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NIH Early-Stage Therapy Development for Alzheimer’s Disease-Related Dementias

The Early-Stage Therapy Development for Alzheimer’s Disease-Related Dementias encourages early-stage development of novel small molecule or biologic therapeutics for NINDS mission-relevant Alzheimer’s Disease-Related Dementias (ADRDs): frontotemporal degeneration (FTD, including Pick’s disease and progressive supranuclear palsy), Lewy body dementias (LBD; including dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD), vascular contributions to cognitive impairment and dementia (VCID), and multiple etiology dementias (MED).

Donor Name: National Institutes of Health (NIH)

State: All States

County: All Counties

U.S. Territories: American Samoa, Guam, Commonwealth of Puerto Rico, Commonwealth of Northern Mariana Islands, U.S. Virgin Islands

Type of Grant: Grant

Deadline: 08/08/2023

Size of the Grant: $500,000

Grant Duration: 5 years

Details:

This NOFO covers four stages of early therapy discovery/development with each stage gated by go/no-go milestones. Applicants may enter the program at the stage appropriate to their research. This NOFO supports research to enable competitive follow-on applications that meet the entry criteria for the Blueprint Neurotherapeutics Network, Blueprint Biologics, or other similar later-stage translational programs.

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 ADRD research priorities for advancing the state-of-the-science toward meeting Goal 1 of the National Plan. One priority is to develop, validate, and refine therapeutic targets through the creation, validation, and use of pre-clinical and translational tools and resources.

This NOFO supports early development of novel small molecule, or biologic therapeutics to targets that are novel, but validated for ADRDs. It is anticipated that successful applicants will be able to meet the entry criteria for the Blueprint Neurotherapeutics Network for Small Molecules, Blueprint for Biologics or other similar later-stage translational programs at the end of the R61/R33 grant period.

This Notice of Funding Opportunity (NOFO) uses the R61/R33 Phased Innovation Award mechanism. The R61 phase supports progression through the following research stages: Stage 1) development of in vitro and/or ex vivo assays that can support therapeutic screening efforts, Stage 2) screening efforts to identify and characterize potential therapeutic agents, and Stage 3) therapeutic optimization, pharmacodynamic and pharmacokinetic studies. The R33 phase Stage 4 supports in vivo efficacy studies in an animal model of disease.

R61 Stage 1: development of in vitro and/or ex vivo assays that can support therapeutic screening efforts

This Stage is intended to support development of new in vitro and/or ex vivo assays, in support of Stage 2. These activities include (but are not limited to) set up and optimization, standardization, and validation of measures of fundamental cellular/molecular events such as binding, bioactivity at the target, and activity downstream of the target relevant to neurological function. The proposed assays must have sufficient throughput for iterative screening of potential therapeutic agents such as small molecules and biologics, if high-throughput screening is proposed in Stage 2.

Examples of activities for this Stage include but are not limited to:

  • Development and validation of assay(s) (including phenotypic assays) to support a succinct testing funnel.
  • Development of in vitro or ex vivo potency/efficacy assays designed to indicate the specific ability of an agent to achieve a desired biological effect, for example: structural changes that may impact product quality, stability and efficacy.
  • Development of assays to evaluate cellular uptake, engagement, infection, aggregation, downstream functional measures in vitro or ex vivo, purity and specificity. Assays to measure DNA, RNA, and protein levels of either endogenous genes or delivered products, downstream in vitro or ex vivo functional read-outs, viral titer, viral particle load stability and specificity.
  • Assay development and/or optimization for High-Throughput Screening (HTS).
  • A combination of assays may be developed to demonstrate relevant biological activity when a single assay may not provide adequate measurement of overall potency due to a complex mechanism of action or multiple activities of a preliminary therapeutic agent.

R61 Stage 2: screening efforts to identify and characterize potential therapeutic agents

This Stage is intended to support screening efforts to identify and characterize novel therapeutic agents for ADRD. This Stage also includes design and preparation of a focused set of therapeutic agents, and characterization thereof.

