MDF is pleased to welcome Dr. Tom Cooper, MD, to our Scientific Advisory Committee (SAC). Dr. Cooper, who joined the SAC in summer 2015, is a renowned myotonic dystrophy (DM) investigator whose laboratory has made major contributions to understanding the molecular pathogenesis of the disease and pointing the way toward rational therapeutic development.

Cooper received his M.D. from Temple University in Philadelphia in 1982 and then completed a postdoctoral fellowship in the laboratory of Dr. Charles Ordahl in the Department of Anatomy at the University of California-San Francisco. In 1989, he moved from UCSF to Baylor College of Medicine in Houston, TX, where he is now a professor in the Department of Molecular Physiology and Biophysics. Dr. Cooper was appointed to the S. Donald Greenberg Endowed Chair in 2003 and to the Fulbright Endowed Chair this year.

DM, particularly the type 1 form, has been an abiding interest for Dr. Cooper since the mid-1990s, when he began probing the role of altered splicing of proteins in this disease, with particular attention to how the binding of CUGBP1 (now called CELF1) to the CUG repeat expansion in the DMPK gene contributes to this phenomenon. We talked with Dr. Cooper in October: 

MDF: When did you first become involved in DM research, and what prompted that involvement?  

TC: It was completely serendipitous. I was working on alternative splicing and, in 1995, I had identified a sequence in skeletal muscle and heart that contained CUG repeats and required splicing. At about that time, I happened to attend a seminar given by Lubov Timchenko [then at Baylor, now at Cincinnati Children’s Hospital Medical Center] in which she described a newly identified protein in skeletal muscle and heart that they were calling CUG binding protein, or CUGBP. [The protein has recently been renamed CELF.]

The defect underlying DM1 had been identified in 1992 as being an expanded CTG repeat in an untranslated region of the DMPK gene on chromosome 19, but I hadn’t paid much attention to that until I heard Dr. Timchenko talk. She described how the newly identified protein they were calling CUGBP binds to the expanded CUG repeats in the RNA from the DMPK gene in DM-affected cells and might play a role in the disease. I realized we had been looking at the same protein, although not at that time with myotonic dystrophy in mind.

After that, we started studying how CUGBP behaves in the nucleus, where it normally regulates splicing, while Lubov’s group concentrated on its role in the cytoplasm, where it regulates translation and destabilizes RNAs.

Normally, CUGBP, or CELF as it’s now called, is downregulated right after birth by about 10-fold. But in DM, it’s upregulated [even though it’s bound to CUG repeats in the nucleus]. Increased levels of CUGBP in DM cause more destabilization of RNA and a shift toward fetal splicing patterns. DM reverses the postnatal splicing changes.

The CUG repeats also bind and sequester [the splicing regulator] MBNL and downregulate it, changing splicing patterns that it controls. Most of our focus is on CELF, with some on MBNL. The CUG repeats in DM also are associated with a decrease in [the transcriptional regulator] MEF2, although we don’t know how that happens.

MDF: How has our understanding of the molecular mechanisms underlying DM changed since the early 1990s?

TC: I would say that, between 1992 and 2000, there was a period of befuddlement, where we were wandering in the wilderness for about eight years. During that time, it wasn’t clear how an expansion in the 3-prime untranslated region of a gene could cause disease.

There were several hypotheses: insufficient DMPK; overexpression of DMPK, at least in the congenital form of DM; and involvement of flanking genes, such as SIX5. But when these hypotheses were tested in mouse models, they didn’t yield strong phenotypes. Knockouts of SIX5 developed cataracts, but they weren’t the same cataracts as in DM. DMPK knockout mice developed cardiac problems, but later studies have suggested those might have been due to other factors. Today, the evidence is that losing DMPK is not a big deal, and there isn’t much evidence of effects of flanking genes contributing to DM.

The idea of an RNA-mediated toxic gain of function may have been proposed in the early 1990s, but it was a new idea, and it didn’t gain strong support until 2000, when Charles Thornton’s group developed a mouse that expressed expanded CUG repeats in a human skeletal muscle actin [HSA] gene. [The paper – Mankodi et al., published Sept. 8, 2000, in Science – showed that expanded CUG RNA repeats, expressed in a context completely removed from the DMPK gene and its surroundings, were associated with development of myotonia and myopathy in the mice, thus supporting the role of RNA gain of function in disease pathogenesis.]

