As a clinician and researcher, Dr. Benedikt Schoser is focused on how research findings can be translated into improved patient care - and how patient concerns can help guide researchers to new areas of interest. “We try to combine clinical data with results from basic science and look at parallels between scientific results and patient outcomes,” he says.

Dr. Schoser is senior consultant in neurology at the Friedrich-Baur Institute (FBI) at Ludwig-Maximilians University of Munich, one of Germany’s largest referral centers for neuromuscular diseases. FBI diagnoses and treats thousands of patients and processes hundreds of muscle biopsies each year.

Dr. Schoser trained as a neurologist and myopathologist (a specialist in muscle dysfunction) at several German universities before joining FBI in 2001. His interest in myotonic dystrophy (DM) dates back about 15 years, when he began working closely with Dr. Kenneth Ricker, then of the University of Wurzburg, one of the original describers of DM2. He has published more than 30 research papers on DM and sees approximately 200 patients with the disease, including some he has been following for decades.

His clinical focus has prompted Dr. Schoser to bring together patients and researchers to improve resources and education for people with DM. He serves on the academic task force of the TREAT-NMD network, an international effort to ensure that promising new therapies for neuromuscular diseases reach patients by connecting patients, clinicians, academic researchers, and representatives of the biomedical industry. And he is the head of Germany's DM registry, which collects information on patients so they can be paired appropriately with clinical trials.

Dr. Schoser is project lead at FBI for the OPTIMISTIC Trial (Link to archived site), a collaboration among researchers and doctors from the Netherlands, Germany, France, and the United Kingdom that seeks to improve standards of care for DM1. The group has launched a study of whether cognitive behavioral therapy can be used to stimulate activity and reduce fatigue in DM patients. The goal of these research efforts is to develop guidelines physicians can use to improve patients’ quality of life.

Dr. Schoser also helped translate the MDF Toolkit into German, adapting it for that country’s patients. The German translation will be available for download soon.

Dr. Schoser is looking forward to this summer’s meeting of the International Myotonic Dystrophy Consortium (IDMC). (He served as chair of IMDC-7 meeting in 2009.) He believes these meetings are special in the medical field because they unite scientists and clinicians. “As clinicians, we see patients and try to understand their symptoms,” he says. “Scientists do fantastic studies and then ask how they can be translated into clinical practice. At these meetings, we share, which is why I always look forward to them.”

He also values the participation of caregivers at the IMDC meetings. “A doctor, if he is lucky, may see a patient for 60 minutes,” he says. “But a caregiver often is with a patient 24 hours a day. That gives them a lot of information we don't have to better understand the disease, which helps improve our work as physicians. And they help identify additional areas for research, based on what patients and caregivers think is important.”

03/26/2015

Measures of Success

The first clinical trial of a new therapy for myotonic dystrophy (DM) in affected patients launched in December 2014. In order to help promote success for this and future clinical trials, DM researchers are working hard to determine what can be measured in clinical trials that will best demonstrate whether a drug really works. To support these efforts, MDF held a science workshop in September 2014 during our annual conference. The workshop brought together more than 50 research experts and industry representatives from around the world to review where we are with respect to developing these measures for DM.

Two kinds of measurements are typically used in clinical trials:

1. "Clinically meaningful endpoints," which measure things that have real impact on a person's day-to-day life. Clinically meaningful endpoints are used to approve a drug.
2. "Biomarkers," which are an indirect way to measure drug impact that is clinically meaningful. For example, a blood measurement that changes as symptoms improve could be a biomarker.

Clinical endpoints and biomarkers may be used for many purposes in drug development, including:

• Identifying the most suitable patients for clinical trials
• Determining if a drug is affecting the disease
• Determining if the drug is working the way it is supposed to

The use of the right biomarkers and endpoints for the right purposes can greatly reduce the time needed to develop a new drug.

At the science workshop, Dr. Richard Moxley of the University of Rochester described the progress in measuring myotonia (a "stiffness of muscle" or inability to relax the muscle). For myotonic dystrophy symptoms, this is currently the best endpoint. The researchers also discussed the potential for developing new DM biomarkers, including:

• Biomarkers that measure how the disease is progressing in an individual
• Biomarkers that are closely linked to the cause of the disease
• Biomarkers that measure disease progression in the heart and the brain (central nervous system), two areas that can be very affected by DM
• Biomarkers that may allow the grouping together of people in whom DM is progressing in a similar way
• A new questionnaire developed to measure how severe people feel their DM disease symptoms are

The investigators agreed that a person’s degree of myotonia is the best biomarker we have at this time, and that it can be used to measure drug impacts in clinical trials, although the most suitable way to measure myotonia has yet to be worked out.