Examples of activities for this Stage include but are not limited to:

  • HTS, comprising screening of large libraries for activity against biological targets via the use of automation, miniaturized assays and large-scale data analysis.
  • Preparation and screening of select series of therapeutic agents using for example medicinal chemistry or biological processes.
  • Preparation of therapeutic agent(s) and confirmation of structure, sequence or biological characteristics.
  • Development and selection of cell lines/vectors to produce bioactive agents with acceptable potency and stability, cellular uptake/engagement, or secondary in vitro functional assays.
  • Assessment of therapeutic agent’s properties using computational analysis and early physicochemical measurements, polar surface area, solubility, cell permeability and efflux.
  • Assessment of initial in vitro parameters such as absorption, distribution, metabolism, and excretion (ADME).
  • Assessment of potential off-target activities.
  • Optimization of therapeutic agent(s) for future in vivo testing.

R61 Stage 3: therapeutic optimization, pharmacodynamic and pharmacokinetic studies.

Prior to preclinical efficacy studies, a combination of in vivo efficacy, pharmacodynamic (PD) and pharmacokinetic (PK) measures are warranted to determine the feasibility of candidate therapeutic agent(s) to serve as a starting point for further therapy development. Combined measures of PK and PD greatly increase the understanding of the in vivo efficacy of the therapeutic agent(s) by exploring the relationship between the concentration of the agent(s) at the site of action and the resulting efficacy measures. PK measurements reflect the body’s effect on the absorption, metabolism, distribution and excretion of the therapeutic agent. For some biologic modalities, traditional PK might not apply; such applicants should still aim to measure the kinetics and distribution as needed for therapeutic development. For the purposes of this NOFO, in vivo efficacy measures reflect the effects of the therapeutic agent on endpoints that are closely tied to the desired clinical endpoints, but do not necessarily reflect target engagement. While PD measures may also reflect the effects of the therapeutic agent on endpoints closely tied to the desired clinical endpoint, they must also reflect target engagement

Pharmacodynamic studies may include but are not limited to determination of 1) target occupancy (e.g., binding) and 2) proximal target activation (i.e., signal transduction, neurotransmission, protein synthesis, and gene regulation and transcription).

Examples of activities for this Stage include but are not limited to:

  • Preparation of the therapeutic agent(s) to support proposed activities.
  • Characterization of therapeutic agent(s). This could include for example, confirmation of purity, stability, in vitro absorption, distribution, metabolism, and excretion, in vitro potency and selectivity.
  • Studies to develop dosage form(s) to support proposed PD measures and/or in vivo studies.
  • Pharmacokinetics studies to determine direct or indirect therapeutic agent levels. For gene and cell therapy, these include characterization of gene copy numbers or tropism in tissues or cell engraftment.
  • Studies to confirm that therapeutic agent(s) reach and engage the target site (directly or indirectly) at a concentration that exceeds in vitro pharmacological potency over the desired period.
  • Studies to confirm selectivity of the therapeutic agent(s).
  • Limited studies to identify potential pharmacodynamic biomarkers specific for the purposes of developing the therapeutic agent(s) to be tested in the application.
  • Studies to inform design and refinement of the PD measure and/or in vivo efficacy models and testing procedures, including examination of model variability to estimate sample size, calibration of the model according to positive and negative controls, along with the age, time course and window of disease that are relevant for therapeutic testing.

R33 Stage 4: in vivo efficacy studies

This stage supports in vivo efficacy studies to demonstrate that proposed therapeutic agent(s) have sufficient biological activity to warrant further development to treat ADRD.

Examples of activities for this Stage include but are not limited to:

  • Rigorously conducted pharmacodynamic and/or in vivo efficacy studies with chemically and biologically characterized therapeutic agent(s) including positive and negative controls, as appropriate.
  • Dose (exposure)-response activity with a route of administration relevant to future clinical studies.
  • Studies correlating pharmacokinetic and pharmacodynamics measures (PK/PD).
  • Preliminary studies to assess early safety (not including IND-enabling toxicity).
  • Validation and replication studies to confirm observed results.

Funding Information

  • NIH intends to commit a total budget of up to $3,750,000 per year to fund up to five awards, contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.
  • Application budgets are limited to no more than $500,000 in direct costs per year and need to reflect the actual needs of the proposed project.

 Project Period

  • The total project period for a combined R61/R33 application submitted in response to this NOFO may not exceed five years, with no more than four years for the R61 phase and no more than three years for the R33 phase. 

Eligibility Criteria

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

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

Foreign Institutions

  • Non-domestic (non-U.S.) Entities (Foreign Institutions) 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.

For more information, visit Grants.gov.

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