# Targeted immunotherapy for amyotrophic lateral sclerosis and frontotemporal dementia

> **NIH NIH R43** · PANORAMA RESEARCH, INC. · 2023 · $299,989

## Abstract

Targeted immunotherapy for amyotrophic lateral sclerosis and frontotemporal
dementia
Abstract
 Frontotemporal dementias (FTD) and amyotrophic lateral sclerosis (ALS) are progressive and fatal
neurodegenerative diseases. A hexanucleotide repeat expansion in C9orf72 accounts for >10% of all cases.
Non-AUG dependent translation of expanded repeats results in accumulation of several dipeptide repeat (DPR)
proteins, of which poly-GA appears central to the pathology of C9orf72 disease. Aggregation of poly-GA inhibits
the proteasome and leads to TDP-43 aggregation. Despite widespread poly-GA expression in C9orf72 mouse
models, specific disease-relevant neuron populations are especially sensitive to poly-GA toxicity. Antisense
oligonucleotides directed to C9orf72 are effective in mice, as is a dominant negative protein kinase R (PKR) that
attenuates poly-GA accumulation. Preliminary data indicate that active vaccination induces high antibody titers
and nearly complete prevention of motor deficits and microglia activation in mice, suggesting poly-GA as a
feasible target to treat C9orf72 FTD/ALS. Poly-GA antibodies block aggregation and spreading of poly-GA and
attenuate downstream TDP-43 pathology in vitro, and improve motor and behavioral deficits in mouse models.
These data suggest that immunotherapy is currently the best approach to reduce toxicity of aggregates that are
found even in pre-symptomatic carriers. Our team has identified potent murine antibodies that demonstrate
activity in a C9orf72 mouse model. During this Phase 1 study, we propose to humanize our lead anti-GA antibody
and conduct preclinical validation of anti-GA antibody therapy in several disease-relevant mouse models.

## Key facts

- **NIH application ID:** 10759808
- **Project number:** 1R43NS134421-01
- **Recipient organization:** PANORAMA RESEARCH, INC.
- **Principal Investigator:** JAMES W LARRICK
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $299,989
- **Award type:** 1
- **Project period:** 2023-09-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10759808

## Citation

> US National Institutes of Health, RePORTER application 10759808, Targeted immunotherapy for amyotrophic lateral sclerosis and frontotemporal dementia (1R43NS134421-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10759808. Licensed CC0.

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