# Design of precision small molecules targeting RNA repeating transcripts to manipulate and study disease biology

> **NIH NIH R35** · SCRIPPS FLORIDA · 2020 · $1,147,500

## Abstract

PROJECT SUMMARY: An extraordinarily challenging problem is to develop general methods to target defective
or malfunctioning RNAs that cause disease selectively. Current therapeutic strategies to target RNAs are based
on specific sequence recognition by oligonucleotides. However, many human disorders are caused by highly
structured RNAs not readily targetable by conventional base pairing, in particular RNA repeat expansions that
cause or contribute to >30 incurable neuromuscular diseases and genetically defined dementia. Thus, allele-
specific ASOs modalities for these microsatellite disorders have been developed by targeting polymorphisms
outside of the repeating sequence. The consequences of this approach are that only patients with the
polymorphisms benefit from treatment and that an ASO has to be developed for each disease, even if caused
by the same repeating sequence. If the toxin in these diseases, the expanded repeat, could be targeted
selectively with a structure-specific small molecule, then a single modality could be a therapeutic or chemical
probe for multiple diseases and for all patients.
 Over the past 14 years, we have shown that RNA structures can be targeted selectively with small molecules
in situ and in vivo, more selectively than oligonucleotides. Indeed, we have designed compounds against many
RNA repeat expansions that selectively recognize the target’s structure and rescue disease-associated
pathobiology in situ and in vivo. Further, these chemical probes have elucidated new mechanisms of disease,
including a previously unknown RNA-mediated transcriptional silencing pathway that operates in fragile X
syndrome. These studies, along with our innovative strategies to synthesize drugs at the site of disease and to
engineer small molecules with novel activities, including antisense- or CRISPR-like modes of action, lay the
foundation for our proposed research program.
 Herein, we propose a comprehensive strategy to study the molecular recognition of RNA repeat expansions
by small molecules in situ and in vivo, enabling the establishment of new chemical biology frameworks to target
RNA using small molecules and the development of preclinical candidates. Our studies span many types of
repeat expansions, differing in both sequence and gene contexts (intron, untranslated region, or open reading
frame). We have devised innovative strategies to: (i) exploit the structures of RNA repeats to coax the disease-
causing RNA to synthesize its own drug; (ii) interface small molecules with natural RNA decay and QC pathways;
and (iii) recruit endogenous nuclease to the repeats with small molecules. We will not only deliver proof-of-
concept small molecules that rescue disease-associated defects in situ and in vivo, but make new discoveries
about how to drug RNA using small molecules. Our proposed work would therefore be well supported by an
R35 award, as the flexibility conferred by this award is truly necessary to ensure sustainable, long-term...

## Key facts

- **NIH application ID:** 9986233
- **Project number:** 1R35NS116846-01
- **Recipient organization:** SCRIPPS FLORIDA
- **Principal Investigator:** Matthew D Disney
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,147,500
- **Award type:** 1
- **Project period:** 2020-05-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986233

## Citation

> US National Institutes of Health, RePORTER application 9986233, Design of precision small molecules targeting RNA repeating transcripts to manipulate and study disease biology (1R35NS116846-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9986233. Licensed CC0.

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