# Development of a SYF2 antisense oligonucleotide treatment for ALS and FTD

> **NIH NIH R44** · ACURASTEM, INC. · 2024 · $1,402,110

## Abstract

Development of a SYF2 antisense oligonucleotide treatment for ALS and FTD
Project Summary
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are complex diseases that result from many
diverse genetic etiologies. Although therapeutic strategies that target specific causal mutations (e.g. C9ORF72 antisense
oligonucleotides (ASOs)) may prove effective against individual forms of ALS or FTD, these approaches cannot address
the vast majority of cases that have unknown genetic etiology. Moreover, given the large number of different genes that
likely contribute to ALS and FTD and the fact that each genetic form is relatively rare, this strategy may be difficult to
implement for all cases. Thus, there is a pressing need for new therapeutic strategies that rescue multiple forms of ALS
and FTD, particularly those with unknown genetic etiologies.
 A hallmark pathological feature of ALS and FTD is the depletion of TAR DNA-binding protein 43 (TDP-43) from the
nucleus of neurons in the brain and spinal cord to the cytoplasm where it aggregates into insoluble inclusion bodies in
>95% of ALS cases and ~45% of FTD cases post mortem. While studies suggest that these neuronal TDP-43 aggregates
drive neurodegeneration58, reduction in TDP-43 from the nucleus also alters the splicing or expression levels of more than
1,500 RNAs9, including disease hallmarks such as STMN2. Thus, both the loss of TDP-43 from the nucleus and its
aggregation in the cytoplasm contribute to neurodegeneration, and it is critical to develop treatments that address both
aspects of this challenging pathology.
 We found that suppressing the gene encoding the spliceosome-associated factor SYF2 alleviates TDP-43 aggregation
and mislocalization, improves TDP-43 activity, and rescues C9ORF72 and sporadic ALS survival. Moreover, Syf2
suppression ameliorates neurodegeneration, neuromuscular junction loss, and motor dysfunction in TDP-43 mice. Mice
with one loss-of-function copy of Syf2 are healthy and humans carrying a loss-of-function SYF2 allele are not affected by
pediatric diseases or known to be affected by disease in adulthood. Thus, suppression of spliceosome-associated factors
such as SYF2 is a promising and broadly-effective genetic target for ALS and FTD.
 Antisense oligonucleotides (ASOs) are an attractive approach for genetic targets in the central nervous system (CNS)
like SYF2 because they can be injected directly into the spinal cord, achieve sustained target engagement throughout the
CNS, and are less likely to cause peripheral toxicity. Leveraging our proprietary ASO design software, we assessed all
possible SYF2 ASO sequences in silico and prioritized several hundred leads predicted to have enhanced stability and
manufacturability, and reduced immunogenicity and off-target effects. The objective of this Direct to Phase 2 project is to
identify a bona fide development candidate SYF2 ASO from among these leads for advancement in investigational new
drug (IND)-enablin...

## Key facts

- **NIH application ID:** 10896120
- **Project number:** 5R44AG085411-02
- **Recipient organization:** ACURASTEM, INC.
- **Principal Investigator:** Samuel V Alworth
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,402,110
- **Award type:** 5
- **Project period:** 2023-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10896120

## Citation

> US National Institutes of Health, RePORTER application 10896120, Development of a SYF2 antisense oligonucleotide treatment for ALS and FTD (5R44AG085411-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10896120. Licensed CC0.

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