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.

Public Health Relevance

Frontotemporal dementia (FTD) and the related disease amyotrophic lateral sclerosis (ALS) are currently untreatable neurodegenerative conditions. This application develops and validates a novel three dimensional human iPSC based microphysiologic model of cortex from patients with FTD/ALS due to mutations in the C9orf72 gene, to identify novel translatable biomarkers for assessment of candidate therapeutics.

National Institute of Health (NIH)
National Center for Advancing Translational Sciences (NCATS)
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Special Emphasis Panel (ZTR1)
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Tagle, Danilo A
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Cedars-Sinai Medical Center
Los Angeles
United States
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