Translational Efforts to Advance Gene-based Therapies for Ultra-Rare Neurological and Neuromuscular Disorders (U01 - Clinical Trial Optional)

Translational Efforts to Advance Gene-based Therapies for Ultra-Rare Neurological and Neuromuscular Disorders (U01 - Clinical Trial Optional) is sponsored by National Institute of Neurological Disorders and Stroke (NINDS) / National Institutes of Health (NIH). This opportunity supports mission-aligned projects and measurable outcomes.

PAR-25-327: Translational Efforts to Advance Gene-based Therapies for Ultra-Rare Neurological and Neuromuscular Disorders (U01 - Clinical Trial Optional) This funding opportunity was updated to align with agency priorities. Carefully reread the full funding opportunity and make any needed adjustments to your application prior to submission. Department of Health and Human Services Part 1.

Overview Information Participating Organization(s) National Institutes of Health ( NIH ) Components of Participating Organizations National Institute of Neurological Disorders and Funding Opportunity Title Translational Efforts to Advance Gene-based Therapies for Ultra-Rare Neurological and Neuromuscular Disorders (U01 - Clinical Trial Optional) U01 Research Project – Cooperative Agreements March 31, 2025 - This funding opportunity was updated to align with agency priorities.

Carefully reread the full funding opportunity and make any needed adjustments to your application prior to submission. April 4, 2024 - Overview of Grant Application and Review Changes for Due Dates on or after January 25, 2025. See Notice NOT-OD-24-084 .

August 31, 2022 - Implementation Changes for Genomic Data Sharing Plans Included with Applications Due on or after January 25, 2023. See Notice NOT-OD-22-198 . August 5, 2022 - Implementation Details for the NIH Data Management and Sharing Policy.

See Notice NOT-OD-22-189 . Funding Opportunity Number (FON) Companion Funding Opportunity See Section III. 3.

Additional Information on Eligibility . Assistance Listing Number(s) Funding Opportunity Purpose The Ultra-Rare Gene-Based Therapy (URGenT) network supports Investigational New Drug (IND)-enabling studies and planning activities for First-in-Human (FIH) clinical testing of gene-based or transcript-directed therapeutics, such as oligonucleotides and viral-based gene therapies, for ultra-rare neurological or neuromuscular disorders.

The goal of this Notice of Funding Opportunity (NOFO) is to accelerate the development of a promising clinical candidate with robust biological rationale and demonstrated proof of concept (POC) data for the intended approach in a model system relevant to a specified patient population towards an IND filing and the initiation of a clinical trial.

Funding Opportunity Goal(s) To support extramural research funded by the National Institute of Neurological Disorders and Stroke (NINDS) including: basic research that explores the fundamental structure and function of the brain and the nervous system; research to understand the causes and origins of pathological conditions of the nervous system with the goal of preventing these disorders; research on the natural course of neurological disorders; improved methods of disease prevention; new methods of diagnosis and treatment; drug development; development of neural devices; clinical trials; and research training in basic, translational and clinical neuroscience.

Open Date (Earliest Submission Date) Renewal / Resubmission / Revision (as allowed) AIDS - New/Renewal/Resubmission/Revision, as allowed 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.

Required Application Instructions 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 Application Guide and the NOFO) is required and strictly enforced.

Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the 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.

Use the NIH ASSIST system to prepare, submit and track your application online. 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. Workspace to prepare and submit your application and eRA Commons to track your application. Part 1.

Overview Information 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 This Notice Of Funding Opportunity (NOFO) is part of the NINDS Ultra-Rare Gene-based Therapy (URGenT) network.

The mission of URGenT is to support and facilitate the development of gene-based or transcript-directed therapeutic agents with compelling proof-of-concept (POC) data towards First-in-Human (FIH) clinical trials for individuals suffering from severely debilitating or life-threatening ultra-rare neurological diseases.

Specifically, this NOFO will support projects ready to complete Investigational New Drug (IND)-enabling studies and initiate clinical trial planning activities. Successful projects ending with an IND cleared by FDA will be eligible to apply for funding to conduct a FIH clinical trial supported by URGenT network resources.

Applicants must have identified and characterized a clinical therapeutic candidate as supported by robust POC data for the intended therapeutic approach and specific disease.

The objective of this program is to support activities, such as process development and cGMP manufacturing, bioassay development, IND-enabling safety/toxicology and biodistribution studies, and pharmacodynamic and pharmacokinetic (PK/PD) studies, to support the development of a clinical protocol, clinical end-point assay development, assembly of a research IND application, and clinical trial planning and preparedness activities.

