Heart dysfunction is the second leading cause of death for DM patients and affects 80% of the population; yet very little is known about the molecular changes that alter the cardiac conduction system. A multi-disciplinary, international team, representing 25 different academic institutions, recently undertook a massive messenger RNA sequencing project to learn more about this. Their findings provide an important understanding of the molecular basis of cardiac dysfunction in DM and may have immediate implications for how DM patients are treated.

Using biopsy or post mortem samples from DM1 and DM2 patients, the team assessed the identity of mis-spliced genes and correlated the pattern of changes with the cardiac dysfunction seen in these patients. Considerable progress has been made in understanding the molecular events behind the skeletal muscle changes in myotonic dystrophy (DM). The CTG or CCTG expansions (“triplet repeat”) in the DNA of patients with DM1 or DM2, respectively, produce aberrant messenger RNAs that alter the expression of two proteins that regulate gene splicing, muscleblind and CUG-binding protein 1. These changes in splicing regulatory proteins, in turn, cause the mis-splicing of key skeletal muscle genes that, in turn, produce myotonia and muscle wasting.

Until now, we have had very little knowledge of these molecular level events regarding the DM heart. The altered synchronization of the heartbeat (arrhythmias) and altered heart rate (ventricular tachycardia) seen in DM are likely the result of alterations in sodium and potassium ion flux. The propagation of electrical impulses across the specialized heart muscle cells that comprise the heart’s conduction system is dependent upon the flux of sodium and potassium ions across the cardiac cell membrane. Among the DM-related splicing changes in the heart, the research team discovered that a sodium channel gene, SCN5A, was mis-spliced. Specifically, there was a switch from SCN5A messenger RNA containing the normal, adult 6B exon to the fetal 6A exon.

This finding was of particular interest since the 6A exon-containing SCN5A is known to exhibit reduced excitability when compared to the normal adult SCN5A. To establish a connection between the molecular event, the DM-related switch from adult to fetal SCN5A isoform, to cardiac dysfunction, the research team developed a mouse model expressing the fetal, rather than the adult, SCN5A isoform. Notably, these mice exhibited similar cardiac conduction system delays and arrhythmias to those characteristic of DM, thereby providing support for a causal relationship between mis-splicing of SCN5A and cardiac dysfunction.

The mis-splicing of SCN5A explains some important changes in the hearts of DM patients. Mutations in SCN5A have been linked to other cardiac diseases, and there is the potential for repurposing the therapeutic and management strategies used in those diseases to DM. Knowledge of the downstream molecular changes that are responsible for changes in heart function will yield important insights into development of novel therapies for myotonic dystrophy.

It should be recognized that this study would not have been possible without the partnership of DM patients and a large scientific team of investigators. The sharing of expertise and resources that lies behind the success of this study needs to be our continuing model for future progress in understanding and treating DM. For information on other scientific studies currently recruiting, please see the Study and Trial Resource Center.

Reference:

Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy.
Freyermuth F, Rau F, Kokunai Y, Linke T, Sellier C, Nakamori M, Kino Y, Arandel L, Jollet A, Thibault C, Philipps M, Vicaire S, Jost B, Udd B, Day JW, Duboc D, Wahbi K, Matsumura T, Fujimura H, Mochizuki H, Deryckere F, Kimura T, Nukina N, Ishiura S, Lacroix V, Campan-Fournier A, Navratil V, Chautard E, Auboeuf D, Horie M, Imoto K, Lee KY, Swanson MS, Lopez de Munain A, Inada S, Itoh H, Nakazawa K, Ashihara T, Wang E, Zimmer T, Furling D, Takahashi MP, Charlet-Berguerand N.
Nat Commun. 2016 Apr 11;7:11067. doi: 10.1038/ncomms11067.

Since its discovery almost 25 years ago, researchers have been working to try to understand the DNA mutation causing myotonic dystrophy type 1 (DM1).

The mutation is known by many names, including “CTG repeat,” “triplet repeat,” “trinucleotide repeat,” “expansion mutation” and many more. Over the years researchers have determined that the mutation is unstable, and most often grows larger in size. Not only does the repeat usually get larger each time it is passed on to children, it can also get larger inside an individual person. 

