Endpoint Award

Dr. Donovan Lott, of the University of Florida, has successfully competed for support of his project, “Development of Magnetic Resonance Imaging as an Endpoint in Myotonic Dystrophy Type 1.” The award is for one year, at $150,000. 

Dr. Lott’s group has extensive experience in developing skeletal muscle MRI as an endpoint measure in neuromuscular disease, including their ongoing interactions with FDA to obtain biomarker qualification. There have been very few imaging studies of myotonic dystrophy skeletal muscle. Given the considerable potential of MRI, an assessment of the feasibility of the approach in DM is essential.

Drug development in myotonic dystrophy (DM) enjoys an important advantage—having the tools in hand to show that a drug candidate gains access to and modifies the primary cause of the disease. Since expanded repeats in DMPK (in DM1) and CNBP (DM2) sequester MBNL1 protein and cause easily assessable molecular (mis-splicing of a large set of genes) and physiological (myotonia) changes, we can get an early signal in Phase 1/2 trials that a candidate therapy engages and modulates a key drug discovery and development target.

The existence of clear endpoints for early stage clinical trials helps de-risk DM for investments by pharmaceutical and biotechnology companies. By contrast, the development of endpoint measures that either establish, or are surrogates for, a clinically meaningful benefit is a clear need for Phase 3 trials in DM, in order to gain regulatory approval for a drug or biologic.

With the objective of meeting this critical need, MDF issued a Request for Applications to identify and support a project with the objective of developing new, clinically meaningful endpoint measures or refining endpoint measures already in development. Dr. Donovan’s project received the highest rating from the MDF peer review panel and was selected for funding.

Dr. Donovan’s team will complete a project in 25 DM1 patients. In these studies, they will quantitatively assess upper and lower limb muscle status by MRI and relate findings to a battery of functional measures, thereby taking the first steps toward development and qualification of MRI as a sensitive and non-invasive biomarker for clinical trials in DM. A qualified endpoint measure, with established linkage to clinically meaningful outcomes for patients, will make each of our clinical trials considerably more efficient and informative.

UK Natural History Grant 

Professor Hanns Lochmuller and Newcastle University are being awarded a $125,000 grant to extend a natural history study of 200-400 adult DM1 patients. 

The Newcastle group is currently funded by the UK National Institute for Health Research to recruit and collect natural history data on the DM1 cohort for one year, through March 31, 2017. MDF funding will leverage this existing funding to allow Professor Lochmuller and colleagues to reach the upper end of their recruitment target and to extend the duration of data collection from this valuable cohort for an additional year. Data collection involves a wide variety of endpoints, with the aggregate data assisting in the planning, design, and recruitment of future clinical trials, as well as supporting identification of putative biomarkers of DM1.

Robust natural history studies are critical to the development of endpoint measures that reflect clinically meaningful benefit for use in registration trials. MDF and the Wyck Foundation are pleased to be able to leverage other grant funding to increase the value and impact of this study.

07/27/2016

The Jensen family has a long tradition of hosting an authentic Louisiana crawfish boil with live music for their family and friends in San Diego. The Crawfish Boil became a fundraiser in 2012 when Taylor Jensen and her young son, River, were diagnosed with myotonic dystrophy type 1 (DM1). The Jensen's learned first-hand how complex DM is and how it impacts an entire family. After struggling with the initial impact of the diagnosis, Taylor and Eric evolved the family tradition into a fundraiser to support Care and a Cure.

The Fundraiser has two ultimate goals: to raise awarness of the most common form of muscular dystrophy known as myotonic dystophy (DM); and to to raise funds to continue the research that will enable treatments and an eventual cure. This year marks the first time people living with DM are receiving a potential therapy. The first DM clinical trial began this year, evaluating a medication that targets not just disease symptoms but the genetic mutation that causes the disease.

