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NIH grant 1R43NS147623-01A1: Development of antisense oligonucleotides against PEG10 in the fight against ALS-FTD
Institute: {'code': 'NS', 'abbreviation': 'NINDS', 'name': 'National Institute of Neurological Disorders and Stroke', 'admin_org_id': '12500053', 'admin_funding_url': ''}. PI: Wendy Overton. Award: $444820.
Start: 2026-09-18T00:00:00.
Project Summary Abstract
Amyotrophic Lateral Sclerosis with frontotemporal dementia (ALS-FTD) is a progressive, fatal
neurodegenerative disease that results from the loss of upper and lower motor neurons, as well as neurons of
the frontal cortex. The resulting symptoms of ALS-FTD are progressive motor and cognitive impairment. There
is no cure for ALS. None of the few treatment options significantly prolong lifespan; 80% of patients die within
2-5 years after diagnosis. Clearly, there is a significant unmet medical need for novel ALS therapeutics.
One potential reason why we still lack effective therapeutics against ALS is because the biology of the
disease is particularly complex. While 90% of ALS cases are sporadic, with no clear genetic component of the
disease, 10% of ALS cases are familial (fALS) and can often be traced to mutation of more than three dozen
ALS-related genes. One way that researchers have sought to understand the disease is by utilizing fALS to
develop model systems that can be probed in depth for molecular determinants of disease. In this proposal,
we leverage discoveries first made at the Whiteley laboratory at University of Colorado, Boulder, to
develop ALS therapeutics against a new target of disease identified through one such model system.
Mutations in the human UBQLN2 gene lead to a portion of fALS-FTD cases, but the mechanism of
disease is poorly understood. UBQLNs are a family of proteasome shuttle factors which facilitate proteasomal
degradation of ‘difficult’ proteasome substrates such as the protein PEG10. PEG10, or ‘paternally expressed
gene 10’, is a ‘domesticated retrotransposon’: it resembles retrotransposons and retroviruses in its overall
structure, but is unable to transpose within the genome. We recently discovered that PEG10 is an active self-
protease and releases a protein fragment containing the nucleic acid-binding region which then traffics to the
nucleus. Expression of this fragment alone is sufficient to upregulate expression of genes involved in axon
remodeling, which are similarly upregulated in ALS-FTD tissues. Therefore, PEG10 is an excellent candidate
for the molecular cause of ALS-FTD upon UBQLN2 dysfunction.
The Whiteley lab at CU Boulder developed an antisense oligonucleotide that specifically and potently
decreases PEG10 protein and holds promise as a potential therapeutic for ALS-FTD. Endios Bio has optioned
this IP and seeks to determine the pharmacokinetics and toxicity profiles of these oligos in mouse models as
a crucial first step of therapeutic development. In this Phase I SBIR application, we hope to determine the
basic properties of these oligonucleotides in a living system. In our first Aim, we optimize the sequence and
length of our molecule to enhance its effectiveness. In our second Aim, we determine PK and toxicity of our
lead oligonucleotide. In our third Aim, we identify target engagement and off-target effects of our lead. At each
step, careful analysis allows for revisitation of our lead compound and the ability to pivot based on new findings,
allowing us to generate critical necessary data to justify IND filing and phase I trials.document fetched 2026-09-27 02:45