Then, in 2001, Laura Ranum and John Day published the identification of CCTG repeat expansions in and intron of the ZNF9 gene as the cause of DM2, and that really cinched the RNA hypothesis. [The paper -- Liquori et al., published in Science Aug. 3, 2001 – showed that patients with DM2, a very similar disorder to DM1, had disease-associated CCTG expansions that, like the CTG expansions in DM1, were transcribed but not translated. The expansions which became CCUG in the RNA in DM2 and CUG in the RNA in DM1, became the major focus in the search for the molecular underpinnings of DM.]

MDF: Since then, you and your colleagues have been working on the downstream effects of the CUG expansion in DM1 and the CCUG expansion in DM2?

TC: We’ve mostly been working on the changes that result from the CUG repeats in DM1. We have not done much with the CCUG repeats. Most of our focus has been on the effects on the CELF proteins, mainly CELF1, and some has been on the MBNL proteins, mainly MBNL1. Maurice Swanson [at the University of Florida in Gainesville] has done most of the MBNL work and has also worked on CELF.

More recently, our group has been looking at MEF2, which is downregulated at the mRNA and protein level in DM1, at least in the heart. MEF2 normally regulates transcription of protein-coding genes and microRNAs. It may be as important in DM1 as MBNL1 and CELF, but it may only be so in the heart.

MDF: There are a lot of mouse models of DM1. Which do you think is the most useful?

TC: Each contributes something, and none is perfect. Which one is best depends on what you want to ask.

The HSA model developed by Charles Thornton’s group is a very nice readout of myotonia and splicing changes in skeletal muscle. However, since the CUG repeats are only expressed in skeletal muscle, the heart and brain are not affected in this model.

Genevieve Gourdon’s group developed a transgenic mouse with 300 repeats in the human DMPK gene, which can expand to about 1,500 repeats over generations. [See, for example, Huguet et al., PLoS Genetics, Nov. 29, 2012.] In the mouse, large expansions seem to repress RNA expression, but this does not happen in human cells. There are weak splicing changes in the muscle in these mice, and they’re seeing some differences in the brain.

Our group developed an inducible mouse model overexpressing DMPK mRNA containing expanded CUG repeats in heart and skeletal muscle, and we saw dramatic effects in both tissues. [See Wang et al., Journal of Clinical Investigation, October 2007; and Orengo et al., Proceedings of the National Academy of Sciences, Feb. 19, 2008.] However, the animals eventually stopped expressing the CUG repeats. We really don’t know why. But now we’ve changed our approach, and we’re developing a skeletal muscle and a heart muscle model that overexpresses the DMPK-expanded CUG repeats RNA using a tetracycline-inducible system. The skeletal muscle model has splicing changes, although they’re not that strong, and shows muscle wasting. The heart model shows very strong splicing changes and cardiomyopathy.

MDF: What do you see as the most promising avenues for development of therapies to treat DM1 and DM2?

TC: An antisense oligonucleotide developed by Isis and Biogen with Charles Thornton [IONIS-DMPKRx] is being tested in patients with DM1 and has done well in safety trials.

There are so many tissues affected in DM, and it would be great if the ASO worked and could be delivered to all these tissues. But a combinatorial approach – ASOs and small molecules – is what I would expect. In mice, DMPKRx did not get into the heart, but it gets into heart and skeletal muscle in monkeys. I’m betting on it getting into the heart in humans, but I doubt it will get into the brain.

MDF: What special role do you anticipate you will play as a member of the MDF Scientific Advisory Committee?

TC: I’m very excited to be involved, because MDF has really grabbed the bull by the horns as far as moving things forward. My role will be on the scientific aspects – providing direction on what kinds of scientific questions to ask – and I’ll also be involved in making decisions about funding Fellows, recruiting and supporting young investigators who are potentially interested in myotonic dystrophy and other funding opportunities MDF releases. We need new ideas and perspectives. We’re at a very exciting point, but this is complex biology, and I think we can expect some bumps in the road.