Drs. Charles Thornton of the University of Rochester, Tom Cooper of Baylor College of Medicine, Andy Berglund of the University of Oregon and Eric Wang of MIT are among the researchers looking at blood samples to determine how gene activity is increased or decreased and how genetic messages and proteins are processed in human cells. By identifying groups of genes where processing changes as the disease progresses, investigators may be able to determine if a potential therapy is having an impact. There has been a lot of progress in this area, but researchers are still trying to identify a group of genes whose processing is tied to disease progression. Also, it is difficult to measure changes the in heart and brain because it is difficult to obtaining tissue, so more measurement options are needed.

Dr. Gordon Tomaselli of the Johns Hopkins School of Medicine described various ways to measure changes in the heart, primarily be using equipment to view the heart as it beats. Some of the changes observed may indicate when a person with DM is going to develop a particular type of heart trouble. Looking at heartbeat patterns using echocardiograms (ECGs) and electrocardiograms (EKGs) could also be useful for measuring drug effects. Unfortunately, there is not enough documentation to use these measurements in trials yet.

Because it is difficult to obtain samples of brain tissue, researchers have developed different ways of imaging brain structures and activity to measure disease-related changes. Dr. John Day of Stanford University described several types of brain imaging techniques that show differences:

• Between people with DM and unaffected individuals
• In people with different levels of disease severity
• In measurements as the disease progresses

These imaging techniques could be very valuable in determining if a therapy could treat DM symptoms associated with the brain.

Dr. Peg Noupoulos of the University of Iowa described a long-term study in Huntington’s disease, a triplet-repeat disease like myotonic dystrophy, which resulted in the development of some very useful biomarkers for that disease. She drew parallels between the lessons learned in those studies and how they could be applied to a new long-term DM study that is currently being carried out through the Myotonic Dystrophy Clinical Research Network (DMCRN).

Dr. Darren Monckton of the University of Glasgow described biomarkers that could be used to identify DM patients with similar disease courses. The ability to do this may be important, particularly in a disease like myotonic dystrophy that progresses slowly and is variable (patients have different symptoms and progress at very different rates). By starting a trial with a group of patients who progress in a similar way, drugs can be tested in smaller groups of patients more quickly, potentially making the process of developing the drug much faster. This area of research is just getting underway.

Finally, Dr. Chad Heatwole of the University of Rochester described a survey tool he developed to determine how people with DM describe their own symptoms and severity. This “patient-reported outcome measurement tool” is being used in clinical trials and research studies, and so far looks like a promising way to use feedback from patients to measure whether a treatment is working.

As more potential DM therapies move into the drug development pipeline, the measurements being developed now will hopefully speed the testing and approval process, getting needed therapies to people living with myotonic dystrophy as soon as possible.

02/26/2015

Tackling DM from Basic Research through Clinical Care

Tetsuo Ashizawa, MD, better known as "Tee" to colleagues and patients, has focused his career on the search for treatments for myotonic dystrophy (DM). As one of seven primary investigators who will participate in the first clinical trial of a potential treatment for DM1, Dr. Ashizawa may be closer than ever to achieving that goal. Yet in addition to pursuing research with dedication and tenacity, he has also been committed to providing the best possible care to people living with DM. Dr. Ashizawa's engagement in myotonic dystrophy spans basic research, translational science, patient-oriented research and clinical care.

Originally trained in neuromuscular diseases, Dr. Ashizawa first became involved in DM as a basic researcher, working with a team at Baylor College of Medicine to hunt for the DM gene. "There were actually several teams working internationally to find the gene," said Dr. Ashizawa. "Interestingly, in 1992 the various research teams all had the same finding, which was identification of DMPK, the genetic mutation responsible for myotonic dystrophy type 1. It was an exciting time, and that was the beginning of our journey to find treatments and a cure."

Patients Play a Key Role with Researchers

In 1998, as Dr. Ashizawa was expanding his research efforts, he received an email that would broaden his perspective. Shannon Lord, the mother of two boys with juvenile-onset DM1, wanted to make a donation to advance DM research. She provided a grant to Dr. Ashizawa through the Hunter Fund, an account named after her older son and established by Shannon and her husband Larry to support DM research projects. The grant was the start of a long-term friendship between Dr. Ashizawa, Shannon and Larry Lord, and ultimately led to a DM scientific meeting organized by Dr. Ashizawa and including the Lord family. "It was so powerful," said Dr. Ashizawa. "Before this meeting, many in the scientific community only saw DM through a microscope. Now investigators could see and understand the human face of the disease. It was a real morale booster for everyone and provided a great deal of momentum to move our work forward."

