# Chemical approaches for precise recognition of a toxic RNA repeat

> **NIH NIH F31** · SCRIPPS FLORIDA · 2020 · $32,520

## Abstract

PROJECT SUMMARY
Recent studies of RNA function in both normal and pathophysiological processes have revealed the growing
importance of RNA as a drug target. One important class of disease-causing RNAs are RNA repeat expansions
which cause greater than 20 neuromuscular disorders including Huntington’s disease (HD) and myotonic
dystrophy types 1 and 2 (DM1 and DM2). Discovery of the central toxic agent in these diseases and others has
illuminated a novel means to treat them—through targeting the disease-causing RNA to prevent protein binding
or translational defects. These RNA repeats have been successfully targeted with both small molecules
recognizing RNA secondary structure and antisense oligonucleotides targeting RNA sequence. Although these
antisense oligonucleotides can improve disease biology, in many cases they cannot discriminate between the
mutant transcript and other RNAs containing shorter non-pathogenic repeats and also suffer from lack of
permeability, blood-brain penetrance, and stimulation of immune response. Thus, a major issue that needs to
be addressed is how to precisely target only the disease-causing gene in vivo with small molecules that can be
easily optimized for selectivity and potency.
Herein, I propose to develop novel small molecule approaches to more precisely target the RNA repeat causative
of DM1 (r(CUG)exp) in vivo. I have previously shown DM1-associated defects can be corrected in vivo using a
small molecule that specifically cleaves r(CUG)exp. To create more potent small molecules targeting r(CUG)exp,
I will first expand on an approach which uses a disease-causing RNA as a catalyst for therapeutic synthesis. In
this approach, monomeric subunits react upon binding to the disease-causing RNA to form potent multivalent
therapeutics, combining the favorable pharmacological properties of small molecules with the potency and
selectivity of multivalent oligomers. This method will be optimized to create a rapid RNA-templated fluorogenic
click reaction for precise recognition and labeling of r(CUG)exp in vivo. Using this approach in vivo will provide a
novel method to potently and selectively target r(CUG)exp and improve DM1-associated defects. To further
enhance the precision of small molecules targeting RNA repeat expansions, I will combine these two small
molecule approaches and terminate an RNA-catalyzed click reaction with a small molecule cleaver. This
approach will create a potent oligomeric cleaver and will greatly reduce the amount of small molecule cleaver
needed to destroy r(CUG)exp and improve DM1-associated defects in vivo. These novel small molecule
approaches to modulate r(CUG)exp in vivo have broad implications from basic biology to medicinal chemistry.
Importantly these methods can be applied to multiple RNA repeat expansions and will greatly impact the way
that these disease-causing RNAs are studied and treated.

## Key facts

- **NIH application ID:** 9850869
- **Project number:** 5F31NS110269-02
- **Recipient organization:** SCRIPPS FLORIDA
- **Principal Investigator:** Alicia Jeannine Angelbello
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $32,520
- **Award type:** 5
- **Project period:** 2018-12-01 → 2020-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9850869

## Citation

> US National Institutes of Health, RePORTER application 9850869, Chemical approaches for precise recognition of a toxic RNA repeat (5F31NS110269-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9850869. Licensed CC0.

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