable research. Methods of euthanasia and justification for selected methods, if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals, is also required but is found in a separate section of the application. For additional information on review of the Vertebrate Animals Section, please refer to the Worksheet for Review of the Vertebrate Animals Section.

Biohazards

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Renewals

Not Applicable

Revisions

Not Applicable

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Intellectual Property (IP) Strategy:

Are potential issues regarding the IP landscape for the therapeutic being developed and the freedom to operate addressed?

Do the IP Strategy attachment and related letters of support address potential concerns?

Are there any known constraints that could impede the development of the therapeutic?

Are IP filing plans described?

If multiple institutions are involved, is IP sharing addressed?

Applications from Foreign Organizations

Not Applicable.

Select Agent Research

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans

Reviewers will comment on whether the Resource Sharing Plan(s) (i.e., Sharing Model Organisms) or the rationale for not sharing the resources, is reasonable.

Authentication of Key Biological and/or Chemical Resources:

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Budget and Period of Support

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NINDS, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications will receive a written critique.

Applications may undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.

Applications will be assigned to the NINDS. Applications will compete for available funds with all other recommended applications submitted in response to this NOFO. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement Section 2.5.1. Just-in-Time Procedures. This request is not a Notice of Award nor should it be construed to be an indicator of possible funding.

Prior to making an award, NIH reviews an applicant’s federal award history in SAM.gov to ensure sound business practices. An applicant can review and comment on any information in the Responsibility/Qualification records available in SAM.gov.  NIH will consider any comments by the applicant in the Responsibility/Qualification records in SAM.gov to ascertain the applicant’s integrity, business ethics, and performance record of managing Federal awards per 2 CFR Part 200.206 “Federal awarding agency review of risk posed by applicants.”  This provision will apply to all NIH grants and cooperative agreements except fellowships.

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement Section 2.4.4 Disposition of Applications.

Section VI. Award Administration Information

1. Award Notices

A Notice of Award (NoA) is the official authorizing document notifying the applicant that an award has been made and that funds may be requested from the designated HHS payment system or office. The NoA is signed by the Grants Management Officer and emailed to the recipient’s business official.

In accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.

Recipients must comply with any funding restrictions described in Section IV.6. Funding Restrictions. Any pre-award costs incurred before receipt of the NoA are at the applicant's own risk.  For more information on the Notice of Award, please refer to the NIH Grants Policy Statement Section 5. The Notice of Award and NIH Grants & Funding website, see Award Process.

Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the recipient must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

2. Administrative and National Policy Requirements

The following Federal wide and HHS-specific policy requirements apply to awards funded through NIH:

• The rules listed at 2 CFR Part 200, Uniform Administrative Requirements, Cost Principles, and Audit Requirements for Federal Awards.
• All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the terms and conditions in the Notice of Award (NoA). The NoA includes the requirements of this NOFO. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities.
• If a recipient receives an award, the recipient must follow all applicable nondiscrimination laws. The recipient agrees to this when registering in SAM.gov. The recipient must also submit an Assurance of Compliance (HHS-690). To learn more, see the Laws and Regulations Enforced by the HHS Office for Civil Rights website. 
  • HHS recognizes that NIH research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this NOFO.

All federal statutes and regulations relevant to federal financial assistance, including those highlighted in NIH Grants Policy Statement Section 4 Public Policy Requirements, Objectives and Other Appropriation Mandates.

Recipients are responsible for ensuring that their activities comply with all applicable federal regulations.  NIH may terminate awards under certain circumstances.  See 2 CFR Part 200.340 Termination and NIH Grants Policy Statement Section 8.5.2 Remedies for Noncompliance or Enforcement Actions: Suspension, Termination, and Withholding of Support. 

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (HHS) grant administration regulations at 2 CFR Part 200, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the recipients is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the recipients for the project as a whole, although specific tasks and activities may be shared among the recipients and NIH as defined below.

