# Immunotherapies for RAN protein diseases

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2022 · $72,556

## Abstract

Project Summary
Repeat expansion mutations cause more than 50 neurodegenerative diseases, including Huntington disease
(HD) and C9orf72 amyotrophic lateral sclerosis. Despite intense research, there are no effective treatments for
any of these disorders. Repeat expansion mutations are often bidirectionally transcribed and can undergo repeat
associated non-AUG (RAN) translation1. This process results in the expansion RNAs being translated into toxic
RAN proteins across all reading frames without the requirement for AUG, or AUG-like initiation codons2. Because
both sense and antisense expansion RNAs can be translated in each reading frame, up to six toxic proteins can
be produced from a single mutation. RAN proteins have been reported to accumulate in disease-affected tissues
of patients for 11 expansion diseases1,3,4, including Huntington’s disease (HD)5 and spinocerebellar ataxia type
86 which are caused by CAG•CTG expansion mutations and C9orf72 which is caused by a G4C2•G2C4
expansion7-9. There is strong evidence that RAN proteins are toxic and contribute to a growing number of repeat-
expansion disorders and could be an attractive therapeutic target. Strong preclinical data in C9-ALS BAC
transgenic mice show that passive immunotherapy reduced RAN proteins, improved behavior, increased
longevity, and improved neuropathological phenotypes including motor neuronal survival in C9-BAC transgenic
mice10. While promising, passive immunotherapy comes with many disadvantages including that it is expensive
to produce these antibodies and that patients must receive frequent injections. The central hypothesis of this
proposal is that vaccination against RAN proteins will be an effective strategy to elicit a beneficial immune
response and mitigate disease in C9orf72 ALS and HD mice. I propose to test this hypothesis by determining if
RNA-based liposome vaccines can elicit beneficial immune responses that reduce RAN protein levels and
improve disease in mouse models of C9-ALS and HD.

## Key facts

- **NIH application ID:** 10622885
- **Project number:** 3R01NS117910-02S1
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Monica Banez-Coronel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $72,556
- **Award type:** 3
- **Project period:** 2021-07-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10622885

## Citation

> US National Institutes of Health, RePORTER application 10622885, Immunotherapies for RAN protein diseases (3R01NS117910-02S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10622885. Licensed CC0.

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