FTD Basic Research: Establish new animal and cellular models (Milestone 4.Q)

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Success Criteria

• At least three new animal and/or cell-based models that replicate key aspects human FTD.
• Develop and/or validate at least two in vivo functional assays for FTD translational research, including with endpoints in animal models that are relevant for FTD biology and/or clinical outcomes.
• One new resource that harmonizes critical FTD datasets across disease stages for data sharing to enable translational research.

Summary of Key Accomplishments

In addition to supporting the development of better FTD disease models through our standard grant mechanisms such as NS097273 which uncovered a potential mechanism contributing to neurodegeneration by the FTD-linked mutation in the C9ORF72 gene, the NIH also released a targeted call for applications in this area in 2019 (PAR-19-167).

Examples of funded awards from this program include the characterization of a non-human primate model found to have a spontaneous mutation identical to that found in people with FTD , the development of mouse models that more completely mimic human disease at the genetic level, and the development of "organs-on-a-chip" that put cells grown in the lab in more biologically-relevant conditions with the potential for informing future clinical trials. Future work is progressing to develop models that better inform on specific disease mechanisms, biomarker discovery, and therapeutic target identification in FTD, while model generation is also being expanded to include computational (i.e., big data) models.

The key accomplishments summary is current as of November 2022.

Accomplishments/Implementation Activities

Funding Initiatives

• RFA-NS-19-027: Human Three-Dimensional Cell Model Systems for Alzheimer's Disease-Related Dementias (ADRDs) (UG3/UH3 Clinical Trial Not Allowed)
• PAR-19-167: Development and Validation of Advanced Mammalian Models for Alzheimer's Disease-Related Dementias (ADRD) (R61/R33 Clinical Trial Not Allowed)
• RFA-TR-19-014: "Clinical Trials" on a Chip: Tissue Chips to Inform Clinical Trial Design and Implementation in Precision Medicine (UG3/UH3 - Clinical Trial Not Allowed
• RFA-NS-21-003: Center without Walls for Mechanisms of Neurodegeneration in Frontotemporal Dementia (FTD) (U54 Clinical Trial Not Allowed)
• RFA-NS-21-007: Mechanisms of Selective Vulnerability in LBD and FTD (R01 Clinical Trial Not Allowed)
• NOT-NS-21-041: Characterization of Genomics of Induced Pluripotent Stem Cell Lines for AD/ADRD Research
• NOT-AG-22-039: Request for Information (RFI) for the National Institute on Aging (NIA) Alzheimer’s Disease (AD) and AD-Related Dementias (ADRD) Real-World Data (RWD) Platform
• RFA-NS-22-055: Functional Target Validation for Alzheimer's Disease-Related Dementias (ADRDs) (R61/R33 Clinical Trial Not Allowed)
• RFA-NS-22-056: Treatments for Lewy Body Dementias and Frontotemporal Dementias--Exploratory Clinical Trial (U01 Clinical Trial Required)
• RFA-NS-22-059: Early-Stage Therapy Development for ADRD (R61/R33 Clinical Trial Not Allowed)
• PAR-22-208: Structural Biology of Alzheimer's Disease Related Dementias (ADRDs) Proteinopathies (R01 Clinical Trial Not Allowed)

Research Programs and Resources

• Development and Validation of Advanced Mammalian Models for Alzheimer's Disease-Related Dementias (ADRD) (R61/R33)
• Human Three-Dimensional Cell Model Systems for Alzheimer's Disease-Related Dementias (ADRDs) (UG3/UH3)
• A microphysiologic multicellular organ-on-chip to inform clinical trials in FTD/ALS
• NINDS Human Cell and Data Repository (NHCDR)
• Select projects in FY21
• Select projects funded in FY22

Research Highlights

• Workshop: Gaps and Opportunities for Real-World Data: Stakeholder Workshop

Relevant Recommendations

• 2016 ADRD Summit: Frontotemporal Lobar Degeneration (FTD) Focus Area 1: Basic Science: Pathogenesis and Toxicity, Recommendation 4
• 2022 ADRD Summit: Frontotemporal Lobar Degeneration (FTD) Milestone 5, Priority 1

Related Milestones