# Development of an UNC13A antisense oligonucleotide treatment for ALS and FTD

> **NIH NIH R44** · ACURASTEM, INC. · 2024 · $1,279,990

## Abstract

Development of an UNC13A antisense oligonucleotide treatment for ALS and FTD
Project Summary
Background: In 97% of ALS cases, and roughly half of FTD cases, TAR DNA-binding protein 43 (TDP-43) is
lost from the nucleus to the cytoplasm, where it forms into aggregates. A major function of TDP-43 in the
nucleus is to repress cryptic exon (CE) inclusion during RNA splicing. Recent studies have shown that a CE is
included in UNC13A mRNA when TDP-43 is depleted from the nucleus of neurons resulting in a loss of
UNC13A protein. UNC13A single nucleotide polymorphisms (SNPs) are among the strongest hits associated
with ALS and FTD in human GWAS studies. The CE is located in the same intronic region as the primary risk
SNP. The risk SNP exacerbates the UNC13A CE inclusion - ALS / FTD patients with both risk alleles have
more CE inclusion than patients with one risk allele, who have more CE inclusion than patients with the
non-risk alleles. Similarly, risk SNP carriers have a dose-dependent reduction in survival. This additive risk
strongly suggests that targeting UNC13A to suppress the CE inclusion could have a substantial therapeutic
benefit. Since nearly all ALS patients have TDP-43 pathology, such a treatment would benefit them and not be
limited to SNP carriers. UNC13A plays a critical role in synaptic transmission and is essential for synaptic
vesicle release at most excitatory synapses and neuromuscular junctions. Among all the genes known to be
dysregulated by the loss of TDP-43 from the nucleus, only UNC13A has such strong genetic validation. Altered
STMN2 expression in the context of TDP-43 depletion is a hallmark of ALS / FTD, yet no link between ALS
risk and STMN2 variants has been established. Thus, UNC13A targeting treatments should be prioritized for
rapid advancement into clinical proof of concept studies.
 AcuraStem’s mission is to identify targets that rescue multiple forms of ALS / FTD. Thus we have
established patient-specific ALS / FTD disease models of both genetically defined and sporadic diseases. We
show in these models that cortical neurons derived from an ALS patient with the risk SNP have more UNC13A
CE inclusion than neurons derived from ALS patients with non-risk alleles. When we depleted TDP-43 in
patient-derived neurons using short interfering RNAs (siRNA) it induced a robust inclusion of CEs and reduced
normal UNC13A mRNA and protein levels across many patient lines. Antisense oligonucleotides (ASOs) are
an attractive approach for genetic targets in the CNS like UNC13A with several successes, including nusinersen
for spinal muscular atrophy (SMA) and tofersen, soon to be approved for SOD1-ALS. We used our proprietary
ASO design platform to synthesize >125 ASOs and identified several novel ASO sequences that potently
blocked CE inclusion and restored UNC13A mRNA and protein levels. AcuraStem is uniquely positioned with
potent UNC13A ASO candidates that can be advanced towards the clinic for ALS and FTD.
Objectives & Impact: T...

## Key facts

- **NIH application ID:** 10914945
- **Project number:** 5R44NS132698-02
- **Recipient organization:** ACURASTEM, INC.
- **Principal Investigator:** Wen-Hsuan Chang
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,279,990
- **Award type:** 5
- **Project period:** 2023-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10914945

## Citation

> US National Institutes of Health, RePORTER application 10914945, Development of an UNC13A antisense oligonucleotide treatment for ALS and FTD (5R44NS132698-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10914945. Licensed CC0.

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