# Developing Drug-like Small Molecules that Target Toxic Repeat RNAs to Alleviate Myotonic Dystrophy Type 1-derived Mis-Splicing

> **NIH NIH R43** · NYMIRUM, INC. · 2020 · $299,267

## Abstract

Project Summary Abstract
Nymirum will utilize its technology platform to identify and optimize a drug-like, orally available small molecule
that binds toxic CUG repeat RNAs to rescue myotonic dystrophy type 1 (DM1) derived mis-splicing and treat
the disease. DM1 is a rare genetic disorder that leads to progressive muscle degeneration, cardiovascular
disease, severe cognitive disabilities, insulin resistance, and a host of other symptoms. There is no cure for
DM1, and the only treatments are palliative. The cause of DM1 is an abnormal CTG trinucleotide repeat
expansion (>34 repeats) in the 3′-UTR of DMPK that are transcribed into toxic CUG RNA repeats that
accumulate in the nucleus of cells. Toxic CUG repeats sequester Muscleblind Like Splicing Regulator 1
(MBNL1), which is needed for normal splicing of hundreds of key neuromuscular related genes. Studies have
shown that small molecules that bind CUG repeats can prevent MBNL1 sequestration and rescue nominal
splicing in cells and animal models. However, these small molecules are bulky, very polar, and non-drug-like
and therefore suffer from delivery and toxicity issues. Therefore the need remains to identify and optimize
drug-like, orally available small molecules that bind CUG repeats and rescue DM1-derived mis-splicing in cells.
Preliminary data highlights that the Nymirum platform has identified two classes of drug-like small molecules
that can bind CUG repeats and can rescue DM1-derived mis-splicing in HeLa cells. This proposal seeks to go
wider and deeper in order to identify and optimize more potent compounds. In Phase I, >2 billion compounds
will be rapidly and accurately screened to identify additional classes of chemically diverse drug-like small
molecule CUG binders. Those hits will then be optimized at the atomic level using the dynamic CUG structure
to guide targeted medicinal chemistry to increase their potency and efficacy in HeLa cells. Phase II will carry
out lead-generation in earnest on the hits identified in Phase I. Ultimately, this proposal will develop an orally
available small molecule therapeutic to treat DM1.

## Key facts

- **NIH application ID:** 10135372
- **Project number:** 1R43NS117184-01A1
- **Recipient organization:** NYMIRUM, INC.
- **Principal Investigator:** Isaac J Kimsey
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $299,267
- **Award type:** 1
- **Project period:** 2020-09-30 → 2022-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10135372

## Citation

> US National Institutes of Health, RePORTER application 10135372, Developing Drug-like Small Molecules that Target Toxic Repeat RNAs to Alleviate Myotonic Dystrophy Type 1-derived Mis-Splicing (1R43NS117184-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10135372. Licensed CC0.

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