This is a milestone-driven cooperative agreement program involving participation of NIH program staff and external subject matter experts (SMEs) in the development of the project plan and monitoring of research progress.

In the United States, a rare disease is defined as a condition that affects fewer than 200,000 people in the United States, based on the definition created by Congress in the Orphan Drug Act of 1983 and adopted by the FDA. Ultra-rare diseases affect substantially fewer people, less than or equal to 6,000; in the U.S., this equates to as few or fewer than one in 50,000 people.

Approximately 95% of rare diseases, including ultra-rare diseases, have no FDA-approved therapeutic available and an estimated 80% of rare diseases have an identified genetic origin. These rare diseases are often due to pathogenic variants in a single gene that alter gene product function.

Many rare and ultra-rare diseases are caused by different pathogenic variants, some of which may be unique to a single individual or to a very small number of individuals. Cumulatively, these diseases represent a large unmet medical need as there are few available effective treatments and limited commercial incentive for therapeutic development.

The NINDS U ltra- R are Gen e-based T herapy (URGenT) network addresses challenges within ultra-rare disease communities by facilitating and supporting the development of tailored therapeutic interventions using established precision medicine platforms for the treatment of individuals diagnosed with a debilitating and often fatal, ultra-rare neurological and/or neuromuscular disease.

Due to the urgency of these individuals’ conditions, rapid intervention in the clinical course of disease is critical. Therefore, the selection of a viable therapeutic approach will require the ability to customize the design, testing, and delivery of these interventions.

URGenT is poised to leverage nonclinical and manufacturing data from one project to another to enable the continuous reassessment of best development practices and clinical outcomes data. This would make a platform approach to therapeutic development more accessible to ultra-rare disease communities and applicable to a broader range of diseases.

In addition, this approach aims to facilitate regulatory harmonization when possible and bring therapeutic interventions to individuals sooner. The design of early-phase clinical trials for gene-based or transcript-directed therapies for ultra-rare patient populations often differs from the design of clinical trials for other types of therapies and relies upon unique collaborations to be successful.

Successful completion of the funded project is expected to lead into a clinical trial, which will be supported by mechanisms targeted to URGenT U01 award recipients through limited competition.

URGenT provides multiple pathways into the network for studies that propose to utilize URGenT infrastructure and resources, culminating in submission of an IND package to the FDA and preparation for a subsequent application to conduct a FIH clinical trial.

One path allows direct access to resources, PAR-25-326 Ultra-Rare Gene-based Therapy (URGenT) Network Resource Access (Clinical Trial Not Allowed)(X01) , for applicants proposing to conduct planning activities and/or limited nonclinical development studies with a clinical candidate therapeutic to generate additional data (as needed) before a pre-Investigational New Drug (IND) meeting or submission of an IND application.

Another path into the network is described in this NOFO and seeks applications proposing to conduct formal IND-enabling activities and clinical trial planning activities. This program will support nonclinical IND-enabling development activities, such as cGMP manufacturing and safety/toxicology studies, of a clinical therapeutic that will lead to the assembly and submission of a research IND application.

Proposals may also include support for the initiation of clinical trial planning activities. PD(s)/PI(s) who have obtained a cleared IND application through the URGenT network, will also have the opportunity to submit applications for conducting a Clinical Trial through the Other Transaction funding mechanism (OTA-24-011 and OTA-24-012).

Funded clinical trials could be conducted within the Network of Excellence in Neuroscience Clinical Trials (NeuroNEXT). Investigators who already have a cleared IND may apply directly to OTA-24-011.

Since a single ultra-rare disease may be caused by many different pathogenic variants, some of which may be unique to a very small numbers of patients, the selection of a viable therapeutic approach will require the ability to customize the design, testing, and delivery of these interventions.

The following gene-based or transcript-directed therapeutic modalities are potentially amenable to the development of precision therapeutic approaches: Oligonucleotide-based approaches Oligonucleotides offer the potential to treat many genetic diseases by either ameliorating splicing pathogenic variants, promoting exon skipping, or targeting dominantly acting transcripts.

Oligonucleotide-based interventions for neurological diseases include but are not limited to antisense oligonucleotides (ASOs), small interfering RNAs (siRNA) or short hairpin RNAs (shRNA).