For example, a common blood test for DM1 taken from the same person several times over many years reveals that the repeat grows slowly over time. It is important to note that a repeat size reported on a genetic test most often reflects an average size, or the most commonly found size of the repeat, it does not represent the size found in every single blood cell. 

Furthermore, the repeat size in the muscles of an individual with DM1 will often be many times bigger than the repeat size found in their blood, making the study of DM1 repeat size a very complicated research field. 

Researchers have puzzled over why the repeat is so unstable, and what drives the repeat to expand so much in some types of cells, and in some people more than others. In order to understand this better, researchers from the University of Costa Rica and the University of Glasgow teamed up to examine the DNA from 199 individuals with DM1 in order to determine what might be driving the repeat to grow. 

This team had previously developed a way to mathematically predict the original repeat size found in an embryo at the time of fertilization, and determined that this predicted repeat size could more accurately predict the age someone with DM1 would first experience any symptoms. In fact, this predicted repeat size was calculated to be responsible for 89% of the variability seen in blood over time. However the remaining forces driving repeat instability were unknown. 

In this recent publication, the same team explored whether there were other genetic factors aside from the repeat that might be inherited, and driving instability. They found that one variation in the genome, inside a gene called MSH3, was strongly connected to an increased amount of instability. 

This gene has previously been connected to the instability of DNA repeats, however this is the first time a naturally occurring variation has been connected to driving instability in people with DM1. Researchers call this variation a “modifier,” because it modifies how the DNA repeat behaves over time. 

Since larger DNA repeats have been previously associated with more severe symptoms, it is possible that future research might show that symptoms can be worse or better depending on which of the two variations of the MSH3 gene you inherit from each of your parents.  

However, that type of study would likely require many more patient samples than this preliminary study of 199 individuals. Interestingly, a study on cancer risk found that this same variation was linked with an altered predisposition to cancer, but the variant that had negative consequences when it came to cancer risk was the variant that saw less instability in DM1. Therefore, this variant can have both positive and negative consequences in humans.

Reference:

A polymorphism in the MSH3 mismatch repair gene is associated with the levels of somatic instability of the expanded CTG repeat in the blood DNA of myotonic dystrophy type 1 patients.
Morales F, Vasquez M, Santamaria C, Cuenca P, Monckton DG.
DNA Repair (Amst). 2016 Mar 8.

Thornton Receives Prestigious National Science Award

Dr. Charles Thornton, neurologist at the University of Rochester Medical Center and MDF Scientific Advisory Committee member, has been awarded a Javits Neuroscience Investigator Award from the National Institutes of Health (NIH) to further his research on muscular dystrophy. Congress established the Senator Jacob Javits Awards in the Neurosciences in honor of the late Senator Javits (R-NY), who was himself afflicted with amyotrophic lateral sclerosis (ALS).

Javits Neuroscience Investigator Award

The Javits Award (R37) is a conditional, seven-year research grant given to scientists for their superior competence and outstanding productivity. Javits Awards provide long-term support to investigators with a history of exceptional talent, imagination and preeminent scientific achievement. The award is initially for a period of four years, after which, based on an administrative review, an additional project period of three years may be awarded.

Investigators may not apply for a Javits Award. Nominations for this award are made by the National Institute of Neurological Disorders and Stroke (NINDS) staff and by members of the National Advisory Neurological Disorders and Stroke (NANDS) Council. These nominations are then reviewed by the Director, NINDS and the NANDS Council.

Particularly Deserving Investigator

MDF reached out to Charles' longtime collaborator, Dr. Richard Moxley, for his thoughts on Charles and the Javits Award. Dr. Moxley noted that his comments about Charles could go on at length. In brief he noted:

"Charles exemplifies the best in superb clinical research. He is a caring physician, a brilliant scientist with innovative insights, a meticulous, thoughtful investigator, and an excellent team builder -- a critically important component of productive translational research."

He also shared the email that he received from Dr. Glen Nuckolls, Program Director of Extramural Research Program at NINDS. Dr. Nuckoll's comments underscore those provided by Dr. Moxley about Charles:

"This is a much deserved award! The NINDS Advisory Council members were universally enthusiastic about [Charles'] scientific accomplishments, service to the research and patient communities and remarkable track record of peer reviewed applications."

