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

> **NIH FDA R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2021 · $98,005

## Abstract

Abstract
 Myotonic dystrophy type-1 (DM1) is the most common form of muscular dystrophy in
adults. Individuals with myotonic dystrophy develop progressive muscle weakness, early
cataracts, cardiac arrhythmias, and other symptoms. The genetic basis is an expansion of CTG
repeats in the non-coding region of DMPK, which causes a deleterious gain-of-function by
DMPK mRNA. RNA binding proteins become trapped on repetitive RNA, causing loss of
splicing regulatory functions.
 The discovery that DM1 is instigated by RNA toxicity and misregulated splicing has led
to therapeutic targets and candidate biomarkers. Several therapeutic approaches are under
development, including 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 are proposing to overcome these limitations by expanding the scope of natural
history data (Aim 1) and completing the steps of biomarker qualification (Aim 2). We plan to
enroll 500 adults with DM1 at eight sites of the Myotonic Dystrophy Clinical Research Network.
Study assessments will be repeated after 1 and 2 years. Our proposed entry criteria are non-
restrictive to capture data across the broad spectrum of DM1 severity. Based on preliminary
data from our current multicenter study of 113 patients, we selected a concise set of clinical
measures showing acceptable reliability and responsivity to progression. The proposed study is
designed to establish minimal clinically important differences, identify baseline characteristics to
predict future progression, and provide a basis for stratification, or sample size selection 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. Our
goal is to optimize methods for sample collection and processing, extend our reference dataset
of splicing measurements, and formally establish that splicing data are archival, so that
biomarker data are comparable across laboratories and to reference data. 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:** 10496809
- **Project number:** 3R01FD006071-02S1
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Nicholas Elwood Johnson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** FDA
- **Fiscal year:** 2021
- **Award amount:** $98,005
- **Award type:** 3
- **Project period:** 2017-09-15 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10496809

## Citation

> US National Institutes of Health, RePORTER application 10496809, Establishing Biomarkers and Clinical Endpoints in Myotonic Dystrophy Type-1 (3R01FD006071-02S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10496809. Licensed CC0.

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