Viral vector-based approaches Viral-based therapeutics (e.g., Adeno-Associated Viruses (AAVs)) and other potential vector and/or delivery vehicles, containing the correct gene construct, may be used as an in vivo therapeutic approach to replace or knockdown expression of a disease-causing gene. Cell therapy-based approaches Gene-modified cell-based therapies may be used for an ex-vivo therapeutic approach.

Only gene targeting cell therapies will be considered for this program. Genome editing-based approaches Several platform technologies such as Zinc Finger Nucleases (ZFNs), Transcription Activator-like Effector-based Nucleases (TALENs) and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-CRISPR-associated protein systems have emerged as promising approaches to correct disease-causing pathogenic variants.

Other gene-based therapeutic approaches Small-molecule drugs that can selectively bind RNA and modulate pre-mRNA splicing have potential as a treatment strategy for human genetic diseases. Therefore, these nucleic acid targeted small molecules have therapeutic potential in the treatment of some ultra-rare neurological and neuromuscular diseases.

Applications submitted in response to this NOFO will utilize a milestone-driven cooperative agreement (U01) mechanism to conduct nonclinical IND-enabling studies, file a research IND, and prepare for a clinical trial. Applications are expected to address objectives for both the nonclinical and clinical trial preparedness milestones and are strongly encouraged to use project management principles as appropriate.

The nonclinical and clinical trial planning milestones combined are generally expected to be completed in not more than 3 years. For each project provided access to the network, the NINDS will assemble a customized Multi-disciplinary Project Team (MPT). The MPT will include NINDS Program Staff plus members of the Program Director/Principal Investigator’s (PD/PI) team and additional SME consultants.

The MPT will establish an overall strategy for the project with milestones, including a plan and timeline, and will develop and coordinate activities across different URGenT contract resources. Leveraging NINDS Contract Research Resources URGenT will provide successful applicants with access to therapeutic development resources and SME consultants.

These NINDS contract resources will assist investigators to rapidly advance patient-customized therapeutics through manufacturing, nonclinical toxicology testing, and evaluation in clinical studies. A list of current URGenT resources can be found at http://www. ninds.

nih. gov/Current-Research/Research-Funded-NINDS/Translational-Research/urgent-network . Applicants that have rational POC data obtained through scientifically rigorous experimentation for a viable gene-based or transcript-directed therapeutic clinical candidate for a specified ultra-rare disease patient population that supports nonclinical and clinical development are encouraged to apply.

A patient or patient population has been identified with an ultra-rare neurological or neuromuscular syndrome due to a defined pathogenic variant. A sufficient understanding of the pathogenic variant exists and is the basis of the proposed therapeutic approach that will allow for a plausible intervention strategy in the specified patient population.

The POC data demonstrated scientific rigor and established the feasibility and rationale for the use of the gene-based therapeutic candidate, as evidenced by an effective dose range using appropriate assays.

The PD/PI has identified a gene-based or transcript-directed therapeutic clinical candidate supported by a substantial body of in vivo and/or in vitro data demonstrating that testing of the efficacy and preliminary safety of the candidate therapeutic in one or more model systems can mimic the planned clinical trial scenario.

The PD/PI has scheduled a Pre-IND meeting or has held formal pre-IND discussions with the relevant FDA division regarding a future regulatory path and other requirements needed by the submission date of the application.

The PD/PI is able to provide an outline of the future clinical trial, detailing aspects such as the proposed study design, study duration, study population, primary outcomes and safety measures, and data analysis methods.

This NOFO encourages applications proposing plans for nonclinical development in parallel with clinical trial planning activities, including, but not limited to: Manufacturing (i.e., technology transfer, process development, analytical methods development, small-scale, engineering runs, and clinical scale cGMP manufacturing of the biological therapeutic at a CMO to be used for IND-enabling studies and FIH clinical trial).

Qualification and/or validation of any bioassays required for IND-enabling nonclinical and clinical studies. Non-clinical and non-interventional clinical studies and to support, for example, drug efficacy biomarker qualification and/or validation. IND-enabling efficacy studies with intended clinical product.

IND-enabling biodistribution, safety, and toxicology testing in relevant animal model(s) for proposed indication in compliance with Good Laboratory Practices (GLP). Assessment of off-target effects as appropriate for the type of intervention under development Evaluation utility of efficacy biomarkers associated with the therapeutic target or disease.

Completion of all clinical trial planning activities necessary for implementation of future clinical trial, including but not limited to IRB approval. Preparation and submission of an IND package to FDA. Because therapeutics development is inherently high risk, it is expected that there may be attrition as projects progress.