This year the Jensen Family had their 5th Annual Crawfish Boil Fundraiser ("Pinching Tails for a Cure") hosted at the San Diego Harley Davidson Dealership. Thanks to the sponsors and donors, the Crawfish Boil was a success, raising over $30,000 - bringing that to a total of $110,000 over the last five years!

You can read more about their personal journey with DM in this letter from the Jensen family.

Are you interested in hosting a fundraiser for Care and a Cure? MDF is here to help.

Caroline Easterling, a former preschool teacher and mother of 11-year-old twin girls has been in two recent DM 1 studies. She’s learned a lot along the way and has solid advice for anyone who wants to make a contribution to the greater good by taking part in research.

1. Do Your Homework

Each study and trial has unique requirements. Find out exactly what those are before you get started. 

For example, drug trials may include side effects. You need to understand the potential consequences of side effects, including how they might impact your daily life during the trial.

Another issue to consider is the time commitment. One study Caroline participated in was close to home. That made it very easy to keep up with appointments. However, another was located more than an hour away. It even required some overnight hotel stays. This presented more of a challenge, especially with child care. With advance planning and family support, Caroline was able to make it work.

“You want to be able to see it through to the end, so find out all the information you can,” says Caroline. “You’ve got to make sure you can do the time commitment. Find out about any side effects ahead of time. You’ve got to be willing to deal with the side effects.”

2. Line Up Support

It’s great to have support when you try something new. Studies are no different, and your research team is there to support you. Don’t be afraid to ask questions, and let them get to know you. Caroline found that her team was a great source of support, not just for the study, but also for her DM concerns. 

“It gave me the insight that people really care,” she said of the researchers she worked with. “They were very willing to answer my questions and give me information. They were happy to help me with family life stuff that I was having issues with. They talked about what may be coming next for me down the line.”

Let your friends and family know what you will be doing and that it may require some changes to your usual shared routines. Caroline and her husband knew they would need to swap some household responsibilities in order for Caroline to participate. With her husband’s support, she was able to fit the studies into their family schedule.

“Make sure your family is OK with the time that you’re asking from them. My husband had to take the kids to school and pick them up. It’s not just you who has to deal with the time," says Caroline.

3. Get a Study Buddy

Having a friend to share an experience with always makes it better, and the buddy system applies to research too.

Caroline’s sister, Mary, also has DM1 and has been in both studies with her. “I lucked out to have someone like my sister to hang out with me,” Caroline says. “We accompanied each other to each appointment.”

Do you know someone who would also be a good candidate for a trial you are considering? Let them know about it, and see if you can participate together. Or maybe you have a friend or family member who can make time to share the drive and attend appointments with you.

Challenges to research participation can be minimized with education, support and advance planning to smooth the way. Caroline emphasizes the rewards. “Research studies are important, because they give us insights that we wouldn’t otherwise have,” says Caroline. “A research study will help the greater good, and I’m hoping one may help me.” 

Caroline took part in a study to find DM1 biomarkers (indicators of disease progression), through a site at the National Institutes of Health (NIH) in Bethesda, Maryland. She is also part of a trial by Ionis Pharmaceuticals to test the safety and tolerability of DMPKRx, an experimental drug that targets the underlying molecular defect in DM1, through a site in Baltimore. 

Find out about studies and trials you can participate in.

07/27/2016

Myotonic dystrophy is characterized by considerable variability in signs and symptoms that involve multiple body systems. In addition to variations resulting from repeat length and tissue-specific somatic repeat expansions, we know that gender can influence disease phenotype. Yet, there is a general lack of understanding of factors underlying heterogeneity of the DM phenotype. This warrants further studies of genetic factors, including the potential for additional disease genes and genetic modifiers.

Dr. Simone Rost and his colleagues at the University of Würzburg have explored the potential involvement of genetic variants in determination of DM-like phenotypes and recently published their results in the European Journal of Human Genetics. The team started with a cohort of 5,280 patients with a primary clinical diagnosis of DM evaluated in the Würzburg molecular genetics lab over a 10-year period. Of the cohort, 38% had repeat expansions in DMPK or CNBP, while a relatively small portion of the cohort (< 0.5%) was found to have mutations in genes associated with other types of muscular dystrophy (e.g., FSHD1, LMNA, PABPN1). 

