# Small Molecule Approaches to Targeting the DNA and RNA in Myotonic Dystrophy

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2020 · $474,854

## Abstract

Project Summary
Myotonic dystrophy type 1 (DM1), the most common form of adult onset muscular dystrophy, is an incurable
neuromuscular disorder. Its genetic origin is a triplet (CTG) repeat expansion in the 3'-untranslated region
(UTR) of the dystrophia myotonica protein kinase (DMPK) gene. No treatment options exist to delay disease
progression. Strong evidence supports a gain-of-function role for the expanded RNA transcript (rCUGexp) and it
is considered the toxic agent that causes DM1. The rCUGexp sequesters important proteins, inhibiting their
normal function. Chief among these proteins is muscleblind-like protein 1 (MBNL1), a key regulator of
alternative splicing. Its sequestration leads to the mis-splicing of >100 pre-mRNAs and many of the symptoms
of DM1. The overall goal of this proposal is to discover novel therapeutic approaches and to identify and
develop agents that target dCTGexp to inhibit its transcription and rCUGexp, if formed, to liberate sequestered
protein. These agents may serve ultimately as new lead therapeutic agents for DM1. Agents that function well
in cell culture models will be assessed for their drug-like abilities (e.g., ADME-tox) and suitable leads will be
tested in sophisticated animal models scoring both phenotypic improvements (e.g., cardiac function) and
correlating this with target-based activity (levels of relevant spliced RNAs). The specific aims of the proposal
are: (1) Discovery and Development of Small Molecules that Bind dCTGexp and rCUGexp, (2) Development of
Self-Assembling Therapeutics Targeting dCTGexp and rCUGexp, (3) Polymer Approaches to Targeting dCTGexp
and rCUGexp, and (4) Evaluation of Promising Agents in Cellular Assays and Drosophila and Mouse Models of
DM1.

## Key facts

- **NIH application ID:** 9840872
- **Project number:** 5R01AR069645-04
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** Steven C. Zimmerman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $474,854
- **Award type:** 5
- **Project period:** 2017-03-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9840872

## Citation

> US National Institutes of Health, RePORTER application 9840872, Small Molecule Approaches to Targeting the DNA and RNA in Myotonic Dystrophy (5R01AR069645-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9840872. Licensed CC0.

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