On September 17, 2015 MDF sponsored a regulatory workshop in Washington D.C. featuring speakers from academia, industry and the Food and Drug Administration (FDA).  As the therapeutic pipeline for myotonic dystrophy has started to fill, the “Myotonic Dystrophy Patient-Centered Therapy Development meeting” sought to explore the development of meaningful and measurable DM clinical endpoints and biomarkers, and to guide and advance the design of clinical trials for the care and cure of patients with myotonic dystrophy.  Click here for the agenda for that meeting, which was moderated by former FDA Deputy Director Dr. Stephen Spielberg, along with links to speaker presentations.

Introductions

Dr. Spielberg made a few introductory remarks at the meeting, noting that we are in an age of revolutionary treatments for rare, genetic diseases and that successful treatment development for these diseases is dependent on patient and family advocacy.

Dr. Spielberg introduced Dr. Richard Moscicki, Deputy Center Director for Science Operations in the Center for Drug Evaluation and Research (CDER) at FDA, who gave an overview of the FDA’s history with orphan drugs.  He noted that more orphan drugs were approved in 2014 than ever before and that the FDA is willing to be very flexible in its approach to serious rare diseases with unmet needs.

Living with Myotonic Dystrophy

Dr. Spielberg introduced a ten minute video produced by MDF featuring individuals with myotonic dystrophy who described what it is like to live day-to-day with the disease, dealing with gastrointestinal symptoms that sometimes left them homebound or unable to eat, myotonia of the tongue and facial muscles that made it difficult for them to communicate, and cognitive symptoms that left one young woman wishing that she “were cleverer.”

The video was followed by a short presentation by Dr. Sarah Clarke, a physician who self-diagnosed and then diagnosed both her young daughters, who are more severely affected.  Dr. Clarke described the helplessness of knowing that she was gradually becoming more affected herself, leaving her husband, also a physician, to be the caretaker for the entire family.  She wondered what would happen to their daughters when they were gone.

Dr. Nicholas Johnson, Assistant Professor of Neurology, Pathology and Pediatrics at the University of Utah then gave an overview of myotonic dystrophy pathology and symptoms, and also provided a look at some new data from his group on the frequency of comorbidities.

Session One: Real World Patient Data

The first of the main meeting sessions explored “Real World Patient Data”—what we have learned from studies and surveys about what people affected by myotonic dystrophy view as their most burdensome symptoms and what therapeutic benefits they would value most highly, as well as what risks they were willing to tolerate for new therapies.

Dr. Richard Moxley described key findings from the University of Rochester PRISM-1 study initiated by Dr. Chad Heatwole to better understand symptom burden.  The data from the PRISM-1 study showed that there was a marked increase in frequency and impact of mobility issues between ages 25 and 35, and that, while the most prevalent symptom was problems with hands and arms, the most impactful symptom was fatigue.

Dr. Katherine Hagerman of Stanford University presented data from the “Christopher Project”, a mailed survey about myotonic dystrophy with over 1400 respondents sponsored by the Marigold Foundation. The survey highlighted that muscle symptoms and fatigue were the heaviest symptom burden and provided insight into numerous aspects of daily living with the disease.

Dr. Sharon Hesterlee, MDF’s Chief Science Officer, presented data from a pilot study that takes a quantitative approach to measuring benefit/risk preferences of those with myotonic dystrophy. The study analyzed the responses of 267 people with adult-onset myotyonic dystrophy about hypothetical treatments with benefits related to relief from muscle weakness, fatigue and myotonia, and symptoms related to fatigue, GI symptoms, and liver damage. The results showed that people with myotonic dystrophy found hypothetical treatments that could reverse, stop or slow muscle weakness to be of greatest value, while treatments that did the same for fatigue to be of least value. Respondents rated liver failure to be the worst risk.

