# Repeat associated neurodegeneration in CANVAS

> **NIH NIH R21** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $424,882

## Abstract

Abstract:
Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a late-onset, slowly
progressive and recessively inherited ataxia characterized by vestibular, cerebellar, and somatosensory
impairments and cerebellar degeneration that results in significant morbidity and early mortality. CANVAS is
caused by a biallelic, non-reference, pentameric AAGGG repeat expansion within the second intron of replication
factor complex subunit 1 (RFC1) gene in both familial and sporadic CANVAS, as well as a significant fraction of
all late-onset degenerative ataxias and sensory neuronopathies. Controls possess an average of 11 AAAAG
repeats at this locus, which is replaced with between 400-2000 AAGGG repeats in CANVAS patients. The
mechanism(s) by which this repeat expansion causes neurodegeneration are unknown. While CANVAS exhibits
a recessive pattern of inheritance, studies to date suggest that RFC1 expression is not impacted by the repeat
expansions. The expansion has the potential to be pathogenic within two different strand-specific contexts. On
the sense strand, the (AAGGG)n repeat sits within the poly(A) tail of an AluSx3 transposable element, while the
antisense strand (CCCTT)n repeat sits within the large second intronic region of RFC1. The goal of this
proposal is to define the mechanisms by which these repeat elements contribute to neurodegeneration
in CANVAS. To accomplish this, we will use a combination of patient-derived iPSC models alongside studies
using repeat-expressing reporters to investigate the expanded repeat within both its endogenous context as well
as within easily manipulable assay systems that will allow us to define the potential of these repeat elements to
elicit toxicity directly. Taken together, these studies will provide critical information needed to define the proximal
mechanism(s) and pathways that underlie neuronal toxicity and neurodegeneration within CANVAS – a critical
first step required for development of disease relevant therapeutics.

## Key facts

- **NIH application ID:** 10536010
- **Project number:** 1R21NS129096-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Peter K Todd
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $424,882
- **Award type:** 1
- **Project period:** 2022-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10536010

## Citation

> US National Institutes of Health, RePORTER application 10536010, Repeat associated neurodegeneration in CANVAS (1R21NS129096-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10536010. Licensed CC0.

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