Clear Go/No-Go milestones will be established by the MPT. The MPT will establish an overall strategy for the project with milestones, including a plan and timeline, to develop and coordinate activities across different URGenT contract resources.

These milestones will be based upon a template outline of achievements necessary to progress through therapeutic development but will be tailored to the specific therapeutic and its intended disease indication.

Successful continuation of projects will be contingent upon: Successful achievement of the milestones Overall feasibility of project advancement, considering data that may not have been captured in the milestones Additional resources needed Clinical Trial Information For applications proposing a clinical trial, note the following definitions and restrictions for this funding announcement: NIH defines clinical trials are research studies in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes.

For this funding announcement, only the following types of clinical trials will be supported: Mechanistic trials , defined as studies designed to understand a biological or behavioral process, the pathophysiology of a disease, or the mechanism of action of an intervention (i.e., HOW an intervention works, but not IF it works or is safe).

Clinical trials that seek to answer specific questions about safety, tolerability, clinical efficacy, effectiveness, clinical management, and/or implementation of pharmacologic, behavioral, biologic, surgical, or device (invasive or non-invasive) interventions, preventive, therapeutic, and services interventions will not be supported under this Translational Efforts to Advance Gene-based Therapies for Ultra-Rare Neurological and Neuromuscular Disorders (U01) NOFO.

Safety and efficacy trials as part of the URGenT network could be supported through a separate funding mechanism including but not limited to the NeuroNEXT network. Please refer to the Ultra-rare Gene-based Therapy (URGenT) Clinical Trials Conducted within NeuroNEXT Research Opportunity Announcement (ROA) OTA-24-011 and OTA-24-012.

For further clarification on how NIH defines the different types of clinical trials, please refer to the following resources: NOT-OD-15-015: Notice of Revised NIH Definition of “Clinical Trial” NIH's Definition of a Clinical Trial Decision Tree for NIH Clinical Trial Definition NIH Definition of Clinical Trial Case Studies Applicants are strongly advised to consult with NINDS Scientific/Research staff prior to submitting an application with human subjects to determine the appropriate funding opportunity.

Applications Not Responsive to this NOFO: Nonresponsive applications include those that involve any of the following activities: Ultra-rare diseases studies for diseases or disorders outside the mission of NINDS Screening to identify and/or optimize lead therapeutic agents Nonclinical studies of disease mechanism or therapeutic mechanism of action studies Development of diagnostics or diagnostic devices Research focused entirely on biomarkers and/or clinical endpoint development Early-stage projects without significant POC data that have not identified a lead clinical candidate ready for IND-directed development Clinical trials that seek to answer specific questions about safety, tolerability, clinical efficacy, effectiveness, clinical management, and/or implementation of pharmacologic, behavioral, biologic, surgical, or device (invasive or non-invasive) interventions, preventive, therapeutic, and services interventions Nonresponsive applications will be administratively withdrawn prior to review.

Intellectual Property Rights and Confidentiality This program is structured so that the recipient institution retains their assignment of intellectual property (IP) rights and gains assignment of IP rights from the URGenT contractors (and thereby control the patent prosecution and licensing negotiations) for candidate therapeutics developed in this network.

It is expected that the recipient institution will take responsibility for patent filings and maintenance and licensing efforts toward eventual commercialization.

The PD/PI is expected to work closely with technology transfer/business development officials at his or her institution to ensure that royalty agreements, patent filings, and all other necessary IP arrangements are completed in a timely manner and that commercialization plans are developed and updated over the course of the project.

Award recipients will be encouraged to identify and foster relationships with potential licensing and commercialization partners early in the drug development process, consistent with the goals of URGenT. All SMEs will treat information as confidential and not disclose data or their assessments to third parties.

Applicants to this NOFO are strongly encouraged to consult with the Scientific/Research staff for the area of science for which they are planning to develop an application. Early contact, at least six (6) weeks prior to the next application receipt date is strongly encouraged as it provides an opportunity for NINDS staff to discuss the scope, goals, and resources needed of the project and to provide guidance to applicants.

Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs. See Section VIII. Other Information for award authorities and regulations.

Section II. Award Information Cooperative Agreement: A financial assistance mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities.

See Section VI. 2 for additional information about the substantial involvement for this NOFO. Application Types Allowed The OER Glossary and the How to Apply Application Guide provide details on these application types.