The PD(s)/PI(s) will have the primary responsibility for:

• The PD(s)/PI(s) will have primary responsibility for defining objectives and approaches, and for planning, conducting, analyzing, interpreting, drawing conclusions on their studies, publishing and sharing the results.
• Recipients are responsible for developing and proposing rigorous quantifiable milestones that will be achieved during the project period.
• Recipients will retain custody of and have all rights to the data and therapy developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.
• Recipients are responsible for pursuing patent protection.Patents should include a reference to NIH funding support by including the grant/cooperative agreement number in the patent.
• Recipients are responsible for providing progress reports with completeness that include experimental design with rigor, including assumptions for the design of the experiments, the results of the investigations, interpretations of the results, and for concluding whether milestones have been met or not. In cases when NINDS Research/Scientific staff request raw data, recipient agree to provide the data.
• Recipients agree to allow NINDS staff to join multi-disciplinary project team meetings.
• Recipients agree to participate at least once a year in progress meetings (teleconferences) that are organized by NINDS staff.
• Regarding meetings and interactions with regulatory agencies, Recipients agree to communicate meeting dates and agenda to the NINDS Research/Scientific staff and invite their participation.
• Recipients agree to communicate study reports from CROs, meeting minutes (and associated data packages if applicable), letters and other forms of communications with regulatory agencies, and other authorities, if applicable. 

NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

• Each project will have the support of one or more Project Scientists from NINDS Research/Scientific staff who are assigned an administrative role for the neurological disorder being studied and have expertise in the implementation of Translational Research.
• The NINDS Project Scientists will have substantial scientific/programmatic involvement during conduct of this activity, through technical assistance, advice, and coordination above and beyond normal program stewardship for grants.
• NINDS Project Scientist(s) provides input on the milestones and makes decisions regarding their finalization.
• NINDS Program Officer(s) will be responsible for assessing the progress of the projects toward the specified milestones, and for recommending if further funds should be released to the project.
• NINDS Project Scientist(s), in consultation with the PD/PIs, may add critical experiments that need to be conducted prior to or during the award as an additional milestone(s). In most cases, these studies will be supported by additional funds from NINDS.
• NINDS Program Scientist(s) participates in meetings together with PD/PIs with regulatory agencies related to the funded project.
• NINDS Program Scientist(s) may join in multi-disciplinary project team meetings
• Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.
• NINDS leadership will make decisions on project continuation based on Research/Scientific staff recommendations, programmatic prioritizations and budget considerations. NINDS Research/Scientific staff may consult as necessary with independent consultants with relevant expertise. If justified, future year milestones may be revised based on data and information obtained during the previous year. If, based on the progress report, a funded project does not meet the milestones, funding for the project may be discontinued. In addition to milestones, the decision regarding continued funding will also be based on the overall robustness of the entire data package that adequately allows an interpretation of the results (regardless if they have been captured in the milestones), overall progress, NINDS portfolio balance and program priorities, competitive landscape, and availability of funds.
• NINDS reserves the right to consult subject matter experts to evaluate the program and advise program staff. 

Areas of Joint Responsibility include:

• The PI/PD and NIH Staff will collaborate on c larifying, negotiating and finalizing the milestones and timelines. 

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between recipients and NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual recipient. This special dispute resolution procedure does not alter the recipient's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and HHS regulation 45 CFR Part 16.

3. Data Management and Sharing

Consistent with the 2023 NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

4. Reporting

When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement Section 8.4.1 Reporting.  To learn more about post-award monitoring and reporting, see the NIH Grants & Funding website, see Post-Award Monitoring and Reporting.

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement Section 8.6 Closeout. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 2 CFR Part 200.301.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: https://www.era.nih.gov/need-help (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-480-7075

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

Please direct all inquiries to the NINDS scientific/research contact at lavautetm@ninds.nih.gov.

Timothy LaVaute, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1447
Email: lavautetm@ninds.nih.gov

Zane Martin, Ph.D.
National Institute on Aging (NIA)
Phone: (301) 827-7130
E-mail: zane.martin@nih.gov

Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9223
Email: nindsreview.nih.gov@mail.nih.gov

Chief Grants Management Officer
National Institute of Neurological Disorders and Stroke (NINDS)
Email: ChiefGrantsManagementOfficer@ninds.nih.gov

Jeni Smits
National Institute on Aging (NIA)
E-mail: jeni.smits@nih.gov

Section VIII. Other Information

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 2 CFR Part 200.