# Development of a PIKFYVE antisense oligonucleotide treatment for FTD

> **NIH NIH R44** · ACURASTEM, INC. · 2022 · $1,480,550

## Abstract

Development of a PIKFYVE suppressing antisense oligonucleotide treatment for FTD
Project Summary
Frontotemporal dementia (FTD) is a complex disease that results from many diverse genetic etiologies. There
are no drugs that slow the progression of FTD. Although therapeutic strategies that target specific causal
mutations (e.g. C9ORF72 ASOs) may prove effective against individual forms of 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 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 FTD, particularly those with unknown genetic etiologies.
 45% of FTD patients display cytosolic aggregates of TDP-43 in cortical neurons, while another 45% harbor
tau aggregates. Studies suggest that these neuronal TDP-43 and tau aggregates drive neurodegeneration. Thus,
to identify new therapeutic targets for FTD, we used cellular reprogramming to generate induced cortical
neurons (iNs) from C9ORF72 FTD patients, who display TDP-43 aggregates, as well as MAPT FTD patients,
who harbor tau aggregates. We then performed chemical screens to identify targets that rescue the degeneration
of both C9ORF72 and MAPT FTD iNs. Inhibitors of PIKFYVE kinase were among the most potent compounds
on both C9ORF72 and MAPT FTD iNs. Antisense oligonucleotide (ASO)-mediated suppression of PIKFYVE
confirmed that blocking PIKFYVE activity rescues FTD iN survival.
 In contrast to small molecules, antisense oligonucleotides (ASOs) provide a facile approach to targeting the
CNS 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. Thus, we are pursuing ASO-mediated suppression of
PIKFYVE as a therapeutic approach for diverse forms of ALS. We have screened hundreds of human
PIKFYVE ASOs and identified ten lead ASOs with potent PIKFYVE knockdown in vitro . We have
tested hundreds of human PIKFYVE ASOs and identified three promising leads for development. The
objective of this Direct to Phase 2 proposal is to further characterize the efficacy of PIKFYVE
suppression, and the safety of the lead ASOs to select a bona fide development candidate for
advancement in GLP toxicity studies. Our discovery of secretory autophagy as a therapeutic approach in
neurodegeneration is high impact for the field because activating the proteasome and autophagy
has had mixed results in neurodegeneration models.

## Key facts

- **NIH application ID:** 10487547
- **Project number:** 5R44NS124454-02
- **Recipient organization:** ACURASTEM, INC.
- **Principal Investigator:** Samuel V Alworth
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,480,550
- **Award type:** 5
- **Project period:** 2021-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10487547

## Citation

> US National Institutes of Health, RePORTER application 10487547, Development of a PIKFYVE antisense oligonucleotide treatment for FTD (5R44NS124454-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10487547. Licensed CC0.

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