# Therapeutic targeting of ATXN2 for sporadic amyotrophic lateral sclerosis (ALS)

> **NIH NIH F30** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $51,752

## Abstract

Project Summary / Abstract
 Amyotrophic lateral sclerosis (ALS) is a fatal, adult onset, neurodegenerative disease for which there is
currently no cure and very limited treatment options. Patients present with increasing muscle weakness and die
from respiratory failure within 3-5 years post symptom onset. Currently, the majority of ALS research is focused
on genetic causes, which account for approximately only 10% of cases (familial), without any treatment
developments for the remaining 90% of patients (sporadic). Although nothing is known about the pathogenesis
or propagation of disease, 97% of all patients share one pathological hallmark: TDP-43 mislocalization. TDP-43
is an essential RNA binding protein that in healthy patients is expressed in spinal cord and cortical motor neuron
nuclei. In ALS it is mislocalized to the cytoplasm where it forms distinct phosphorylated aggregates which may
be toxic to the neurons. Recently, Ataxin-2 (ATXN2) has been identified as a potential modulator of TDP-43
toxicity in yeast and animal models. To support this finding, 5% of patients with ALS have intermediate length
repeat expansions in the polyQ region of the gene, compared to 2% of non-neurological controls. Furthermore,
our group and others have demonstrated that regardless of repeat length, ALS patients demonstrate
perturbations in the distribution of ATXN2 in motor neurons. Taken together, these suggest that ATXN2 may be
a candidate for antisense oligonucleotide (ASO) therapeutic potential, however, the question remains as to
whether therapy would benefit all sporadic patients or be dependent on polyQ length.
 This project proposes a series of experiments designed to examine ATXN2 as a potential therapeutic
target in human tissue directly from patients with disease, comparing patients with and without intermediate
length repeat expansions. The aims will explore target characterization and phenotype by examining expression
levels and pathways involved in disease. The proposal examines target engagement via knocking down levels
of ATXN2 and related proteins in the pathway and exploring the changes in genomic and proteomic signature to
develop a disease cellular profile. Lastly, it will verify target efficacy with ATXN2-targeted ASO treatment in order
to identify the subset of patients likely to benefit from therapy.
 Due to the devastating nature of ALS it is imperative that research focus on therapeutic potential in a
directly translatable manner in order to expedite treatments for current patients. This proposal will stratify the
patient population of those likely to benefit from ATXN2 directed therapy, however, the field remains optimistic
that removal of ATXN2 will benefit all patients, not just the small percentage of those with intermediate length
repeats. This directly translatable proposal, along with monthly patient contact in the largest ALS clinic in San
Diego, will provide ideal physician scientist training in a collaborative research and cl...

## Key facts

- **NIH application ID:** 10223182
- **Project number:** 5F30AG063486-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Amy Elizabeth Taylor
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $51,752
- **Award type:** 5
- **Project period:** 2019-09-16 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10223182

## Citation

> US National Institutes of Health, RePORTER application 10223182, Therapeutic targeting of ATXN2 for sporadic amyotrophic lateral sclerosis (ALS) (5F30AG063486-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10223182. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*