Ms. Pujita Vaidya from the Office of Strategic Programs at CDER, FDA described the Program’s efforts to conduct a series of Patient Focused Drug Development (PFDD) meetings to better understand patient needs and priorities. The results of these meetings are used to complete the first two rows of CDER’s Benefit-Risk Framework, which in turn is used in making regulatory decisions. Although myotonic dystrophy was not selected as one of the disease areas for CDER’s official PFDD program, Dr. Vaidya pointed out that CDER encourages the development of externally-led meetings that use the official PFDD meetings as a template.

Session Two: Myotonic Dystrophy Trial Endpoint Selection

Dr. Charles Thornton of the University of Rochester described what his group has learned from a three year study of functional measurements in 58 people with myotonic dystrophy. He showed that there was a large variance between all subjects with all measurements; that the 30 foot walk/run had the greatest reliability among measurements to show decline; that grip strength is also a sensitive measurement for progression, although it has a floor effect; and that composite myometry of mid-limb and distal muscles may have advantages for detecting improvement in moderately and heavily affected muscles.

Dr. Cynthia Gagnon of the Université de Sherbrooke described the Saguenay Longitudinal Study with over 15 years of follow-up data on 125 people with myotonic dystrophy. The goal of this study is to have a more comprehensive model to understand the relationships between impairments, disabilities, activities and participation in DM1. For example, Dr. Gagnon was able to show that lower extremity strength reliably correlates with the degree of mobility-related participation in social activities.

Dr. Nikunj Patel of the Clinical Outcomes Assessment Staff in CDER’s Office of New Drugs described the FDA’s approach to outcome measure development or selection. Dr. Patel explained that clinical outcome assessments must measure the right thing, in the right way, with the right amount of reliability to be able to say that there is a clear treatment benefit. He provided numerous links to appropriate FDA Guidances.

Session Three: Trial Design for a Slow-Progressing Heterogeneous Disease

Dr. Ronald Farkas from the Division of Neurology Products at CDER discussed clinical trial design for slowly progressing, heterogeneous rare diseases. In general, he explained, the FDA is very flexible about things like the size of the trial, the size of the safety database, and the length and number of trials needed to submit a New Drug Application (NDA) as long as the studies are conducted rigorously and the results are very clear-cut and convincing. He also made the point that there is not currently an FDA “preferred endpoint” for myotonic dystrophy and that many different types of measurements could be considered.

Session Four: Candidate DM Biomarkers

Dr. John Day of Stanford University provided an overview of biomarker development for myotonic dystrophy. He showed that candidate biomarkers for DM currently include myotonia, cardiac conduction changes, gastroparesis, endocrine/metabolic changes, CNS functional changes and transcriptome panels.

Dr. John Carulli of Biogen Idec discussed muscle and blood-based biomarkers for myotonic dystrophy clinical trials, pointing out that we are beginning to understand sources of splicing biomarker variability, which allows us to distinguish therapy-related changes from normal fluctuation. He feels that we still need to understand which markers are most sensitive to CUG repeat changes, that we need a statistical framework by which to interpret changes in splicing patterns and that we need to better correlate molecular markers with clinical measures of disease manifestation.

Dr. Shashi Amur of the Biomarker Qualification Program in CDER’s Office of Translational Sciences described the difference between qualifying a biomarker for use in multiple drug development programs and using the biomarker in a single drug development program. Qualifying a biomarker is a very structured process that typically takes between three and a half and five and a half years. Dr. Amur provided numerous references to guidance from the FDA on the biomarker qualification process and suggested that early engagement with the FDA on biomarkers is encouraged. She emphasized that qualification is not required to use a biomarker in a single drug development program.

Conclusions

Dr. Spielberg summarized the day’s meeting, noting particularly that there is a need to develop earlier predictors of efficacy and to define go/no-go decision making points to cut time and effort and limit risk. He also noted the need to better define biomarkers and expedite studies, pointing out that the FDA has regulatory but not disease area experience and is listening to the experts.

Meeting agenda and presentation links.

