MDF is pleased to announce that clinical psychologist Dr. Benjamin Gallais, Ph.D., a Postdoctoral Fellow in the Interdisciplinary Research Group on Neuromuscular Disorders at the Université de Sherbrooke has been awarded a 2016-2017 postdoctoral fellowship.

Dr. Gallais’ research project is titled “A 14‐year Longitudinal Study of Cognition and Central Nervous System Involvement in Adult- and Late‐Onset Phenotypes of Myotonic Dystrophy Type 1.” In this study Dr. Gallais and his colleagues will continue what is currently the largest and longest-running longitudinal study in patients with the adult-onset and late-onset types of type 1 myotonic dystrophy (DM1). That study, conducted on a very large group of patients over a nine-year period, produced strong results on the progression of intellectual and cognitive abilities.

The present project aims to extend the follow-up period and answer questions that include how symptoms progress over time, what the rate of progression is, whether progression is similar among patients, whether cognitive involvement progresses to dementia and what assessment tools will best permit assessment of change during clinical trials.

Dr. Gallais received his doctorate in clinical psychology from Paris 8 University in France in 2010. He is particularly interested in the cognitive and psychological effects of motor disorders. Dr. Gallais first became interested in studying DM1 when he was working with brain-injured patients in a sleep lab where a DM1 study was also taking place. We recently talked with Dr. Gallais to learn more:

MDF: How did you first become interested in studying the CNS aspects of DM1?

BG: About 15 years ago I was working in Paris on a study of sleep and fatigue in brain-injury patients in a sleep lab. In the same lab there was also a study in DM1 patients, and that was how I met these patients for the first time. I was about to start my Ph.D. studies in psychology, and I learned that the CNS aspects of DM1 had not been much studied. I decided to focus on the psychological and other CNS aspects of DM1 for my Ph.D. studies, and I got together with Dr. Bruno Eymard, a neuromuscular disease clinician and researcher in Paris.

The central nervous system (CNS) aspects of DM1 and the associated cognitive, personality and sleep-related features of the disease have not been studied as thoroughly as other effects of the disease. Dr. Gallais and colleagues want to study the long-term natural history of the CNS aspects of DM1 in people with the adult-onset and late-onset forms of the disease. They also want to see what changes (if any) occur in CNS-related functions over the course of a year, a typical time course for a clinical trial.

MDF: What is the typical cognitive and/or psychological profile in the adult forms of DM1?

BG: For the late-onset type of DM1 – which we define as having symptom-onset after age 40 – there is almost no description of cognitive and psychological features. That’s one reason why I think our study is very important.

For the classic adult-onset type of DM1, which we define as having symptom-onset between the ages of 20 and 40, there is a typical profile, although it varies among patients. There is often mild intellectual disability, executive dysfunction, visual-spatial and visual-constructional alterations, and attention deficit. Memory impairment has been described in some studies but not in others. There is also a high prevalence of fatigue, daytime sleepiness, and emotional and behavioral withdrawal.

Our research team has already conducted a nine-year study on a very large sample of patients with adult-onset and late-onset DM1 from the Saguenay-Lac-Saint-Jean region of Quebec province, where the prevalence of DM1 is much higher than in the rest of the world. The new project will extend the follow-up period and enroll some new participants.

Our study has two main objectives. The first is to learn a lot about the natural history of the cognitive and other CNS aspects of the disease. The second objective is to measure the progression of these aspects of the disease over a time period that mimics a future treatment trial. We are including a one-year re-test of the participants that will allow us to develop valid CNS outcome measures for trials.

MDF: What have you seen so far?

BG: At the June 2015 IDMC-10 meeting, we presented some results of our nine-year study, which started with 200 patients. [See Highlights from IDMC-10.] At the beginning of the study most participants showed some mild impairment in executive function, language and visual memory. Nine years later, the 115 people who completed the study also showed declines in verbal memory, visual attention and processing speed. Language and IQ remained stable.