By then Dr. Ashizawa had also co-founded the International Myotonic Dystrophy Consortium (IDMC) to bring together scientists and clinicians focusing on DM. Shannon Lord attended the third biennial IDMC meeting in Kyoto in 2001, serving in the role of patient advocate and introducing patient advocacy to the IDMC research community. By the fourth meeting, about one hundred patients and families attended, and the participation of a large number of patients at these international meetings has since become routine. Today, IDMC meetings provide a unique opportunity for global researchers, clinicians and patients to come together; IDMC 10 will be held next June in Paris, France. "Without patient involvement, we wouldn't be able to push forward on the research frontier," Dr. Ashizawa said.

Research Moves Out of the Lab

By 2011, DM science had progressed significantly in the development of potential treatments for DM1. Seven research and clinical institutions around the country are currently preparing to launch the first clinical trial in affected patients to test the efficacy of an antisense oligonucleotide (ASO) therapy, DMPKrx, in people affected by DM1. The University of Florida (UF) will serve as one of these sites, with Dr. Ashizawa as the Primary Investigator for the institution.

Dr. Ashizawa has recently started a project looking at DM1 patient-derived, induced pluripotent stem cells (iPSCs), which can be developed into different cell types needed for research, e.g. muscle, heart, or even brain cells. These cells can help researchers understand how DM affects different body systems and causes disease symptoms. While the clinical use of these cells may be a long way off, iPSCs have a more immediate and critical function as a platform for the screening of compounds to find drugs that have therapeutic potential in DM1. "It's a very exciting time in DM research," Dr. Ashizawa says.

Providing Multidisciplinary Care in the Clinic

In addition to his research projects, Dr. Ashizawa oversees the clinical program at the University of Florida. Patients benefit from a multidisciplinary team of doctors that includes cardiologists, anesthesiologists and geneticists. "We help patients access any clinical trials for which they may be eligible," he says. "And when new treatments become available we are committed to helping our patients access them as soon as possible."

Dr. Ashizawa has published over 190 research papers and 35 book chapters. He is currently Executive Director at the McKnight Brain Institute at UF and Professor and Chair of the Department of Neurology at the UF College of Medicine, and he serves on MDF's Scientific Advisory Committee. With Drs. Maurice Swanson and S.H. Subramony, he has recruited Dr. Laura Ranum to UF and is in the process of recruiting a handful of other key DM investigators to build one of the strongest DM research teams in the world. "We are very hopeful about the research and treatment possibilities on the horizon. We have a distance to go and there are many questions to answer, but we won't stop working," says Dr. Ashizawa. "We are dedicated to our patients and to collaborating with them to find a cure."

12/09/2014

Dahlqvist et al
European Journal of Neurology

Dr. John Vissing and his colleagues at the University of Copenhagen recently tracked a group of 68 adults with myotonic dystrophy type 1 (DM1), measuring their endocrine function change over 8 years.  The authors examined bloodwork for many endocrine dysfunctions including diabetes (HbA1c blood test), hyperparathyroidism (PTH blood test), and androgen insufficiency (testosterone blood test in men), and found that these dysfunctions became more common over time in people with DM1.  The authors recommend that doctors treating people with DM1 should screen for endocrine functions regularly, as the dysfunctions occurs more frequently in DM1 than the general population.

Click here to read the abstract for this study.

Click here for a PDF of this paper.

10/16/2014

A Toxic RNA Catalyzes the In Cellulo Synthesis of Its Own Inhibitor

Researchers from Dr. Matthew Disney's lab at the Scripps Research Institute of Florida, including Suzanne Rzuczek, PhD, a 2013 MDF Fund-a-Fellow grant recipient, recently published an article describing a new chemical they designed to inhibit the unhealthy repeat-containing RNA molecule seen in myotonic dystrophy type 2. This project was supported by a postdoctoral fellowship awarded by MDF. The study describes the design of a pair of molecules that seek out the unhealthy repeat RNA and attach to it. When both of the molecules attach near each other on the RNA, they join together and permanently attach to each other, forming a strong inhibitor of the RNA. The authors state that they are "using the cell as a reaction vessel and a disease-causing RNA as a catalyst." By this they mean that only cells that have the large DM2 repeat-containing RNA will create their own chemical to inhibit the negative effects of the DM2 RNA. They were able to show that their chemicals reduced the number of unhealthy RNA clumps found in DM2 cells, and were able to partially reverse the improper processing that normally occurs in those with DM2 as a result of the unhealthy RNA.