MDF's board and staff join many others in extending our very enthusiastic congratulations to Dr. Thornton for this outstanding recognition, and thank him for his transformative work on myotonic dystrophy research.

Read the University of Rochester Medical Center announcement here.

The University of Iowa’s DM1 Brain Imaging Research Group is excited to announce that its study (previously in a pilot phase of data collection) has been awarded a grant by the National Institute of Neurological Disorders and Stroke (NINDS), a division of the National Institutes of Health (NIH), to fund a 3-year longitudinal study of adults with a family history of DM1. 

This study seeks to identify, measure and track over time common symptoms and changes in the brain that may be happening to individuals living with DM1 and those at risk for DM1. 

The study is looking for adults aged 18 through 65 years old and living in the US who either:

1)    Have been diagnosed with DM1 after the age of 21 OR
2)    Have not been diagnosed with DM1 but have a family history of DM1 (i.e. are “at-risk” for developing DM1)

Research participants will be invited to come to the University of Iowa, located in Iowa City, Iowa, for three yearly study visits, each lasting about 8 hours. Study participants will be compensated for their time and travel.  

Eligible persons interested in participating should contact Stephen Cross, the Research Associate for this study, directly at (319) 384-9391 or email. Learn more about research trials and studies, and read about Dr. Ian DeVolver's study on the brain. 

In a collaboration with pharmaceutical company Sanofi-Aventis, University of Florida investigators Dr. Andrew Berglund, Dr. Eric Wang and Dr. Kausiki Datta have been awarded $200,000 by MDF to screen for new drugs to treat DM1 and DM2.

The group will first optimize an assay designed to identify compounds that inhibit the transcription of the repeats in the DM1 and/or DM2 genes, and then will work with Sanofi to conduct a high throughput screen to identify drug candidates. By targeting transcription of the repeats, the group hopes that a variety of potential downstream toxic effects will be corrected, from protein sequestration to improper signaling to protein production through RNA translation.

This work builds on a previous discovery by Dr. Berglund and colleagues that the antibiotic Actinomycin D can block transcription of CUG repeats at nanomolar concentrations.

Reference:

MDF is pleased to welcome Dr. Kathie Bishop, Ph.D., to its Scientific Advisory Committee(SAC). Dr. Bishop, who joined the SAC in summer 2015, is a seasoned expert in neurological and neuromuscular research and drug development.

She received her Ph.D. in neurosciences from the University of Alberta (Canada) in 1997 and then completed a postdoctoral fellowship in molecular neurobiology at the Salk Institute in La Jolla, Calif.

From 2001 to 2009, Dr. Bishop was at Ceregene, a San Diego biotechnology company developing gene therapies for neurological disorders. At Ceregene, where she was Director of Research and Development, she worked on preclinical and clinical programs in Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, retinal degenerations, and amyotrophic lateral sclerosis (ALS).

In 2009, Dr. Bishop moved to Ionis (formerly Isis) Pharmaceuticals in Carlsbad, Calif., a biotech company specializing in antisense oligonucleotide-based therapeutics. While at Ionis, she led programs within the neurology franchise, including leading development for programs for spinal muscular atrophy, amyotrophic lateral sclerosis, type 1 myotonic dystrophy (DM1), and other rare genetic neurological disorders. She left Ionis Pharmaceuticals in 2015, as Vice President of Clinical Development.

She is now Chief Scientific Officer at Tioga Pharmaceuticals, a San Diego biotechnology company developing treatments for chronic pruritus. We talked with Dr. Bishop in October 2015:

MDF: What prompted your decision to move from academia to industry?

KB: I’ve always been interested in genetic neurologic diseases. My original degree was in genetics, and my Ph.D. is in neuroscience. While at the Salk Institute for my postdoctoral fellowship, I worked on development of the brain and spinal cord and found I wanted to apply the science to drug discovery and development.

MDF: What kinds of drug development programs have you worked on?

KB: At Ceregene, we were developing gene therapies for Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and ALS [amyotrophic lateral sclerosis].