These were both expected and unexpected findings. We found worsening in several cognitive functions, such as verbal memory, visual attention and processing speed, but interestingly, these were not the cognitive functions in which we expected to see progression.

The functions that are typically impaired in the classic type of DM1 did not decline, but other functions did. And the late-onset patients showed similar cognitive symptoms to the adult-onset patients, sometimes progressing faster than the adult-onset patients.

My interpretation is that there are two processes going on. One is more developmental, occurring early in life and leading to the typical DM1 profile. Those functions seem to reach a plateau and do not continue to decline.

Other functions that are not part of the typical DM1 profile start to decline in a second process, which appears to be more degenerative. It may be that in DM1 cognitive functions are fragile, and it may be that they become more fragile with advancing age.

As with all aspects of DM1, there is wide variability in the way the CNS aspects present themselves (or don’t). The number of CTG repeats is a factor in this variability, but it does not appear to be the only factor.

MDF: There are some DM1 patients who do not fit the typical DM1 cognitive and psychological profile. What might account for that?

BG: The variation in DM1 can be explained in part by the number of CTG repeats, but now there are hypotheses about the role of epigenetics in patient onset, severity and disease progression. It may be that there are epigenetic variations that make one patient totally express the CTG repeats while another one will have a factor of protection.

In addition there are differences in patients’ coping strategies and adaptive skills. Some people with mild impairment will become totally withdrawn and others will fight. Family and environment can also play a role in the differences between patients. The level of “handicap” can be thought of as the discrepancy between the impairment and the abilities. Very mild impairment with little to no support can yield a very large handicap, just as significant impairment that is coupled with compensation from a caregiver or spouse can yield a lower overall disease handicap.

In DM1 there is a high level of unemployment. People who don’t work and who stay at home don’t have the same stimulation as individuals who are employed. This may be a possible secondary contributor to the cognitive profile.

There is also often respiratory impairment, and there are links with respiratory events and some cognitive functions. Lack of oxygen in the brain can lead to deterioration of the brain and theoretically to cognitive dysfunction.

So we speculate that the progression of cognitive and psychological symptoms is not only explained by the direct effects of the disease but also by secondary factors – indirect effects. We do know however that cognitive deterioration is not statistically correlated with muscular impairment.

Understanding the CNS aspects of DM1 should lead to better outcome measures by which to measure the effects of new treatments, but it’s also crucial for providing optimal care to patients, whether or not they are in a study.

MDF: How will understanding CNS disease impacts help with DM research or therapy development?

BG: The project will permit the selection and validation of CNS-related outcome measures for use in trials. I hope that one day a CNS-targeting treatment will improve the psychological and brain-related symptoms of DM, but adequately assessing the symptoms is crucial. The CNS symptom measurement tools must be sensitive enough to demonstrate that the level of fatigue or apathy or memory has changed as a result of the treatment.

Understanding the cognitive and psychological effects is also important for clinical care. Understanding disease progression can help clinicians anticipate problems that may eventually occur and help patients prepare for them. Early preparation may help patients to more easily adapt to cognitive changes and assist them in informing family members and others. Eventually this information may help patients communicate their disease-related cognitive changes to their employers and successfully advocate for workplace adaptations, allowing them to remain in the world of work.

MDF: Do you think it may be possible to change CNS-related disease progression?

BG: Cognitive rehabilitation programs such as cognitive stimulation and adaptive strategies could be helpful, and we are interested in developing these in the future. 

Building a Better Mouse

MDF has entered into a one-year, $90,000 partnership with Dr. Cat Lutz and Jackson Laboratory (Bar Harbor, ME) to develop a new mouse model of myotonic dystrophy type 1 (DM1).

The most commonly used DM1 mouse model, the HSALR mouse developed in Dr. Charles Thornton’s lab, has been an invaluable contributor to the understanding of pathogenic mechanisms in DM1 and has served in the development of preclinical rationale (proof of concept) to drive clinical trials in DM1. HSALR mice exhibit aberrant splicing of many genes that are mis-spliced in DM1, including Clcn1 and, consequently, show prominent myotonia. However, this model has limitations that include expression of the untranslated CUG repeat in an mRNA unrelated to DM1, tissue-limited CUG repeat expression (e.g., absent from critical brain and heart tissues, since regulation is driven by the HSA promoter), and the mouse lacks many of the multi-systemic features of DM1.