Click here to read the full article. You can also view a presentation from the 2014 MDF Annual Conference by Dr. Rzuczek where she discusses this research.

09/25/2014

Dr. Katharine Hagerman, Research Associate at Stanford University Neuromuscular Division and Clinics, has prepared the following summary of the recently published study, "Parental Age Effects, But No Evidence for an Intrauterine Effect in the Transmission of Myotonic Dystrophy Type 1" in the Journal of Human Genetics. 

Researchers from the laboratories of Fernando Morales from the University of Costa Rica, and Darren Monckton from the University of Glasgow collaborated in a recent study examining how the DNA mutation causing myotonic dystrophy type 1 (DM1) worsens from one generation to the next. Previous studies have shown that the DM1 mutation behaves differently depending on whether it is passed on from the father or mother. However, there has been conflicting information regarding whether the age of the parent’s symptom onset or parent’s age at conception of their affected child can change the degree to which the child is affected by DM1.

The conflict in research findings is likely the result of using different methods to assess the size of the DM1 mutation, and failing to account for the age of the parent at the time the blood was collected, since the mutation grows throughout their lifetime. This study uses a newer technique called "small pool PCR" to assess the mutation size, and a complex statistical analysis to predict what the original size of the repeat was at birth. This method clarified the relationship between parent and child with regard to CTG repeat size and symptom onset, confirming that children born with DM1 have an inherited repeat that is larger than their parent’s repeat about 95% of the time, and symptom onset comes earlier in the child than their affected parent around 86% of the time. Furthermore, the parent’s age of onset is correlated with the child’s age of onset, but the correlation is much stronger in affected mothers than fathers.

What really stood out in this paper was a completely new finding that the age of the affected parent at conception correlates with the repeat size in their child. In other words, as people with DM1 age, the size of the repeat in their eggs or sperm grows larger. Basic genetic principles dictate that there is a 50% chance of an affected parent passing on the mutation to their child.

This paper found that if the child inherits the mutation from their mother and gets DM1, there is a 64% risk of the child’s DM1 being congenital if the mother’s repeat size is above 164 CTGs. There are very few cases of an affected father having a congenitally affected child, and none were found in this study. Unfortunately, current procedures for diagnosing DM1 do not use the same experimental method as in this paper and do not predict what the individual’s repeat was at birth. Therefore this predicted risk cannot be applied to mothers whose repeat was sized using conventional methods for diagnosis.

The authors estimate that the diagnostic test most women get to determine the size of their repeat would also predict that if their offspring inherit the expanded repeat, they would be congenitally affected 64% of the time when the mother's repeat length is over 284 CTGs.

Genetic counseling for families with DM1 can be very complicated, as many factors such as the repeat size and sex of the DM1-affected parent can alter any predictions as to how severely a child may be affected. Overall, this study clarifies how the growing repeat size in adults with DM1 can affect their children, and brings to light a new factor to be considered by genetic counselors when advising families of the risks of transmitting DM1.

Click here to view the article abstract. Click here for an interview on genetic counseling with Carly Siskind of Stanford University Hospital and Clinics.

08/20/2014

A team of researchers at the University of Illinois at Urbana-Champaign recently published the results of a study in which they designed small molecules to combat myotonic dystrophy type 2 (DM2). Dr. Katharine Hagerman, Research Associate at Stanford University Neuromuscular Division and Clinics, provided MDF with the summary below. The study was published in ChemMedChem. 

Previous studies have suggested that the main problem in the cells of people with DM2 is an expansion of a CCTG DNA repeat sequence in the ZNF9 gene. This DNA mutation is transcribed into RNA, where it forms abnormal structures that pull other proteins into clumps and prevent them from performing their normal activities.

In this study, researchers redesigned a small molecule that disrupted the improper interaction of repeat-containing RNA with other proteins, but was highly toxic to cells. Their new molecule still disrupted the desired RNA-protein interaction, but was less toxic and was able to enter cells with greater ease.

Future studies will take the small molecules and test them in fruit flies and mice to see if the molecules will be safe in organisms while continuing to disrupt the RNA-protein interaction associated with DM2. Click here to access the abstract and article.

07/23/2014

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

Ionis Pharmaceuticals, Inc. (formerly Isis Pharmaceuticals, Inc.) announced today that it has launched a Phase 1 clinical trial for IONIS-DMPKRX. Ionis earned a $14 million milestone payment from Biogen Idec associated with this achievement. IONIS-DMPKRX is designed to reduce the production of toxic dystrophia myotonic-protein kinase (DMPK) RNA in cells, including muscle cells, for the treatment of Myotonic Dystrophy Type 1 (DM1).