Antisense Oligonucleotides and DM1

Targeting antisense oligonucleotides (ASOs) to expanded CUG repeats has received increasing interest as a means to suppress the RNA-mediated toxicity that is mechanistic in DM1. While the strategy initially focused on using ASOs to sterically block the binding of MBNL protein to structural hairpins formed by the expanded triplet repeats in DMPK (Wheeler et al., 2009), there appears to now be a consensus toward instead triggering RNase H-mediated degradation of the toxic RNA (Lee et al., 2012; Wheeler et al., 2012). Clinical trials based upon this strategy (IONIS-DMPK-2.5 Rx) did not achieve adequate bioavailability at the skeletal muscle target, but there appear to be multiple alternatives to correct this delivery problem. Strategies range from further optimizing ASO backbone chemistry to conjugation with any of a variety of agents capable of mediating translocation across the sarcolemma.

Evolving a Promising Strategy

Penetration of ASO drugs into muscle fibers for exon skipping in Duchenne muscular dystrophy is thought to be mediated, at least in part, by the frank sarcolemmal breaks present in this disease. Sarcolemmal disruption, however, is not a component of the pathogenesis of DM1. Linking large molecule drugs, such as ASOs, to cell-penetrating peptides represents one strategy to augment the often slow and limited transition of these drugs across an intact sarcolemma. A new paper in Journal of Clinical Investigation from Drs. Matthew Wood (Oxford University) and Denis Furling (Institute of Myology) and their colleagues explore the potential of an arginine-rich Pip6a cell-penetrating peptide to enhance bioavailability and efficacy of PMO-based ASOs in a mouse model of DM1 (Klein et al., 2019).

Low dose treatment of mice with the Pip6a-PMO-CAG conjugate proved superior to both naked PMO and other previously published ASO chemistries in reversing mis-splicing defects and myotonia in HSA^LR mice. Systemically delivered Pip6a-PMO-CAG (2-3 iv injections at 12.5 mg/kg each) produced complete splice correction of three test transcripts, reduced expanded repeat RNA and nuclear foci, and abolished myotonia. Splicing correction duration was reported as extending as long as six months.

Efficacy with the Pip6a conjugate tested here was achieved at doses 5-10x less than those reported in previous publications with other ASO formulations. Transcriptome analysis further established that broad splicing correction was obtained. These findings contrasted with little or no effect obtained with naked PMO. The research team also demonstrated biodistribution to cardiac muscle.

Finally, the research team showed that the Pip6a-PMO-CAG conjugate displaced MBNL from nuclear foci, reduced toxic RNA levels, and corrected splicing in four test transcripts in treated DM1 patient muscle cell cultures with large expansions (2600 and >1300 repeats). Again, effects were superior to naked PMO.

Going Forward

The authors have tested one candidate cell-penetrating peptide as a delivery vehicle for ASOs based upon an RNase H strategy to mitigate DM1. While efforts to select the optimal cell-penetrating peptide are still warranted (since no head-to-head tests of alternative peptides were done here), these data provide additional proof of principle that enhanced delivery may help overcome the hurdles encountered in DM1 clinical trials to date. Taken together, these findings support the renewed efforts to improve the delivery of ASOs to DM1 patient skeletal muscle and thereby address what is most likely the primary barrier to the efficacy of this therapeutic strategy.

References:

Reversal of RNA dominance by displacement of protein sequestered on triplet repeat RNA.
Wheeler TM, Sobczak K, Lueck JD, Osborne RJ, Lin X, Dirksen RT, Thornton CA.
Science. 2009 Jul 17;325(5938):336-9. doi: 10.1126/science.1173110.

RNase H-mediated degradation of toxic RNA in myotonic dystrophy type 1.
Lee JE, Bennett CF, Cooper TA.
Proc Natl Acad Sci U S A. 2012 Mar 13;109(11):4221-6. doi: 10.1073/pnas.1117019109. Epub 2012 Feb 27.

Targeting nuclear RNA for in vivo correction of myotonic dystrophy.
Wheeler TM, Leger AJ, Pandey SK, MacLeod AR, Nakamori M, Cheng SH, Wentworth BM, Bennett CF, Thornton CA.
Nature. 2012 Aug 2;488(7409):111-5. doi: 10.1038/nature11362.

