Functional Target Validation for Alzheimer's Disease-Related Dementias (R61/R33 Clinical Trial Not Allowed) | RFA NS 25 011

Opportunity Information: Apply for RFA NS 25 011

The NIH funding opportunity titled "Functional Target Validation for Alzheimer's Disease-Related Dementias (R61/R33 Clinical Trial Not Allowed)" (RFA-NS-25-011) supports projects that move beyond target discovery and focus on proving, in a rigorous and reproducible way, whether newly identified therapeutic targets actually matter in disease biology. The central goal is to de-risk future drug development by generating solid functional evidence that changing a target's activity or expression produces meaningful and consistent effects in relevant experimental systems. It is aimed at accelerating the path from human-data-driven target identification to credible, translationally useful validation packages that can justify later-stage therapy development efforts.

A key requirement is that the target or pathway being validated must already be supported by human evidence, specifically from tissue expression data or human genetics generated in human samples. In other words, this program is not for purely hypothesis-driven targets without a human anchor; it is designed for targets that emerged from human datasets and now need functional testing to determine whether they are causal, modulatory, or simply correlated with disease. The validation work proposed is expected to be comprehensive, meaning applicants should do more than a single assay or a single model and instead build a cohesive plan that tests biological consequences of modulating the target in systems that can speak to disease mechanisms.

The award uses a two-phase R61/R33 structure. The first phase (R61) lasts up to two years and functions as a feasibility and development stage. During this period, the project should create or adapt the tools needed to manipulate the target (for example, genetic perturbation strategies, pharmacologic or biologic modulators, or other customized approaches) and establish the models and protocols required to read out functional consequences. This includes developing and optimizing in vitro and/or in vivo disease models and the measurement methods needed to monitor downstream biology when the target is increased, decreased, or otherwise modulated. The emphasis in R61 is on building the technical foundation and demonstrating that the proposed perturbation and measurement strategy is workable and informative.

The second phase (R33) is designed to deliver careful, reproducible validation results once feasibility is established. In R33, the work shifts toward robust measurement and cross-validation, with explicit expectations around rigor and reproducibility consistent with NIH guidelines. A distinguishing feature of this NOFO is the strong expectation for collaboration among independent laboratories, with cross-lab testing of the target modulation effects using different modalities and approaches. The intent is to reduce the chance that a promising result is limited to one lab, one assay, or one experimental setup, and instead produce findings that hold up under independent replication and complementary validation strategies.

This opportunity is not limited to classic Alzheimer's disease alone and is explicitly broadened to the Alzheimer's disease-related dementias (ADRD) spectrum. Covered disorders include frontotemporal degeneration (FTD), Lewy body dementias (LBD) including dementia with Lewy bodies (DLB), Parkinson disease dementia (PDD), vascular contributions to cognitive impairment and dementia (VCID), and mixed dementias. The inclusion of mixed dementias and multiple-etiology diagnostic challenges highlights that applicants can address targets relevant to overlapping pathologies and complex clinical presentations, as long as the project remains centered on functional target validation rather than clinical testing.

Clinical trials are not allowed under this NOFO, so the proposed studies must remain in preclinical or mechanistic domains and avoid interventional studies in human participants that meet the NIH definition of a clinical trial. The funding instrument is a grant, and it falls under NIH health research activities with CFDA numbers 93.853 and 93.866. The original closing date listed is 2024-11-08, and the opportunity was created on 2024-05-31. While the listing includes an "AwardCeiling" field, no ceiling amount is specified in the provided source information.

Eligibility is broad across many U.S.-based organization types, including state, county, and local governments; public and private institutions of higher education; federally recognized tribal governments; certain tribal organizations; public housing authorities; nonprofits with or without 501(c)(3) status (other than institutions of higher education); for-profit organizations (other than small businesses); and small businesses. The NOFO also highlights a range of institution types often emphasized for inclusive participation, such as Historically Black Colleges and Universities (HBCUs), Hispanic-serving Institutions, Tribally Controlled Colleges and Universities (TCCUs), Alaska Native and Native Hawaiian Serving Institutions, and Asian American Native American Pacific Islander Serving Institutions (AANAPISI). Faith-based or community-based organizations and U.S. territories or possessions are also included among eligible applicant categories in the provided text.

Foreign organizations are not eligible to apply, and non-domestic components of U.S. organizations are not eligible. However, "foreign components" as defined in the NIH Grants Policy Statement are allowed, which typically means a U.S. applicant organization can include a clearly justified foreign element of the project under NIH rules, even though the applicant institution itself must be domestic. Overall, the opportunity is built for teams that can connect human-evidence targets to rigorous functional tests, develop the right perturbation and readout toolkit in R61, and then deliver reproducible, cross-laboratory validation outcomes in R33 that make later translational investments safer and faster.

• The National Institutes of Health in the health sector is offering a public funding opportunity titled "Functional Target Validation for Alzheimer's Disease-Related Dementias (R61/R33 Clinical Trial Not Allowed)" and is now available to receive applicants.
• Interested and eligible applicants and submit their applications by referencing the CFDA number(s): 93.853, 93.866.
• This funding opportunity was created on 2024-05-31.
• Applicants must submit their applications by 2024-11-08. (Agency may still review applications by suitable applicants for the remaining/unused allocated funding in 2026.)
• Eligible applicants include: State governments, County governments, City or township governments, Special district governments, Independent school districts, Public and State controlled institutions of higher education, Native American tribal governments (Federally recognized), Public housing authorities/Indian housing authorities, Native American tribal organizations (other than Federally recognized tribal governments), Nonprofits having a 501 (c) (3) status with the IRS, other than institutions of higher education, Nonprofits that do not have a 501 (c) (3) status with the IRS, other than institutions of higher education, Private institutions of higher education, For-profit organizations other than small businesses, Small businesses, Others.

Apply for RFA NS 25 011

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