# Establishing Biomarkers and Clinical Endpoints in Myotonic Dystrophy Type-1 (Renewal)

> **NIH FDA R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2024 · $399,847

## Abstract

Abstract
 Myotonic dystrophy type-1 (DM1) is the most common form of muscular dystrophy in adults. The genetic
basis is an expansion of CTG repeats in the non-coding region of DMPK, the gene encoding DM protein kinase.
Individuals with myotonic dystrophy develop progressive muscle weakness, early cataracts, cardiac arrhythmias,
and other symptoms. The disease mechanism involves a deleterious gain-of-function by the mutant DMPK
mRNA, a process first described in DM1, known as RNA toxicity. RNA binding proteins become trapped on
repetitive RNA, causing loss of splicing regulatory functions. Splicing changes contribute to DM1 symptoms and
also may serve as biomarkers of disease severity.
 The discovery that DM1 is instigated by toxicity of one RNA species and characterized by misregulated
splicing of other RNAs has furnished good therapeutic targets and candidate biomarkers. Several therapeutic
approaches are under development and two are in early phase clinical trials. However, the design and conduct
of clinical trials is limited by disease heterogeneity, scarcity of natural history data, and the lack of proven clinical
endpoints or biomarkers of drug impact. We have begun a natural history study to define clinical endpoints,
biomarkers, and patient characteristics for clinical trials. This study, END-DM1, has enrolled 277 participants but
early progress was hampered by the COVID-19 pandemic.
 The current renewal application seeks to complete the study of clinical outcome assessments (Aim 1)
and biomarkers (Aim 2) in DM1. We will complete enrollment of 700 adults with DM1 at 16 sites of the Myotonic
Dystrophy Clinical Research Network with return visits at 12 and 24 months. Based on preliminary data, we
selected a concise set of clinical measures showing acceptable reliability and responsivity to disease
progression. The proposed study is designed to establish minimal clinically important differences for different
measures in this population, identify baseline characteristics that predict future progression, and provide a
rational basis for stratification, selection of sample size, or enrichment in future trials. Aim 2 will build on our
previous efforts to develop RNA splicing biomarkers of DM1 severity and therapeutic response. This Aim is
focused on tissue biomarkers that provide direct evidence of target engagement in skeletal muscle. We will
assess a panel of DM1-affected splice events using a novel method that involves targeted high-throughput
sequencing. Completion of this study is the logical next step to lay the groundwork for effective clinical trials in
DM1, and keep pace with the rapidly expanding preclinical efforts to develop an effective drug treatment.

## Key facts

- **NIH application ID:** 10705792
- **Project number:** 5R01FD006071-04
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Nicholas Elwood Johnson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** FDA
- **Fiscal year:** 2024
- **Award amount:** $399,847
- **Award type:** 5
- **Project period:** 2022-09-15 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10705792

## Citation

> US National Institutes of Health, RePORTER application 10705792, Establishing Biomarkers and Clinical Endpoints in Myotonic Dystrophy Type-1 (Renewal) (5R01FD006071-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10705792. Licensed CC0.

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