Establishing biomarkers and clinical endpoints in myotonic dystrophy type 1 (END-DM1)

Mechanistic studies of DM1 have recently revealed a novel RNA-mediated disease
process. The field has reached consensus that RNA toxicity is the core
mechanism for DM1 pathogenesis. Good molecular targets have been identified,
and recently there has been rapid progress in developing targeted therapies.
Studies have shown that RNA toxicity is reversible in mouse models, encouraging
us to believe that targeted treatments may have transformative effects on DM1
patients. However, recent meetings of stakeholders, including representatives
from FDA, industry, academia, and advocacy, have indicated that three obstacles
stand in the way of capitalizing on this opportunity: (1) insufficient data on
natural history; (2) lack of reliable biomarkers; and (3) incomplete
characterization and limited biological understanding of the phenotypic
heterogeneity of DM1.

Building on previous work of the Myotonic Dystrophy Clinical Research Network
(DMCRN), the present study seeks to overcome these roadblocks. Previously we
used long study visits and extensive data collection to assess small cohorts of
patients (n = 113 in our most recent study). In the current study we are
transitioning to focused data collection on a larger cohort. This will expand
the scope of natural history data and help us develop strategies for managing
patient heterogeneity going forward. For example, we hope to identify clinical
measures or patient characteristics that predict future disease progression. In
addition, we have made substantial progress in developing biomarkers of DM1
severity and therapeutic response, based on RNA alternative splicing in muscle
tissue. We have carried out large
discovery studies to comprehensively identify DM1-associated splicing defects,
and then develop highthroughput assays for candidate biomarkers. Further work
is needed to assess test-retest reliability, examine associations with disease
severity, and optimize methods for sample collection and RNA analysis.

The overall goal of this study is to accelerate the development of new
therapies for DM1 by validating new clinical assessments for measuring disease
status and collecting data and biological samples to help understand disease
progression and severity . This provides valuable information and material for
further research on DM1, for the development of new therapies and for the
future design of new drug investigators. The aim of the study is to determine
the best way to assess how patients are affected by DM1. The research will
investigate the effects of DM1 on muscles, heart, blood and nervous system.
Walking speed, muscle strength, myotonia, heart rate and overall health will be
assessed by trained study personnel. The way in which is thought and
information is processed is assessed by means of an automated test. Using
questionnaires, test subjects are asked to record their own ideas about the
consequences of DM1. During the study, the condition will be evaluated over a
2-year period to determine how DM1 changes over time. The research also
identifies the biomarkers of DM1. Biomarkers are needed for future research to
determine how DM1 may respond to new treatments.

This study will enroll 700 adult patients (18 to 70 years old, inclusive) with
DM1 in the United States and Europe. No treatment will be administered as part
of this natural history study. Patients will receive standard of care as
determined by their treating physician. Study visits occur at baseline/0
months, 12 months, and 24 months. Study visits can take place over two days,
provided that day 2 is within 7 days of day 1.

Risks:
- During the collection of blood samples, the participant may experience pain
and/or bruising at the needle site. Although rare, localized clot formation and
infections may occur.
- Muscle strength testing may cause the participant*s muscles to be sore and
the participant to feel weak.
- Breathing tests may cause the participant to have difficulty breathing or
he/she may feel fatigued during the test.
Completing questionnaires about the participant's symptoms could cause the
participant to become tired after concentrating for a long period of time. Some
questions may cause minor psychological stress.
- Release of medical information/genetic tests could result in a potential loss
of privacy. There is a small chance that some research may yield results that
will have a negative impact on participants, family members, other individuals,
or groups. This impact may include ability to be insured or employed, or
changes in family relationships
- The greatest risk to genetic testing is loss of confidentiality.

Benefits
There are no direct benefits that participants can expect to receive as a
result of taking part in this study