# Development of RNA-Directed Therapeutics for Myotonic Dystrophy Type 1 Neuropathology

> **NIH NIH F32** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $34,281

## Abstract

Currently incurable, Myotonic Dystrophy type 1 (DM1) is the most common inherited muscular dystrophy in
adults. It is caused by the expansion of CTG trinucleotide repeats in the 3’-UTR of the dystrophia myotonica-
protein kinase (DMPK) gene. These expanded repeats in turn lead to the accumulation of toxic ribonuclear foci
and subsequent dysregulation of RNA binding proteins (RBPs) that are critical for alternative splicing. Although
traditionally classified as a myopathy, DM1 is a multisystem disorder that also causes many different neurological
deficits that greatly diminish the quality of life of patients. For example, individuals with DM1 experience cognitive
impairments including deficits in executive function and attention, social impairments, and reduced IQ-values,
suggestive of a frontal lobe dysfunction. Indeed, widespread toxic RNA foci along with the dysregulation of RBPs
have been identified within the frontal cortex of patients with DM1. However, how CUG RNA toxicity causes
these neurocognitive symptoms remains unclear, making an effective treatment strategy elusive. Interestingly,
recent studies have identified altered expression and/or hyperphosphorylation of several synaptic vesicle
proteins, along with the dysregulation of neurotransmitters within cortical tissue of both human patients and
mouse models of DM1, that do not result from the missplicing of their coding transcripts. Together these data
imply that CUG RNA toxicity causes neurocognitive dysfunction by disrupting synaptic transmission in the cortex
through a mechanism independent of alternative splicing. It also highlights that the neuropathology underlying
neurological symptoms of DM1 is complex with a multitude of pathological pathways occurring simultaneously.
Thus, our central hypothesis is that therapeutic interventions for central nervous system (CNS)-specific
symptoms of DM1 need to be centered on directly eliminating the primary toxicity underpinning this disorder.
The overall objective of this proposal is to enhance our understanding of DM1 neuropathology in order to develop
effective therapeutic approaches for neurological symptoms of DM1. In Aim 1 we will determine if the
dysregulation of RBPs in DM1 disrupts the stability of transcripts required for synaptic transmission in DM1
patient induced pluripotent stem cell-derived cortical organoids using crosslinking immunoprecipitation coupled
with deep sequencing (eCLIP). This study will determine if mechanisms independent of missplicing contribute to
DM1’s CNS-specific manifestations. It will also augment the molecular description of DM1 neuropathology
revealing novel human-specific biomarkers that can be used to evaluate the utility of potential therapies or as
therapeutic targets themselves. Further, in Aim 2 we will engineer a compact, cell-specific, low-immunogenicity
RNA-targeting Cas system designed to eliminate CUG-expanded transcripts in the CNS. This study will result in
a long-lasting gene therapy that s...

## Key facts

- **NIH application ID:** 10242670
- **Project number:** 5F32NS112654-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Kathryn H Morelli
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $34,281
- **Award type:** 5
- **Project period:** 2019-07-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242670

## Citation

> US National Institutes of Health, RePORTER application 10242670, Development of RNA-Directed Therapeutics for Myotonic Dystrophy Type 1 Neuropathology (5F32NS112654-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10242670. Licensed CC0.

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