The deficiencies of the HSALR mouse model may be a consequence of the insertion site, length, developmental expression and/or flanking sequences of the CUG repeat. The partnership with Jackson Laboratory addresses these issues by seeking to develop a DM1 mouse model that more closely mimics the genetics of DM1. Dr. Lutz will develop a BAC transgenic mouse with insertion of an expanded repeat tract DMPK gene and flanking regions isolated from a DM patient BAC library. This new mouse should better replicate the molecular and cellular pathogenic mechanisms that operate in DM1, and may then better express the wider organ system involvement that is seen in DM1 patients.

By working with Jackson Laboratory, MDF intends to have the new DM1 model readily available to both academic researchers and drug developers at modest cost and without Intellectual Property restrictions within the next 12 months.

Creation and Distribution of DM Cell Lines for Research and Therapy Development

MDF is collaborating with the Human Cell and Data Repository (NHCDR), a joint venture involving the National Institute of Neurological Disorders and Stroke (NINDS) and RUCDR Infinite Biologics at Rutgers University. The partners in the collaboration are dedicated to the development of new fibroblast and iPSC lines, including isogenic iPSC lines for neurological disorders.

Over the next year, the collaboration will develop DM1 and DM2 fibroblast cell lines and at least four iPSC lines each from DM1 and DM2 patient cells. Through this collaboration, we will achieve unencumbered access and distribution of cell lines essential to mechanistic and drug discovery studies in academia and companies.

Availability of quality controlled, isogenic iPSC lines will mitigate, if not eliminate, an early stage barrier to entry of biotechnology and pharmaceutical companies into high-throughput screening programs for DM1 and DM2. Given the multi-system consequences of DM, availability of iPSC lines is of particular importance, as they provide the means to derive myoblast, cardiomyoblast, neuronal, or other cell types for use in studies of tissue-specific disease mechanisms and/or testing and optimizing specifically targeted candidate therapeutics.

When available, the DM patient-derived cell lines will be accessed through the NHCDR on-line catalog. The ensuing collaboration between MDF and academic and government partners will assure the availability of critical patient-derived resources at modest cost and without Intellectual Property restrictions that could hinder commercial drug development.

A variety of tools are being brought to bear in order to study one of the least understood consequences of DM: the impact upon brain cognitive function. Lead author, Dr. Dimitri Renard, recently reported his team's findings using 18F-deoxy-glucose positron emission tomography (FDG-PET) in 48 DM1 patients seen in their clinic in Nimes, France. Their findings are consistent with reduced activity in a brain area responsible for rapid eye movements (saccades) and are consistent with prior reports of eye movement abnormalities in DM1.

Several research groups in the U.S. and elsewhere are using brain imaging techniques, most commonly MRI, in conjunction with psychological evaluations, in order to understand what brain areas and what functions are impacted in DM. FDG-PET imaging provides a unique capability in that it assesses function through increases or decreases in metabolism within specific brain regions. FDG-PET works by measuring the use of a key energy source, glucose, by imaging differences in the uptake of a modified glucose molecule carrying a radioactive tag. Any differences in FDG uptake between impaired and normal tissue then are visualized by imaging the tagged glucose.

Dr. Renard and colleagues studied 48 symptomatic and genetically confirmed DM1 patients (including early and late onset DM1), in comparison to a matched control group, using FDG-PET brain imaging. The most striking observation was reduced FDG-uptake in Brodmann’s area 8, an area known as the “frontal eye fields.” Although patients exhibited a range of expanded CTG repeat lengths (83 to 2000), there was no significant correlation between repeat length and degree of impairment in FDG uptake. Since the authors determined CTG repeat length from blood samples, and repeat length can differ in blood, muscle, and brain of the same patient, the authors acknowledge that tissue differences may explain the lack of a correlation. Likewise, this study did not find differences between early and late onset patients, but the sample size may not have been sufficient to draw statistically meaningful conclusions on FDG-uptake versus age of onset.