When I moved to Ionis, my first program was developing antisense against SOD1 for ALS. We did a phase 1 clinical trial administering IONIS-SOD1Rx into the CSF [cerebrospinal fluid] in patients with the genetic form of ALS, and no safety issues were found. [See Miller et al., Lancet Neurology, May 2013.] At the time, we were concentrating on whether the CSF delivery of antisense drugs would be feasible and safe, which it was

I led the SMA [spinal muscular atrophy] program at Ionis from the preclinical stage through the phase 1 and phase 2 trials and up to trial design and initiation of phase 3 studies. IONIS-SMNRx acts on the SMN2 gene to change SMN2 splicing so that a functional protein is made. It acts right on the disease mechanism. This antisense [ASO] drug is the same chemistry as IONIS-SOD1Rx, but it doesn’t downregulate the SMN protein the way IONIS-SOD1Rx downregulates the SOD1 protein. The ASO doesn’t have a gap for an enzyme to bind that would downregulate the SMN RNA. It’s now in phase 3 studies in infants and in children with SMA.

I was also involved with developing IONIS-DMPKRx, an ASO against the DMPK RNA to treat type 1 myotonic dystrophy [DM1]. We completed a phase 1, single-dose study in healthy volunteers, and a multiple-dose study in adults with DM1 is ongoing. IONIS-DMPKRx destroys the DMPK RNA, which is thought to be the cause of DM1. It also affects the wild-type DMPK allele, but it may have a preference for the [abnormally expanded] DMPK RNA that’s stuck in the nucleus.

MDF: Do you see other therapeutic avenues for DM?

KB: Yes, absolutely. I think any one therapy, even one which acts on the genetic mechanism in DM, might not work perfectly in longstanding disease and might not work on all aspects of the disease or in all patients. We may need other compounds, such as muscle-enhancing drugs, to supplement it and be taken together with it. We will also need additional drugs that work on other aspects of DM, such as drugs that help stop degeneration in smooth muscle and heart, as well as CNS [central nervous system] drugs. Antisense drugs such as IONIS-DMPKRx do not penetrate into the CNS when given systemically, and particularly in the congenital and juvenile-onset forms of the disease, the CNS effects need treatment.

MDF: What do you see as the main challenges to drug development for DM and other rare disorders? For example, how can small companies meet the demands of patients for expanded access to compounds in development while pursuing full regulatory approval for these compounds?

KB: I think it’s the responsibility of people like me, who work in drug development, and of drug companies to communicate effectively about the development process and the risks involved to patients, their families, and their caregivers. We have to make it clear that experimental treatments could be harmful, and we have to be realistic and honest about the potential benefits. There is a lot of hope, but we also need to communicate better with the patient community about the drug development process.

That said, I would like to see the drug approval process be more efficient and go faster for diseases where the drug has a clear mechanism that acts directly on the underlying genetic cause of the disease. I think the FDA [U.S. Food and Drug Administration] is on board with this, but they aren’t going to come up with solutions. The drug developers have to do that.

MDF: What particular challenges do you see with drug development for DM?

KB: The clinical outcome measures used in this disease change very slowly, so you need long trials to measure decline. We need molecular markers, such as those reflecting splicing changes downstream of the mutant DMPK RNA that are linked to clinical changes. These are known as surrogate markers, and companies have to provide the data on these markers and clinical outcomes to the FDA.

MDF: What particular skills and insights will you bring to the MDF Scientific Advisory Committee?

KB: I plan to advise MDF on DM drug development and on incorporating science into drug development. I hope to help with encouraging and supporting new drug discovery and development programs for treatments for DM, advising on clinical trials, developing surrogate markers in DM, and having an effective working relationship with the FDA.

Although up to 25% of people with myotonic dystrophy report that gastrointestinal symptoms are their most troubling issue, we still understand little about their cause. MDF Fellow Dr. Melissa Hinman at the University of Oregon is tackling this issue with Dr. Andy Berglund of the University of Florida using zebrafish models.

Hinman, who received a Case Western University Doctoral Excellence award in 2014 for her work on the NF1 gene, says she was drawn to work on myotonic dystrophy for her postdoctoral fellowship because of the complicated nature of the pathology. “The mechanisms of most genetic diseases that you hear about are a bit boring to me,” she explains, “a mutation in DNA leads to loss or gain of function of some protein, which causes disease phenotypes. RNA-related diseases are much more creative in their mechanisms and it’s a fascinating puzzle try to figure out how they work.”