Only those application types listed here are allowed for this NOFO. Optional: Accepting applications that either propose or do not propose clinical trial(s). Need help determining whether you are doing a clinical trial?

Funds Available and Anticipated Number of Awards The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications. Application budgets are not limited but need to reflect the actual needs of the proposed project. The scope of the proposed project should determine the project period.

The project period must not exceed 3 years. 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 Higher Education Institutions Public/State Controlled Institutions of Higher Education Private Institutions of Higher Education 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 (Other than Small Businesses) City or Township Governments Special District Governments Indian/Native American Tribal Governments (Federally Recognized) Indian/Native American Tribal Governments (Other than Federally Recognized).

Eligible Agencies of the Federal Government U.S. Territory or Possession 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 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 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 the NIH Grants Policy Statement Section 2.

3. 9. 2 Electronically Submitted Applications .

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.

Eligible Individuals (Program Director/Principal Investigator) 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.

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. 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 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 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. For this specific NOFO, the Research Strategy section is limited to 30 pages.

Instructions for Application Submission 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. SF424(R&R) Project/Performance Site Locations All instructions in the How to Apply-Application Guide must be followed.

SF424(R&R) Other Project Information All instructions in the How to Apply-Application Guide must be followed. Additional Required Pre-IND Meeting Minutes Documents: As part of the application submission, applicants are required to include any available minutes from pre-IND meetings with the FDA. These minutes should be submitted under the "Other Attachments" section of the application.

This requirement is essential to provide context on prior discussions with regulatory authorities and to assess the alignment of the proposed research with regulatory feedback. Please ensure that the minutes are detailed and reflect all points of discussion and any recommendations or concerns raised. Please make sure that these points have been addressed in the proposed research plan.

Please upload the document as “Other Attachments_Pre-IND Meeting Minutes_Contact PI Name”. If the minutes from the pre-IND meeting with the FDA are not available at the time of submission, please explain any FDA feedback received and provide the minutes as soon as they are available (refer to Post-Submission Material in this section).

Intellectual Property Documentation: In alignment with the intellectual property rights and confidentiality provisions of this program, applicants are required to submit relevant, comprehensive intellectual property documentation as part of their application. This includes: Details of Existing IP : Information on any existing patents, patent applications, or other IP filings related to the proposed research.

Plans for IP Management : A description of the plans for patent filings, maintenance, and licensing, including how these efforts will be managed and coordinated with technology transfer or business development officials. Commercialization Strategy : An outline of the commercialization plans, including strategies for fostering relationships with potential licensing and commercialization partners.

This information is crucial for evaluating the potential for commercialization, ensuring that IP issues are appropriately addressed, and evaluating the applicant’s readiness to manage IP and commercialization efforts effectively throughout the project.

Please include a summary of the IP status and any agreements or licenses that may impact the project, along with a copy of any pertinent documents and ensure that they are named as “Other Attachments_IP Documentation_Contact PI Name”. SF424(R&R) Senior/Key Person Profile All instructions in the How to Apply- Application Guide must be followed.

The proposed nonclinical activities and clinical trial planning activities must be directed by PD(s)/PI(s), or including a co-PD/PI, with experience in the conduct of studies leading up to IND submissions and clinical trials for individuals with ultra-rare disorders. Such experience must be documented in the biosketch, including timely submission of primary publications from previous studies and/or clinical trials.

The application should also indicate the prior experience of other study team members. All instructions in the How to Apply- Application Guide must be followed. All instructions in the How to Apply-Application Guide must be followed.

PHS 398 Cover Page Supplement 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: Preliminary Studies: Present the major findings of the nonclinical studies that led to the pre-IND meeting with the relevant FDA division.

Ensure that the data supporting the proposed study meets the NIH scientific rigor guidelines (NOT-OD-15-103) . If nonclinical data (e.g., animal studies) do not meet the rigor guidelines, the applicant should discuss the limitations of the data and any plans to address those gaps in knowledge through the current study design. Discuss the potential biases and/or challenges in the feasibility of the study and how they will be addressed.

Specific Aims: The Specific Aims section should include Aims delineated for both the nonclinical and clinical trial planning activities of the project.

Research Strategy: The Research Strategy must include the entire scope of the project and provide a clear description of requested activities and/or services including: Clinical Impact (Significance) Biological Rationale and Profile of the Therapeutic Modality (Significance) Early or Late Strategy (Approach) Clinical Impact (Significance): 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.

Provide a Target Product Profile (TPP) that