Taken together, progress in understanding the central nervous system consequences of DM will require application of both modern brain imaging and neuropsychological testing. It is essential that we understand changes in the brain, both to improve clinical management of DM patients, as well as to develop targeted therapies for the brain. The increase in research on the DM brain in the last few years is encouraging.

Reference:

In myotonic dystrophy type 1 reduced FDG-uptake on FDG-PET is most severe in Brodmann area 8.
Renard D, Collombier L, Castelli C, Pouget JP, Kotzki PO, Boudousq V.
BMC Neurol. 2016 Jul 13.

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

The annual Biotechnology Innovation Organization's (BIO) International Convention was held in San Francisco, CA earlier this summer. BIO represents more than 1,100 biotechnology companies and other organizations, and the annual Convention usually attracts more than 15,000 attendees. BIO is the trade organization that represents biotechnology and pharmaceutical companies, academic institutions, and biotechnology centers and organizations dedicated to innovation in biotechnology. The annual BIO Convention provides unprecedented partnering opportunities, and thus is a critically important forum for MDF to both learn from and educate potential partners in drug development for myotonic dystrophy.

The BIO Convention provided MDF with myriad opportunities to meet with industry partners that are already working in drug development for DM, have potential interest in DM, or are developing technology that MDF believes could be used to create potential therapies for DM patients. 

MDF staff and board member Dr. Woodie Kessel met with senior representatives of 11 different biotechnology companies at BIO, who are either existing partners with drugs in preclinical or clinical development for DM (including AMO Pharma and Amorchem/Roche), or currently in early stage development efforts. 

Staff also used the face-to-face meetings to evaluate the applicability of technologies such as gene therapy via companies experienced in cell line development as potential DM treatments. MDF used the meetings to describe the comprehensive infrastructure, data collection, funding and other efforts put in place by DM stakeholders (including MDF) to lower the risks to new DM drug development, to help ensure that the DM drug development pipeline continues to expand.

Drug discovery and development programs are inherently high-risk investments for pharmaceutical and biotechnology companies. Engagement and recruitment of new companies to work on DM, as well as continuing efforts to foster companies already working in the area, are critically important goals for MDF. 

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.

Dr. Yao Yao, a former MDF Fellow, has brought us a step closer to effective muscle stem cell therapies for muscular dystrophy.

Dr. Yao identified a cell signaling mechanism by which muscle stem cells are directed to aid muscle regeneration. His work was recently published in the prestigious research journal, Nature Communications.

Muscle stem cells are responsible for the growth and regeneration of skeletal muscles. They are located immediately adjacent to muscle fibers and divide and fuse with the muscle fiber to increase its size and strength, for example, when you exercise.

These stem cells are also the means by which damaged and weakened muscles are strengthened and repaired. The process is very similar, whether the muscle damage is due to an injury or a muscle wasting disease, like DM.

Because of their vital role in muscle regeneration, muscle stem cells are a potentially important target for developing therapies. Increasing their activity should improve muscle repair.

The development of cell therapies has been difficult, however, because we don’t sufficiently understand stem cell biology. Muscle stem cells participate in both muscle regeneration and the fatty deterioration of muscle. Understanding the regulation of muscle stem cell fate is a critical, early step in therapy development.

A better understanding of the properties of muscle stem cells (and the molecular and cellular mechanisms that control their fate) will be essential to using them in therapies. MDF is pleased to have supported Dr. Yao’s advances in the therapeutic potential for muscle stem cells.

Dr. Yao currently holds a faculty position in the College of Pharmacy at the University of Minnesota, Duluth. For more details on Dr. Yao’s lab, click here.

Reference:

Laminin regulates PDGFRβ(+) cell stemness and muscle development.
Yao Y, Norris EH, E Mason C, Strickland S. 
Nat Commun. 2016 May 3.