Focusing in on gastrointestinal (GI) changes in DM, she has hypothesized that inappropriate GI motility in DM causes changes in gut microbiota, which then feed back to impact disease phenotypes. To get at this question, Hinman will characterize whether and how gut motility differs in DM model zebrafish, and use tissue-specific expression of CUG repeats to narrow down the tissues that are responsible for gut phenotypes. She will then use established methods for manipulating zebrafish gut bacteria to determine whether microbiota are necessary for DM related phenotypes, and whether altered bacteria cause DM-related phenotypes in wild type fish.

“It is becoming increasingly clear that human health is influenced not just by our own genome, but also by the genes of the microbes that live on and within us, or the microbiom,” says Hinman. “Deviations from normal microbiota have been shown to contribute to many human disorders such as inflammatory bowel disease, cancer, and obesity. Individuals with diseases that impair gut motility, such as Hirschprung’s disease, often have altered microbiota, which are thought to influence disease severity. Since gut motility is also affected in DM, we are investigating whether there are associated changes in microbiota and how these changes might influence disease symptoms.”

After several months of prep work she is finally ready to start characterizing several new stable models of DM in zebrafish, and is looking forward to seeing what light they may be able to shed on gut phenotypes. Although mentor Andy Berglund’s focus on myotonic dystrophy matched her interests well, Hinman says that it’s an added bonus that the University of Oregon is the birthplace of the zebrafish as a model organism and home to many zebrafish experts, including her co-mentor Karen Guillemin (because Berglund has moved to the University of Florida, Hinman is finishing her project in Guillemin’s laboratory). In the future she would like to delve deeper into the molecular mechanisms behind myotonic dystrophy and speculates that zebrafish would be an ideal model for this goal, as well as for screening therapeutic compounds.

Hinman will be giving a talk about her work at the MDF Annual Conference in Washington, DC, on September 19th. She says she is most looking forward to meeting people who are living with the disease, saying “I never got the opportunity to meet anyone with NF1 (the disease that I studied in graduate school), and as a result I felt like I didn’t fully understand the disease.” Dr. Hinman’s talk will be recorded and available to view on the MDF website by the end of September.

09/15/2015

Researchers at the University of Virginia recently published a paper describing a biological pathway they believe is affected in people with myotonic dystrophy (DM). Previous studies have identified the DNA mutations causing both types of DM, and determined that the RNA molecule made from the DNA is the culprit in causing toxicity in the cell and leading to symptoms of DM.

Though DM symptoms such as myotonia have been linked to the toxic RNA molecule, other symptoms such as muscle weakness and muscle wasting have not been fully explained. This study identifies a possible pathway, the TWEAK/Fn14 pathway, which appears to be activated in DM mouse models and in muscles of people with DM1. The authors suggest this pathway may be responsible for muscle degeneration in DM1, and that blocking the pathway might prove beneficial. A drug blocking this pathway, known as the anti-TWEAK antibody, is currently in trials for other diseases.

When the anti-TWEAK antibody was tested on a very small sample of DM mouse models, there were improvements in muscle appearance and function. However, the treatment was not sufficient to reverse myotonia or cardiac conduction defects in the mouse models. The authors concluded that the treatment will likely not cure myotonic dystrophy, but instead may be better suited for a therapeutic approach involving a combination of experimental treatments.

Further analysis is necessary to determine whether the TWEAK/Fn14 pathway and targeting it in individuals with DM1 provides a worthwhile therapeutic strategy. The pharmaceutical company Biogen Idec and the Mahadevan Lab at the University of Virginia have been conducting an investigative collaboration for several years studying the pathway and the anti-TWEAK molecule. Anti-TWEAK may be used at some point in the future to target specific diseases that may or may not include DM, but plans and dates have not been formulated. MDF will keep the community apprised if developments become available.

05/21/2015

Studying the Causes of DM Disease Severity

UK geneticist Darren Monckton’s fascination with human genetics dates back to his six-month undergraduate placement in the lab of geneticist Alan Roses at Duke University. At that time, the late 1980s, no one knew the genetic basis for inherited conditions such as myotonic dystrophy (DM), Huntington’s disease, or cystic fibrosis, Darren recalls, “and much of our effort focused on family analysis, what we call ‘mapping,’ trying to identify the disease-causing gene.”

