# Directly Converted Neurons as a Novel Cellular Model for ALS and FTD

> **NIH NIH R21** · WASHINGTON UNIVERSITY · 2024 · $427,625

## Abstract

Modeling human adult-onset neurodegenerative diseases has been historically difficult, with current
induced pluripotent stem cell (iPSC) models often showing mild phenotypes. While iPSC systems capture
disease-associated genetic variants, generating these cells erases cellular age – a critical component of many
neurodegenerative diseases. An alternative approach is the direct conversion of fibroblasts into neurons, which
preserves the epigenetic age of the starting cells. As such, this approach has been highly successful in modeling
pathologies of various neurodegenerative diseases including tauopathies, Huntington’s disease, and Alzheimer’s
disease.
 In the proposed research project, we will employ direct neuronal conversion as a new tool to investigate
amyotrophic lateral sclerosis (ALS) and associated frontotemporal dementia (FTD). We will initially study familial
ALS cells that have been converted into induced motor neurons and subsequently probe for neurodegenerative
phenotypes. We have already observed stress-induced degeneration in the context of multiple ALS-associated
mutations. Removal of epigenetic age via iPSC conversion and antisense oligonucleotide knockdown of mutant
proteins will establish the specificity of this system. We will further expand our studies to sporadic ALS lines,
investigating neurodegeneration-associated features including nuclear pore deficits. Finally, cells from ALS/FTD
patients will be converted into a cortical identity to provide a novel model for FTD. With these models, we can
interrogate disease mechanisms in ALS/FTD. Further, the development of a tractable, patient-derived in vitro
model of familial and sporadic ALS would represent a considerable breakthrough for the ALS research
community, facilitating the eventual development of novel therapeutic agents.

## Key facts

- **NIH application ID:** 10952676
- **Project number:** 1R21NS139222-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** TIMOTHY M. MILLER
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $427,625
- **Award type:** 1
- **Project period:** 2024-07-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10952676

## Citation

> US National Institutes of Health, RePORTER application 10952676, Directly Converted Neurons as a Novel Cellular Model for ALS and FTD (1R21NS139222-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10952676. Licensed CC0.

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