A subset of the patients lacking the traditional DM1 and DM2 repeat expansions, but with DM symptomology verified by neurological exam, underwent further genetic analyses. No additional pathologic variants were identified in DMPK, CNBP, or CUGBP; patients were also free of mutations in 27 other muscle disease genes. The study identified three unrelated patients with potentially pathogenic variants in MBNL1.

Mice with mutations in Mbnl1 appear to phenocopy mice containing large DMPK repeat expansions, consistent with the known role of Mbnl1 in the pathogenesis of DM. To evaluate potential splicing changes due to the MBNL1 variants, the Würzburg team performed splicing assays for six genes that are mis-spliced in DM1, using peripheral blood leukocytes from the three patients. The authors failed to identify splicing alterations, but acknowledge the potential tissue specificity of DM mis-splicing.  

Taken together, Dr. Rost and colleagues have linked MBNL1 variants to a DM phenotype. However, despite careful analysis of thousands of patients with DM-like symptoms, only a small number of MBNL1 variants were identified. These findings suggest that MBNL1 mutations may not be more than a minority contributor to DM, and thus other potential gene variants or modifiers should be prioritized for population studies.

Reference:

Identification of variants in MBNL1 in patients with a myotonic dystrophy-like phenotype.
Larsen M, Kress W, Schoser B, Hehr U, Müller CR, Rost S.
Eur J Hum Genet. 2016 May 25. doi: 10.1038/ejhg.2016.41.

Endpoint Award

Dr. Donovan Lott, of the University of Florida, has successfully competed for support of his project, “Development of Magnetic Resonance Imaging as an Endpoint in Myotonic Dystrophy Type 1.” The award is for one year, at $150,000. 

Dr. Lott’s group has extensive experience in developing skeletal muscle MRI as an endpoint measure in neuromuscular disease, including their ongoing interactions with FDA to obtain biomarker qualification. There have been very few imaging studies of myotonic dystrophy skeletal muscle. Given the considerable potential of MRI, an assessment of the feasibility of the approach in DM is essential.

Drug development in myotonic dystrophy (DM) enjoys an important advantage—having the tools in hand to show that a drug candidate gains access to and modifies the primary cause of the disease. Since expanded repeats in DMPK (in DM1) and CNBP (DM2) sequester MBNL1 protein and cause easily assessable molecular (mis-splicing of a large set of genes) and physiological (myotonia) changes, we can get an early signal in Phase 1/2 trials that a candidate therapy engages and modulates a key drug discovery and development target.

The existence of clear endpoints for early stage clinical trials helps de-risk DM for investments by pharmaceutical and biotechnology companies. By contrast, the development of endpoint measures that either establish, or are surrogates for, a clinically meaningful benefit is a clear need for Phase 3 trials in DM, in order to gain regulatory approval for a drug or biologic.

With the objective of meeting this critical need, MDF issued a Request for Applications to identify and support a project with the objective of developing new, clinically meaningful endpoint measures or refining endpoint measures already in development. Dr. Donovan’s project received the highest rating from the MDF peer review panel and was selected for funding.

Dr. Donovan’s team will complete a project in 25 DM1 patients. In these studies, they will quantitatively assess upper and lower limb muscle status by MRI and relate findings to a battery of functional measures, thereby taking the first steps toward development and qualification of MRI as a sensitive and non-invasive biomarker for clinical trials in DM. A qualified endpoint measure, with established linkage to clinically meaningful outcomes for patients, will make each of our clinical trials considerably more efficient and informative.

UK Natural History Grant 

Professor Hanns Lochmuller and Newcastle University are being awarded a $125,000 grant to extend a natural history study of 200-400 adult DM1 patients. 