Later, as a PhD student at the University of Leicester back in the UK, Darren worked in the lab of Alec Jeffreys, helping to understand the biology underlying the high levels of individual specific variation revealed by DNA “fingerprinting” - work that focused on understanding repeated sequences within the DNA. Then, just as he was finishing his PhD in the 1990s, researchers began discovering that alterations of repeated DNA sequences were becoming associated with a number of genetic diseases, including DM. “This brought together my longstanding interest in genetic disease with my expertise on DNA repeated sequences I’d gotten during my PhD,” Darren says. “It was a perfect fit.”

Darren subsequently applied for and received a fellowship from the Muscular Dystrophy Association to work in the lab of Tom Caskey at Baylor College of Medicine in Houston, one of the labs that first identified the CTG expansion in the DMPK gene as the genetic underpinning of DM.

Correlating genetics with symptoms

Today, Darren heads up a major genetic disease research group, focused largely on DM, at the University of Glasgow in Scotland. Once again, as in his undergraduate days, his work focuses mostly on families, now trying to understand the relationship between the disease’s underlying genetics and symptoms in families and individuals. “We work with a very collaborative group of clinicians in Scotland - neurologists, clinical geneticists - who've got an excellent system organized in terms of caring for and managing families with myotonic dystrophy,” Darren explains. “Through them we recruit patients for our genetic studies.”

The lab also works with other researchers - including from the US, Canada, and Costa Rica - who have access to groups of patients with complete medical records that allow them to be tracked over time, comparing their clinical symptoms with their underlying disease process as revealed by genetic testing. “Having cohorts of patients that have been carefully followed over a number of years is absolutely key to what we're doing,” Darren says.

A variable disease

This work is essential because DM is such a variable disease. It’s known, for example, that the underlying number of CTG repeats responsible for the condition increases from one generation to the next resulting in more severe symptoms at an earlier age in each succeeding generation, a phenomenon known as anticipation. “We’re trying to understand the dynamics of that process,” Darren says.

Researchers have also discovered that repeats tend to increase throughout the lifetime of the individual. “That happens at different rates in different tissues,” Darren says, “faster in muscle cells and brain cells, which appears to correlate very strongly with the tissues in which we see the most symptoms. That may explain why the symptoms become worse with age.”

That finding has profound implication for DM testing, says Darren, making it difficult to predict the severity of future symptoms or, in the case of a couple considering having a child, how severe symptoms might be in the next generation. “When we're trying to correlate the number of repeats a person has with the relative severity of the symptoms. That's complicated by the fact that the number of repeats itself is changing.”

So the team is working to develop methods that make such predictions more reliable. “What we've found is that by looking not just at the average number of repeats within a population of cells, but by looking at a lot of individual cells, we can build up an understanding of the overall degree of variation in the number of repeats. Using mathematical models and other approaches, we can then predict the number of repeats the individual was born with. When we do that, we’ve found that it's much more accurate in predicting how severe the symptoms will be.”

Variant repeats

Another key recent finding by the researchers is that in some a relatively small proportion (around 5%) of families, the DNA may include other sequences mixed in with the CTG repeats, so called “variant repeats,” and that this can be associated with profound differences in the symptoms of those family members. Sometimes the variant repeats may be associated with additional symptoms, such as neuropathy, but more often they seem to make the DM symptoms less severe.

“These individuals have either very mild symptoms, or, in some cases, have no symptoms at all,” Darren says. “They have essentially self-cured in a genetic kind of way. That gives a lot of insight. If we could reproduce that effect in individuals who have inherited a pure CTG tract, then that would potentially be very beneficial.”

Darren describes his work as a quest to “understand the natural history of the disease as it relates to its underlying genetics.” This understanding is particularly crucial as researchers begin clinical trials of drugs that may one day be used to treat the disease. “One of the challenges with myotonic dystrophy is that the disease is so incredibly variable,” he says. “In a clinical trial, you have groups of treated patients and untreated patients, but obviously with DM, those individuals were going to be very different before you had any sort of intervention. Determining whether the drug has been effective at all can be quite difficult. By better understanding why different individuals have very different symptoms and how their symptoms were likely to have changed in the absence of a drug, we can better understand whether a drug is actually working or not.”

