# A microphysiologic multicellular organ-on-chip to inform clinical trials in FTD/ALS

> **NIH NIH UH3** · CEDARS-SINAI MEDICAL CENTER · 2024 · $697,574

## Abstract

Project Summary/Abstract
Frontotemporal dementia (FTD) is a common dementia syndrome in patients under age 65, while
amyotrophic lateral sclerosis (ALS) is a progressive degeneration of motor neurons causing death
from respiratory failure within 3-5 years. FTD and ALS represent a spectrum of
neurodegeneration, with significant overlap clinically, pathologically, and genetically. Aggregates
of TDP-43 are the defining pathology of FTD (FTLD-TDP variant) and ALS, and the most common
genetic cause of both FTD and ALS are repeat expansions in the C9orf72 gene. C9orf72 is
expressed in multiple cell types in the brain including in microglia and neurons, and there is strong
evidence that interaction between different cell types are necessary for pathogenesis of FTD/ALS.
We will develop a microphysiologic system (MPS) using human induced pluripotent stem cell
(iPSC) derived cortical neurons, astrocytes and microglia on a 3D platform that includes a blood
brain barrier (BBB) component to model C9-FTD/ALS forebrain on a chip. Our goal in this project
is to develop a highly reproducible and translatable in vitro human cell-based model of FTD/ALS
to discover and validate translatable biomarkers for preclinical efficacy testing, and to assist in
patient stratification for clinical trial design. We propose to i) develop and validate robustness of
a 3D forebrain MPS incorporating cortical neurons and astrocytes, microglia and brain
microvascular endothelial cells (BMECs) derived from human iPSCs; ii) utilize FTD and ALS
patient derived forebrain MPS's to identify disease biomarkers in C9orf72 related FTD/ALS; iii)
cross validate biomarkers identified using clinical data and pathology from C9-FTD/ALS patients
used to seed the chips, and iv) assess and stratify responses of C9-FTD/ALS fMPS models to
five different therapeutics entering early phase clinical trials ranging from antisense
oligonucleotides to small molecule modulators of mitochondrial function, endocytic trafficking and
cell death pathways.

## Key facts

- **NIH application ID:** 10849733
- **Project number:** 5UH3TR003264-05
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** CLIVE Niels SVENDSEN
- **Activity code:** UH3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $697,574
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10849733

## Citation

> US National Institutes of Health, RePORTER application 10849733, A microphysiologic multicellular organ-on-chip to inform clinical trials in FTD/ALS (5UH3TR003264-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10849733. Licensed CC0.

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