The Newcastle group is currently funded by the UK National Institute for Health Research to recruit and collect natural history data on the DM1 cohort for one year, through March 31, 2017. MDF funding will leverage this existing funding to allow Professor Lochmuller and colleagues to reach the upper end of their recruitment target and to extend the duration of data collection from this valuable cohort for an additional year. Data collection involves a wide variety of endpoints, with the aggregate data assisting in the planning, design, and recruitment of future clinical trials, as well as supporting identification of putative biomarkers of DM1.

Robust natural history studies are critical to the development of endpoint measures that reflect clinically meaningful benefit for use in registration trials. MDF and MDF UK are pleased to be able to leverage other grant funding to increase the value and impact of this study.

There has been relatively little research on quality of life for DM2 patients, and DM2 is often considered “less severe” than DM1. However, a new study identified a subset of DM2 patients who are impacted as severely as those with DM1.

Dr. Dusanka Savic-Pavicevic and colleagues recently published a comparison of genetically confirmed DM2 and DM1 patients using a variety of quality of life measures.

The research team found no differences between DM2 and DM1 in the overall and physical composite scores of the survey.

Emotional and mental composite scores were typically better in DM2 patients, as were independence and body image scores. Disease impact on cognition, strength, heart function, breathing and cataracts were also less severe in DM2.

The DM2 patients who reported worse scores were typically older, weaker, and had higher fatigue levels than the DM2 patients who scored better on certain segments of the surveys. Lower quality of life scores were also associated with lower cognitive achievement, memory impairment and lower educational levels.

A deeper understanding of the correlation of age, strength, and fatigue with quality of life in DM2 is needed to facilitate better patient outcomes. More DM2 studies like this will pave the way for higher quality care.

Reference:

Quality of life in patients with myotonic dystrophy type 2.
Rakocevic Stojanovic V, Peric S, Paunic T, Pesovic J, Vujnic M, Peric M, Nikolic A, Lavrnic D, Savic Pavicevic D.
J Neurol Sci. 2016 Jun 15. 

While it has been widely recognized by clinicians treating DM that gender plays an important role in determining disease heterogeneity and progression, there is little hard data to support differential response of males and females to DM.

Dr. Guillaume Bassez and a large team in France and Canada have recently published an analysis of gender as a modifying factor of the DM1 phenotype. In the study, they evaluated 1,409 adult DM1 patients in the French DM-Scope registry. Importantly, findings were validated using additional cohorts from the AFM-Telethon DM1 survey and the French National Health Service Database.

The research team identified clear differences in symptoms detected by gender. Adult males were much more likely to present with “traditional” DM1 signs and symptoms, including muscle weakness and myotonia, cognitive impairment, and cardiac and respiratory involvement. By contrast, adult females had symptoms that were less suggestive of “traditional” DM1, instead showing predominance of cataracts, obesity, thyroid signs, and GI symptoms.  

The differing constellation of symptoms in the two sexes led the research team to conclude that women were often less symptomatic of DM1 and thus often undiagnosed, although this was potentially offset by the finding that women appeared to more often seek specialist care for DM1 symptoms.

Gender matters in DM1. The biologic mechanisms underlying the gender differences that the French group has documented for DM1 are unknown. To improve diagnosis and management of DM1, as well as to better plan for inclusion of both genders in clinical trials, it will be important to understand the factors responsible for the very different onset and progression of DM1 in males and females.

The heterogeneity (variability) that characterizes the clinical manifestations of myotonic dystrophy type 1 (DM1) has been well recognized by physicians, patients, and family members. Although the length of CTG expansions in the DMPK gene correlates with age of onset and severity of DM1, knowledge of other factors that impact progression of DM1 currently is rather limited.  

Intensive analysis of large cohorts of DM1 and DM2 patients are underway to identify both genetic modifiers, gene variants that can speed or slow disease onset or progression, and biomarkers, measurable indicators in blood or other tissues that can be critical for studies of disease progression and clinical trials. 

MDF is partnering with the research community to identify biomarkers and move them toward qualification by the regulatory authorities as drug development tools.