Peptide-conjugated oligonucleotides evoke long-lasting myotonic dystrophy correction in patient-derived cells and mice.
Klein AF, Varela MA, Arandel L, Holland A, Naouar N, Arzumanov A, Seoane D, Revillod L, Bassez G, Ferry A, Jauvin D, Gourdon G, Puymirat J, Gait MJ, Furling D, Wood MJA.
J Clin Invest. 2019 Sep 3. pii: 128205. doi: 10.1172/JCI128205. [Epub ahead of print]

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

Clinical trials are a critical part of the search for promising treatments for myotonic dystrophy. Your participation in clinical trials and other research studies is invaluable; we won’t learn important information about the disease and advance the search for effective therapies without you. That said, being a smart trial or study participant is a major responsibility, so we have partnered with the leaders of current clinical trials and research studies to give you the best information about successful participation.

Clinical Trials: the Do’s and Don’ts of Digital Communication

When you join a clinical trial, you become part of a community of scientists and fellow participants who agree to protect and promote the accuracy and reliability of the data collected. While it is usually appropriate to confidentially tell your immediate family and friends that you are a participant, it is important that you avoid sharing details about your participation online, including on Facebook or in any other social media or online forums. 

Why? Because these online comments can distort the results of the study and essentially cause the trial to fail.

Whether positive or negative, what you post can influence how other people perceive or report their own symptoms, making it hard to tell whether a given drug is working. If the study is blinded (meaning neither you nor the clinical trial site team know whether you are on an active drug or a placebo), some patients may be taking a placebo. Information you share could lead them to report symptoms that they are not actually experiencing. Any of these communications could sway the trial results.

In addition, comments you make online can sometimes be misinterpreted by the public, journalists and others.

Tips for Getting It Right

Do:

• Do discuss your experience confidentially with your family and other people who are close to you.
• Do talk with your family doctor and other healthcare providers. It’s important to let them know that you are in a clinical trial.
• Do ask your clinical trial team to provide guidance about where to obtain reliable educational material online.
• Do keep a journal or take notes on your cell phone so you can make a list of things to talk about with your clinical trial doctor and study team at your clinical trial.

Don’t:

• Don’t talk publicly, including online, about your participation in a clinical trial.
• Don’t post about your experience in the trial, including about side effects or about how you think the drug is working.
• Don’t solicit trial advice or information from online friends or people other than the clinical coordinator or primary investigator at your clinical trial site.
• Don’t respond to questions or comments online related to the trial you’re involved in. If you do see trial posts online, please tell MDF or your trial site.
• Don’t share or take anonymous advice from “experts” online.

The need for confidentiality during clinical trials is a critical issue for our community. Help spread the word by posting these tips on Facebook and elsewhere. If you see misinformation in online forums, groups or group discussions, point people to verified, accurate information provided in places such as MDF's Study & Trial Resource Center.

Thank you! You are helping change the face and future of this disease. You are an essential part of Care and a Cure for DM.

Questions?

Contact MDF at 415-800-7777 or at info@myotonic.org.

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

An Interview with Dr. Geneviève Gourdon

In the early 1990s, French geneticist Geneviève Gourdon was finishing up postdoctoral work at Oxford University and thinking about the next step on her professional path. Up to that point, her work had been focused on the fundamentals of genetics and gene regulation. She decided to return to France and to look for a research area related to a specific disease. “I wanted to do research that could be helpful for patients,” she recalls.

In 1994, Gourdon joined the lab of pioneering researcher Dr. Claudine Junien, who was then working on myotonic dystrophy (DM). “They were looking for someone to develop a mouse model to study the disease, and that was part of my training at Oxford,” Gourdon recalls. “So when I arrived, we started work on a mouse model for myotonic dystrophy.”

Twenty years later, Geneviève Gourdon directs a laboratory of eight researchers studying the genetic causes of DM for Inserm, the French national institute for research medicine. She feels fortunate that she and her coworkers are now based at the Institute des Maladies Génétiques (Imagine), a brand new, technology-packed facility devoted exclusively to the study of genetic diseases. With 850 staff, Imagine is an unmatched place to do this kind of research, Gourdon says. “Even if researchers are not working in the same field, it’s nice to share ideas and get input from other genetic scientists on what you are doing.”

