# A destabilizing mechanism of expanded trinucleotide repeats as a potential therapeutic strategy for myotonic dystrophy

> **NIH NIH R03** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2020 · $82,500

## Abstract

Large expansion of CTG trinucleotide repeats in the 3’ untranslated region of the DMPK gene
cause myotonic dystrophy type 1 (DM1), the most common form of adult muscular dystrophy.
Toxic CUG repeats-containing RNAs transcribed from the DMPK gene sequester and disable
RNA binding proteins that are critical for cell function. At present, there is no therapeutic approach
to reduce disease severity or delay disease onset. Several labs are considering approaches
aimed at neutralizing the toxic RNA. These could provide short-term effects, unless continuously
applied. A strategy that induces the contraction or deletion of the expanded CTG repeats could
provide an alternative approach to permanently eliminate the production of the toxic RNA.
Expanded CTG repeats have the potential to form hairpins structures in vitro and a mechanism
that involves the failure to resolve secondary structures that form sporadically during lagging
strand synthesis has been proposed to explain trinucleotide instability. Several lines of evidence
suggest that specialized helicases can either facilitate or antagonize expansion of repeat
sequences. However, to what extent and under what circumstances specific helicases contribute
to repeat stability in vivo is not known. The WRN protein is a member of the RecQ family of
helicases that has been shown to resolve secondary structures formed by repetitive G-rich
sequences, and in vitro studies from our and other labs have indicated that WRN prevents stalling
of the replicative polymerase at these repetitive sequences. To determine whether WRN
influences the stability of expanded CTG repeats in vivo, we crossed Wrn knock-out mice with
transgenic mice bearing expanded CTG repeats that recapitulate DM1-specific skeletal muscle
pathologies. Our preliminary data indicate that Wrn deficiency results in the stochastic loss of the
expanded repeats, suggesting that this helicase contributes to the maintenance of long
pathogenic CTG repeats in vivo. To gain critical insights on the relationship between WRN and
expanded CTG repeats stability and explore the therapeutic potential of WRN inhibition for DM1,
we propose to characterize CTG instability in Wrn deficient mice, assess the effects of Wrn
deficiency on the skeletal muscle phenotype of DM1 mice, and gain insights on factors that
influence CTG repeat instability resulting from WRN deficiency. These studies will reveal the
potential value of approaches that target WRN for developing novel therapeutic strategies for
DM1.

## Key facts

- **NIH application ID:** 9875489
- **Project number:** 5R03NS107724-02
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** LUCIO COMAI
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $82,500
- **Award type:** 5
- **Project period:** 2019-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9875489

## Citation

> US National Institutes of Health, RePORTER application 9875489, A destabilizing mechanism of expanded trinucleotide repeats as a potential therapeutic strategy for myotonic dystrophy (5R03NS107724-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9875489. Licensed CC0.

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