Understanding of the biological factors behind heterogeneity of DM1 is critical to help patients better understand their disease, as well as to help drug developers design successful clinical trials. The studies necessary to identify the underlying factors require large cohorts of affected individuals—for this reason, it is essential that patients become involved in research efforts that build the requisite databases, such as the Myotonic Dystrophy Family Registry. 

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.

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. 

Poor communication, fatigue and gastrointestinal problems worry parents most.

Dr. Nicholas Johnson at the University of Utah and colleagues released the results of an MDF-funded multinational study on the impact of congenital myotonic dystrophy (CDM). The study relied upon a survey filled out by 150 American, Canadian and Swedish parents to better understand both the frequency and the impact of symptoms in children with different repeat lengths and different types of CDM. The survey inquired about 325 symptoms of importance and 20 “symptomatic themes.” Children in the study were divided into three groups: congenital DM (CDM), with symptom onset at birth; childhood onset DM (ChDM), with symptoms starting between ages one and ten; and juvenile onset DM (JDM), with symptoms starting after age 10 but before age 18.

Frequency of Symptoms

Parents reported that communication issues (81%), problems with hands or fingers (79.6%) and fatigue (78.6%) were the most common symptomatic themes across all children in the study, while the most common individual symptoms were hand weakness, difficulty opening jars or bottles and learning difficulties. The investigators also examined the influence of repeat length and age on both symptom themes and individual symptoms. Many symptom themes were found to be more common as children became older, such as hand or finger problems, emotional issues, fatigue, pain, inability to do activities, myotonia, gastrointestinal issues and social issues. Children with higher repeat counts showed increased frequency of leg and trunk weakness and problems with bowel control, although myotonia was less frequent in children with higher repeat counts. Interestingly, emotional issues, changes in body image, social issues and impaired sleep were more common when the mutation was inherited from the father.

Impact of Symptoms

The authors looked at the impact of symptoms on children in two ways: first they analyzed the impact of symptoms for the individual, then they analyzed the impact of symptoms for all children with congenital or childhood myotonic dystrophy—the “population impact”— by multiplying the individual impact by the frequency of the symptom. The symptom themes that parents reported had the greatest impact on their individual children’s lives were gastrointestinal issues, problems with urinary or bowel control and decreased performance in social situations. The authors make the point that these symptom themes are different from those identified by adults with DM, namely fatigue and mobility and activity limitations (DM2 patients identified fatigue and other disease symptoms as having the greatest impact on daily living in an article published by MDF in Decmber 2015). Parents of children with greater repeat lengths reported a higher life impact for leg weakness and parents of children who inherited the mutation from their fathers reported a higher life impact for pain. The symptom themes with the greatest population impact were found to be communication issues, fatigue and gastrointestinal issues. The specific symptoms with the greatest population impact were learning difficulties, reliance on family members, and difficulty with math.

Additional Factors

From a social standpoint, many children required special assistance in school, such as speech therapy (55.3%), occupational therapy (40.7%), physical therapy (35.3%), smaller class size (42.7%), test modifications (42%), and augmentative speech methods (19.2%). The survey also showed that children with DM1 who are now adults have difficulty in getting jobs. Parents reported that 15.8% of children had anesthesia complications (56.8% reported no problems and 27.4% had never had anesthesia), and 24.1% had cardiac arrhythmias. Finally, the rate of intellectual disability in children in the study was 28.3% - 45.8% compared to 0.71% in the general population. In particular, children in the study had higher rates of autism spectrum disorder (ASD) and attention deficit hyperactivity disorder.

Take Home Messages

The authors conclude by noting that the high rate of communication problems should be addressed with early referrals for speech therapy and that early cardiac monitoring should be performed. Also, the rate of anesthesia complications reinforces the need for special attention in this group. Overall, the authors emphasize that the high frequency of social and cognitive issues associated with the disease make the need for a multi-disciplinary approach to care much more important.