Research

Evolving Strategies Using Oligonucleotides for DM1

Published on Thu, 09/24/2015

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 HSALR 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]

MDF Fellow Profile: Dr. Melissa Hinman

Published on Thu, 09/10/2015

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

Careful! Social Media Can Undermine Clinical Trials

Published on Mon, 07/06/2015

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.

Possible Muscle Damage Pathway Identified in DM

Published on Tue, 05/19/2015

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

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

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

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

05/21/2015

Darren Monckton

Published on Thu, 05/14/2015

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

MDF 3.0

Published on Wed, 05/06/2015

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

Dr. Geneviève Gourdon on Developing a Myotonic Mouse

Published on Thu, 04/23/2015

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

Myotonic Dystrophy Stem Cells

Published on Thu, 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

Dr. Benedikt Schoser: Focus on the Patient

Published on Mon, 03/16/2015

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

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

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

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

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

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

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

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

03/26/2015

MDF Workshop Examines Clinical Trial Endpoints and Biomarkers

Published on Thu, 02/19/2015

Measures of Success

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

Two kinds of measurements are typically used in clinical trials:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

02/26/2015