# Mechanisms underlying differential efficacy of DM1 therapeutics

> **NIH NIH P50** · UNIVERSITY OF FLORIDA · 2024 · $288,204

## Abstract

The therapeutic landscape for myotonic dystrophy type 1 (DM1) has advanced dramatically in the past 5 years,
but conflicting observations about the metabolism of expanded CUG mRNA (transcription, export, turnover, and
translation) present challenges for how to interpret results from clinical trials and direct future therapeutic
strategies. Fully understanding these fundamental pathophysiological mechanisms in DM1 has been severely
limited due to lack of an animal model containing repeat lengths reflective of human disease states and expressed
with appropriate spatiotemporal dynamics. To address this problem, we have developed a new mouse model of
DM1 (Dmpk CTGexp), which expresses >1700 CTG repeats within native mouse Dmpk. Heterozygous mice display
disease features including nuclear foci, splicing defects, myotonia, and myopathy. Further, the expanded allele
in this model is tagged with a single nucleotide polymorphism (SNP) for tracking mRNA accumulation,
knockdown, and transport. By using this model, we will determine strengths and weaknesses of leading
therapeutic strategies, helping to focus clinical efforts on those with greatest potential. Three therapeutic
platforms – antisense oligonucleotides (ASOs), siRNAs, and phosphoramidite morpholino oligonucleotides
(PMOs) – are in or are rapidly advancing toward early phase trials in DM1. Based on observations that mutant
DMPK RNA sequesters MBNL proteins to form nuclear foci, causing extensive changes in the muscle
transcriptome, these agents either degrade DMPK transcripts or release MBNL protein from nuclear foci by tiling
the CUG repeat tract. While initial results are encouraging, there is vigorous debate surrounding the strengths
and weaknesses of each strategy. In Aim 1, we will first clarify mechanisms regulating the life cycle of expanded
Dmpk mRNA. We will study the effects of expanded CUG repeats on transcription, turnover, subcellular
localization, and translation of host Dmpk mRNA. In Aim 2, we will compare three major therapeutic strategies:
ASOs, siRNA, and PMOs. We will elucidate mechanisms, strengths, and limitations of each using validated
skeletal muscle readouts. In Aim 3, we will evaluate multi-systemic treatments by testing a PMO conjugate and
MyoAAV-miRNA, to test the hypothesis that such approaches can rescue splicing defects in skeletal, cardiac
and/or smooth muscle.

## Key facts

- **NIH application ID:** 10992317
- **Project number:** 1P50NS132955-01A1
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Eric T Wang
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $288,204
- **Award type:** 1
- **Project period:** 2024-08-15 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10992317

## Citation

> US National Institutes of Health, RePORTER application 10992317, Mechanisms underlying differential efficacy of DM1 therapeutics (1P50NS132955-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10992317. Licensed CC0.

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