Mouse Models for DM

Central to the lab’s work is the use of the transgenic mouse models for DM such as the ones that Gourdon helped to develop in the 1990s. “Transgenic” means that the mice carry human genes related to the disease, and Gourdon’s team has developed mice that show very high levels of the CTG repeat expansion in the DMPK gene that causes DM. Using the mice, the team studies the mechanisms responsible for the repeat, its consequences in the body, and possible ways of interfering with the damage the repeat causes.

“By understanding the molecular mechanisms,” Gourdon says, “we can know where to act to try repair what is going on in the cell.”

One important line of research has been on the effects of DM in the brain. For a long time, DM was thought to be primarily a muscle disease. But brain changes are of enormous importance to patients and families, as was brought home to Gourdon during a meeting with Shannon Lord at the third meeting of the International Myotonic Dystrophy Consortium (IDMC-3) in Kyoto, Japan, in 2001. Lord, who would become the founding chair of MDF, was affected by a mild form of DM and had two sons with the childhood-onset form of the disease. After hearing Lord’s description of troubling mental changes caused by DM, “I decided to focus my own research on using mouse models to study these brain abnormalities,” Gourdon says. “I believe that, for the moment, we have one of the few mouse models that allows the study of brain changes due to the genetic mutation.”

Gourdon’s lab also is researching the defect in the neonatal period, she says, “because we think our model might reproduce some aspects of the congenital form of the disease.”

Looking Forward to IDMC-10

Gourdon has attended every biennial gathering of the International Myotonic Dystrophy Consortium (IDMC), beginning with the first one in Paris in 1997, and she serves as the co-chair of the IDMC-10 conference in Paris in June. “Since it’s the tenth one, we are hoping to celebrate the anniversary of the creation of the IDMC,” she says.

Gourdon says that she “couldn’t imagine missing an IDMC meeting. All the people who are working on DM are usually there. It’s a place to establish collaboration with colleagues from other countries. We know each other very well - some of us have become friends. There’s a very good spirit in the community, which is not always the case in other research areas. Of course, there is competition, which is good, but also is a lot of collaboration and good communication, which is good for the patient, because it means the research goes faster.”

Looking back, Gourdon is pleased with the decision she made twenty years ago to beginning researching DM. “It’s a pleasure to collaborate with these people. And from a scientific point of view, the disease is very intriguing. Although the challenge to find a cure is great, there is the potential to help a lot of people.”

04/23/2015

Modifying the DNA of DM Stem Cells to Treat Symptoms

Researchers at the University of Florida, led by Dr. Tetsuo Ashizawa, recently published a study in which they developed a strategy for DM1 stem cell therapy involving gene modification. This proof-of-concept study demonstrated that the genetic approach designed by the Ashizawa lab could be effective in reversing cellular defects that cause DM symptoms. Someday successful gene modification could be used to enable personalized stem cell therapy, in which cells are obtained from a person with DM1, treated to address the gene mutation, and transplanted back into the patient with the hope of restoring normal tissue function and treating symptoms.

Dr. Ashizawa's lab used cells obtained from skin biopsies of people with DM1. The cells were converted to stem cells called induced pluripotent stem cells (iPSCs) that can produce cells for every tissue in the body. The stem cells were then converted to develop brain cells. Following this conversion, the DMPK gene in the brain cells was targeted to reverse negative effects of the DM1 mutation that causes disease symptoms. This strategy proved to be effective, as the lab successfully genetically modified the brain cells, and restored normal cell function.

Despite the positive study results, limitations and challenges exist that must be addressed before this approach can be used to treat people with DM1. First, additional research must demonstrate that this genetic approach is safe as a treatment. Genetic modification of cells can result in unexpected side effects, such as unwanted mutations elsewhere in the gene. Secondly, the modification to the DMPK gene may have negative effects on normal gene function, and we need to explore this possibility. In addition, we need to improve the transfer of modified stem cells into brain, muscle, and heart tissue in order to get the best possible impact on disease symptoms.

While Dr. Ashizawa's team and others are conducting studies to address these challenges, this study is an exciting first step in efforts to build a stem cell therapy for DM1 and move gene therapy for DM1 to the clinic.

Read the abstract of this study.

04/23/2015