Expanding the Scope of DM Research

A little over three years ago, MDF awarded a grant to support the establishment of the first-ever Myotonic Dystrophy Clinical Research Network (DMCRN). Based on input from university researchers and pharmaceutical companies, MDF felt it was critically important to expand the scope of DM research and prepare for upcoming trials of potential treatments.

Developing Targeted DM Treatments

A targeted treatment is one that is tailor-made and specifically designed for a particular disease. Targeted treatment development is a lengthy process that involves at least nine different steps. The targeted treatment development process for myotonic dystrophy was started when the DM1 genetic mutation was discovered in 1992, and continued with the identification of the DM2 mutation in 2001. The pace of scientific discovery has accelerated significantly in recent years. Isis Pharmaceuticals is scheduled to begin testing the first targeted treatment in DM patients later this year, with more options from other industry members to follow in the future. While it is likely that progress in treating DM will come in several steps rather than one giant leap, and the best treatment approach may involve a combination of drugs to best meet individual patient needs, this accelerated progress has been very encouraging.

Why We Need the Network

Testing a new drug involves a series of studies, called clinical trials, that are designed to answer several key questions:

• Does the drug have a beneficial effect? If not, why not?
• What benefits can the drug provide and what are the potential side effects?
• If the drug is effective, what is the best dose? How long does it last? When should it be started?

To answer these questions we need reliable testing procedures with proven accuracy, and a group of research sites to monitor the treatment and carry out the measurements. The testing procedures must be carefully selected and standardized, and the teams at each site should have extensive experience using the procedures to ensure that test results are consistent. The Clinical Research Network is focused on making this happen.

Goals of the DMCRN

1. To develop research teams at each site, with team members who are committed to myotonic dystrophy and experience with the research procedures.
2. To learn more about DM - there is still much we don't know. For example, researchers do not have a detailed understanding of why myotonic dystrophy is so variable from person to person, what controls the size of the repeat expansion, or what exactly leads to the muscle weakness, gastrointestinal symptoms, or central nervous system effects.  Answering these questions will help researchers undestand how people respond to therapies and may lead to the design of new targeted treatments.
3. To collect additional data needed for clinical trials, including:

• ​Outcome measures (how the success of a trial will be measured)
• Disease progression (how and why DM becomes more severe over time)
• Biomarkers (something in a cell or body tissue that can help indicate the presence of a disease like DM, and help measure changes in that disease due to the effects of a drug)
• Endpoints (outcomes of drug treatment that demonstrate whether a drug is effective, e.g. improved strength, interrupted disease progression, etc.)

A major focus in setting up the DMCRN was making sure that all researchers in the Network would have free and unrestricted access to the data collected through DMCRN studies, and that they would all be able to publish the results of these studies. In addition, DMCRN stakeholders committed to making access to study results available to researchers across the US and the world, in both the academic sector and in industry. The objective with these Network design decisions was to help lower barriers to advancing DM science and research, and continue the remarkably collaborative and friendly research environment that has been a hallmark of the DM research community to date.

DMCRN Members

The DMCRN is comprised of eight medical centers with significant proficiency in myotonic dystrophy clinical care and research. The current DMCRN sites are:

1. University of Florida McKnight Brain Institute - Dr. S. Subramony,  Primary Investigator
2. University of Kansas Medical Center Research Institute - Dr. Richard Barohn, Primary Investigator
3. Ohio State University Medical Center, Dr. John Kissel - Primary Investigator
4. Stanford University School of Medicine, Dr. John Day - Primary Investigator
5. University of Rochester - Drs. Richard Moxley and Charles Thornton, DMCRN Primary Investigator
6. National Institutes of Health - Dr. Ami Mankodi, Primary Investigator
7. University of Utah - Dr. Nicholas E. Johnson - Primary Investigator
8. Houston Methodist - Dr. Tetsuo Ashizawa - Primary Investigator

The University of Rochester is the lead DMCRN site, with Dr. Charles Thornton as the DMCRN PI. Data from the DMCRN studies are processed in the Data Management Center at Rochester, as is analysis of tissue and blood samples from the current DMCRN study. While Dr. Thornton and the University of Rochester initiated the current DMCRN research study, future studies may originate from any of the sites. Other DMCRN sites may be added in the future.

DMCRN Funding

DMCRN financial support has come from a broad consortium of stakeholders in the DM community. These include MDF, along with other patient advocacy organizations such as the Marigold Foundation and the Muscular Dystrophy Association; the National Institutes of Health (NIH) through their support of the Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center in Rochester; and industry, through support from pharmaceutical company Biogen Idec.

DMCRN Activities and Progress

Since the Network's launch last year, DMCRN researchers have initiated a number of projects to achieve the goals described above. Standardized equipment to measure myotonia and muscle strength is now in place at all DMCRN sites, and training sessions for research coordinators and evaluators have been carried out. Research teams at each site now have experience with specialized measurements of muscle strength and myotonia and the procedures used to obtain biopsy samples of muscle tissue. A study of biomarkers was completed and published in December 2013 and a study to select biomarkers for use in clinical trials is currently underway. The Network has launched a longitudinal (long-term) study to track the progression of DM over time in 100 patients.

What's Next

The DMCRN is moving forward quickly, and meeting the interim goals established for the first 3-5 years. Equally hopeful, the drug development pipeline continues to grow with additional pharmaceutical companies engaging in DM treatment development. The establishment of the DMCRN and other infrastructure projects like the Myotonic Dystrophy Family Registry, the University of Rochester FSHD and DM Registry, and DM biobanks are demonstrating to pharmaceutical and biotech companies that myotonic dystrophy is a good bet for drug development. Overall, DMCRN members are very pleased with the progress they have achieved with the Network. In the words of DMCRN Primary Investigator Dr. Charles Thornton, "The pieces are falling into place, and we hope that the DMCRN will prove to be a historic partnership of industry, advocacy groups, academic researchers and government to develop a truly effective treatment for myotonic dystrophy."

07/23/2014