Looking forward to IDMC

Darren is looking forward to June’s IDMC-10 meeting in Paris. He’s attended all of the IDMC meetings over the years and appreciates the unique degree of collaboration among researcher in the DM field. “It's really a great field in that everybody is really open, very collaborative, willing to share unpublished data,” he says. “The meetings are a great way to get up to speed on what's going on and to form new collaborations and to try to help one another out.”

Like many researchers, he’s particularly looking forward to any updates that may be forthcoming about the pioneering drug trial that was recently launched in the US. “A lot of scientists are working on this disease because it is so unusual and complicated. But we are now at a point where we have a pretty good idea what’s going on, and that’s changed over the last four or five years. At the last few IDMC meetings we've had people saying, ‘ok, now we know what's going on inside the cells, how do we actually develop treatments?’ It's very exciting that one of those agents that was effective first in cells and then in an animal model is now going into clinical trials. It's exciting to see how that's all progressing.”

05/21/2015

A Three Year, Multi-Million Dollar Roadmap to Accelerate Care and a Cure

Back in February of this year, we reported out on our annual strategic planning offsite. We reaffirmed our commitment to capitalizing upon the unprecedented current interest in myotonic dystrophy to improve quality of life for people living with the disease. We noted then that we would report back when we had a final 3-year plan to share with you.

The development of that plan has been our major focus for the past few months, and we are very pleased to communicate the results to you. MDF has pledged our resources to a number of significant initiatives developed to accelerate Care and a Cure for the next three years.

Goals

The goals for the next 3 years of work are aggressive:

• Drive community-wide access to high quality DM care and shorten the diagnostic odyssey via care standards, clinical networks and improved patient access
• Deepen and strengthen the academic research bench to support more DM scientific discovery
• Expand the drug development pipeline with additional industry participation and additional drug discovery-focused research
• Expedite the therapy approval process via a targeted and immediate education and outreach effort with legislators, regulators, and other federal agencies
• Lay the groundwork for patient access to approved therapies through outreach and activism with insurers

Care

In the Care arena, MDF has identified a number of high impact initiatives to help achieve these goals, some of which we have described below.

Care Considerations

There are currently no standards of care for treatment of myotonic dystrophy, and patients and family members often find themselves educating their physicians with regard to symptoms and treatment options. The lack of standardized care protocols also makes tracking the impact of potential therapies in trials more difficult, since it can be unclear what impacts to attribute to the therapy and what is due to differences in individual participants’ care and disease course.

MDF, members of our Scientific Advisory Board, the Centers for Disease Control and others will partner to create consensus-based Care Considerations that can be used by doctors, pharmaceutical companies and federal regulators reviewing potential therapies for approval until more rigorous and comprehensive Practice Parameters are developed. We are scheduling the development of final draft considerations for mid-2016.

Research Focused on Women & DM

In order to improve understanding of disease impacts, disease course and progression in women living with myotonic dystrophy, and improve the quality of care women receive, MDF will fund the research and publication of studies focused on how myotonic dystrophy affects women. An example of such studies is the recently study that examined how women with myotonic dystrophy (DM) are impacted by pregnancy.

Expanded Fellows Award Program

To attract and retain high quality young investigators, drive retention at clinical care and research sites, support senior DM investigators and their labs and improve the quality of care delivered to people living with DM, MDF will expand the Fellows program to include pre-doctoral students, clinical fellows and fellows identified by senior research leadership.

The fellows receive training in grant writing and travel funds to attend major meetings, in addition to funding for their research projects. Two former MDF fellows have now received faculty appointments in the field.

Certified Clinical Network

MDF will explore the need and opportunity to create certification standards and a process to certify clinical centers in order to identify and support centers of excellence for people and families living with myotonic dystrophy.

Expansion of Current Care Resources and Programming

MDF is working to expand the resources and support we offer to community members now, in order to make the quality of life of people living with DM the best it can be. To that end, we will launch additional regionally-based support groups, upload more recommendations on the Find A Doctor map, expand programming at the MDF Annual Conference, and much more. MDF will also undertake a significant Care programs assessment effort, including review of the Myotonic Dystrophy Family Registry and a community survey, to identify new Care program needs and opportunities.