"[IONIS]-DMPKRX is an example of the broad applicability of our antisense technology to develop novel drugs to treat patients with severe and rare disease. IONIS-DMPKRX is the first drug to enter our pipeline that is designed to target a toxic RNA, the first systemically administered drug to enter development from our Biogen Idec partnership and the second generation 2.5 drug to enter clinical development," said C. Frank Bennett, Ph.D., senior vice president of research at Isis.  "Myotonic dystrophy represents an ideal opportunity for antisense as the disease-causing gene produces a toxic RNA, which is not accessible by traditional therapeutic approaches but is uniquely accessible with our antisense technology. We look forward to rapidly advancing the development of IONIS-DMPKRX."

"Our collaboration with Biogen Idec has been very productive. [IONIS]-DMPKRX has rapidly advanced to the clinic, and we continue to make progress across the board in our drug discovery programs with Biogen Idec. All of these successes advance our neuromuscular disease franchise and translate into the potential for significant revenue as our drugs and programs progress," said B. Lynne Parshall, chief operating officer at Isis.

DM1 is a rare genetic neuromuscular disease characterized by progressive muscle atrophy, weakness and muscle spasms. DM1, the most common form of muscular dystrophy in adults, affects approximately 150,000 patients in the US, Europe and Japan. Patients with DM1 have a genetic defect in their DMPK gene in which a sequence of three nucleotides repeats extensively, creating an abnormally long toxic RNA, which accumulates in the nucleus of cells and prevents the production of proteins needed for normal cellular function. The number of triplet repeats increases from one generation to the next, resulting in the possibility of more severe disease in each subsequent generation. There are currently no disease-modifying therapies that address more than one symptom of the disease. IONIS-DMPKRX is designed to improve the underlying genetic defect that causes DM1.

"Myotonic dystrophy is a progressive and debilitating disease that affects thousands of patients for whom there are no direct therapeutic options. The innovative science behind IONIS-DMPKRX is compelling and targets the underlying genetic defect that causes myotonic dystrophy," said Molly White, executive director of MDF. "IONIS-DMPKRX has a chance to fill the therapeutic void for DM1 patients and transform the hopes and futures of thousands of patients and families."

07/09/2014

A recently released study identifies the gene that may be responsible for increased side effects in DM2 patients taking statins to lower cholesterol. Katharine Hagerman, PhD, Research Associate at Stanford University Neuromuscular Division and Clinics, provides MDF with a summary of the study conducted at the University of Helsinki in Finland.

Abnormal Splicing of NEDD4 in Myotonic Dystrophy Type 2: A Possible Link to Statin Adverse Reactions
Screen M, Jonson PH, Raheem O, Palmio J, Laaksonen R, Lehtimäki T, Sirito M, Krahe R, Hackman P, Udd B.(June 4, 2014).
American Journal of Pathology. e-publication ahead of printing.

A research study headed by Dr. Bjarne Udd at the University of Helsinki recently described biological pathways affected in both myotonic dystrophy type 2 (DM2) and hyperlipidemia (a medical condition most often characterized by high cholesterol or high triglycerides). Previous studies have shown that 63 percent of people with DM2 have high cholesterol, as well as 41 percent of people with DM1. Statins, a class of drugs used to lower cholesterol levels, are commonly prescribed to treat hyperlipidemia, elevated levels of lipid proteins in the blood, as they can block the action of a liver chemical that helps create cholesterol.

One of the side effects of statins is the development of myopathy, including muscle pain, weakness, and cramping. Approximately 5-10 percent of individuals taking statins can develop these symptoms. Individuals with DM have an increased incidence of myopathic side effects when taking statins, and there are many documented cases where statin-induced myopathy is the first muscle symptom experienced in adults eventually diagnosed with DM2.

In order to identify biological pathways that may be affected by both DM2 and statin therapies, these researchers looked at genes that were regulated differently in healthy muscles compared to DM2 muscles and statin-treated muscle cells. They identified a gene, NEDD4, that had increased expression in DM2 (and DM1), and decreased expression in statin-treated individuals with no muscle condition. Furthermore, they showed that the NEDD4 gene was processed differently in DM2 muscles, and made a few different forms of the protein that weren't seen in healthy muscles. The authors suggest that biological pathways involving NEDD4 may be altered in DM, and may be associated with increased statin side effects. According to DM2 research reviews, statins do not have to be avoided. However, if statin treatment produces or amplifies muscle symptoms, there may be other drugs available to combat hyperlipidemia that do not have these side effects in individuals with DM.

07/01/2014