# p75NTR ligands for ALS therapy

> **NIH VA I21** · VETERANS AFFAIRS MED CTR SAN FRANCISCO · 2020 · —

## Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive, disabling and ultimately fatal
neuromuscular disease which has increased incidence in veterans and upon which currently
available therapies have only nominal effects. The overall goal of this proposal is to determine
whether a small molecule modulator of the p75 neurotrophin receptor (p75NTR) will inhibit
progression of pathology and improve outcomes in ALS. Impaired neurotrophin-mediated
signaling and activation of p75NTR-associated death mechanisms have been implicated as
potential drivers of ALS pathology. Moreover, p75NTR is upregulated in motor neurons at risk for
injury and death in ALS, and shedding of the extracellular domain of the receptor, a reflection of
ligand engagement and signaling, correlates with disease progression. Prior studies employing
peptide ligands and receptor down-regulation to therapeutically target p75NTR have yielded
mixed results, perhaps in part due peptide instability, inadequate dosing, lack of target
engagement, and/or interference with positive aspects of p75NTR activity. Non-peptide small
molecule orally-bioavailable p75NTR ligands have been developed that can inhibit injurious
signaling and promote survival pathways via the receptor. They have been found to have
positive effects on signaling, pathology and behavioral outcomes in several neurodegenerative
and injury paradigms, including ALS cell culture models. We hypothesize that LM11A-31, a
p75NTR ligand currently in phase II testing for Alzheimer’s disease, will inhibit the initiation and/or
progression of ALS-associated cell death signaling, pathology, symptoms and mortality. We will
determine LM11A-31 effects on the course of functional status, weight and survival in animals
carrying the ALS-inducing SOD1G93A mutation, and examine: LM11A-31 pharmacokinetics;
effects on p75NTR proteolytic processing, urinary excretion and binding to its native ligands; and,
activation of death and survival-related signaling pathways. In addition to classical apoptotic
pathways, we will examine effects on necroptotic death pathways which may be associated with
the disease. A second ALS mouse model, bearing the FUSR521C mutation and known to have
deficits in neurotrophic signaling, will be examined for p75NTR expression patterns as well as
effects of LM11A-31 on signaling. We expect that treatment with LM11A-31 will delay onset
and/or progression of symptoms and death in the SOD1G93A mice, and will normalize much of
the associated deleterious signaling in those and FUS R521C mice. Positive results of these
studies would support p75NTR as a therapeutic target in ALS, and would facilitate testing of
LM11A-31 in ALS patients. Further, these results could add to knowledge of the role of p75NTR
in ALS and its relationship to non-apoptotic death mechanisms.

## Key facts

- **NIH application ID:** 9974285
- **Project number:** 5I21BX004612-02
- **Recipient organization:** VETERANS AFFAIRS MED CTR SAN FRANCISCO
- **Principal Investigator:** STEPHEN M. MASSA
- **Activity code:** I21 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9974285

## Citation

> US National Institutes of Health, RePORTER application 9974285, p75NTR ligands for ALS therapy (5I21BX004612-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9974285. Licensed CC0.

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