Cure

Most of the work in the research cure bucket is focused on making it as efficient and easy as possible for the scientific community to develop and test new drugs for myotonic dystrophy. This process is called “de-risking” and it is aimed squarely at making the numbers work for drug companies that are considering investing in the myotonic dystrophy space. For example, company X has developed an experimental compound that might help build new muscle. The company could test it on elderly people who lose muscle strength as they age, or test it in myotonic dystrophy - we want to give them every reason to choose myotonic dystrophy.

Myotonic Dystrophy Clinical Research Network Expansion

To this end, one major focus of MDF’s research plan is bolstering the capabilities of the Myotonic Dystrophy Clinical Research Network (DMCRN) - a network of six clinical sites launched in 2013 that are centrally coordinated to conduct research studies key to informing trial design and disease understanding, and to run multi-site clinical trials for myotonic dystrophy. We will do this by expanding the network from six sites to nine sites and providing the central coordinating center at the University of Rochester with additional resources for oversight and management.

This expansion is necessary to accommodate the larger clinical trials that will be required to approve a new drug for myotonic dystrophy. It will also help investigators gather data on the normal progression of the disease, which is needed to determine from a statistical standpoint how many people should be included in future clinical trials and what types of things we should measure to know if an experimental DM therapeutic is working.

Advocacy with Policymakers, Regulators & Insurers

While we are at it, we will also help to make the case to insurance companies and government health agencies that new treatments for myotonic dystrophy are cost effective and should be covered because the cost of not treating the disease is higher. To do this we will document the “burden” of myotonic dystrophy by researching the insurance claims data of many thousands of people who have been diagnosed with myotonic dystrophy and determining the average cost per year of the disease. Become an advocate now.

In the same vein, MDF will host a strategic workshop with the Food and Drug Administration (FDA), researchers and companies interested in myotonic dystrophy therapy development later this year. Our objective in bringing these professionals together is to educate them on the specific challenges and complications of myotonic dystrophy in order to inform efforts to develop clinical trial endpoints, biomarkers and advance the discovery of new therapies. Ensuring that FDA regulators and companies understand how variable and multi-systemic this disease will help inform clinical trial design. Hearing from the FDA about the rigorous process involved in approving endpoints for trials will help researchers and companies best target their biomarker, endpoint and trial development efforts. At the workshop’s conclusion, our community should be better positioned for successful therapy development and clinical trial testing.

DM Prevalence Study

We are also launching a study to determine, not just the number of people who have been officially diagnosed with myotonic dystrophy, but also how common the expanded repeat mutation is in the general population - we believe it’s likely that this study will show that myotonic dystrophy is more common than previously assumed because it often takes many years for people to receive an official diagnosis. If the disease is actually more common than thought this means that the burden associated with the disease will also higher. This information is a critical component to making the case for pharmaceutical company investment, insurance reimbursement and for policy making that affects the myotonic dystrophy community.

New Research Studies

In addition to the prevalence and burden of disease studies, we are also releasing requests for research proposals (RFPs) seeking researchers interested in identifying “biomarkers,” such as changes in blood proteins that would indicate how the disease progresses, and to developing new “endpoints,” or measurements that will demonstrate if an experimental therapeutic is working. Learn more about current research studies.

Mega Mouse

The research community has also emphasized the need to create a mouse that more realistically mimics the disease that we see in humans so that we can test therapeutic approaches quickly and efficiently - we will fund the creation of the new mouse this year.

We Need Your Help

These are some of the major initiatives MDF has launched or scheduled for the next three years. It is an ambitious and urgent array of work. You have a role to play in many of these efforts, including participating in research studies conducted through the DMCRN and other university centers, enrolling in DM patient registries, participating in surveys and helping advocate for specific legislation and initiatives that can help improve quality of life and drive therapy discovery forward.

Let us know if you would like more information or have comments on the strategic plan work described above, and please watch the Dispatch and our other communication for alerts regarding how you can support this work and other efforts on behalf of Care and a Cure. Together we will change the face of myotonic dystrophy.

05/07/2015