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

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

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

Tackling DM from Basic Research through Clinical Care

Tetsuo Ashizawa, MD, better known as "Tee" to colleagues and patients, has focused his career on the search for treatments for myotonic dystrophy (DM). As one of seven primary investigators who will participate in the first clinical trial of a potential treatment for DM1, Dr. Ashizawa may be closer than ever to achieving that goal. Yet in addition to pursuing research with dedication and tenacity, he has also been committed to providing the best possible care to people living with DM. Dr. Ashizawa's engagement in myotonic dystrophy spans basic research, translational science, patient-oriented research and clinical care.

Originally trained in neuromuscular diseases, Dr. Ashizawa first became involved in DM as a basic researcher, working with a team at Baylor College of Medicine to hunt for the DM gene. "There were actually several teams working internationally to find the gene," said Dr. Ashizawa. "Interestingly, in 1992 the various research teams all had the same finding, which was identification of DMPK, the genetic mutation responsible for myotonic dystrophy type 1. It was an exciting time, and that was the beginning of our journey to find treatments and a cure."

Patients Play a Key Role with Researchers

In 1998, as Dr. Ashizawa was expanding his research efforts, he received an email that would broaden his perspective. Shannon Lord, the mother of two boys with juvenile-onset DM1, wanted to make a donation to advance DM research. She provided a grant to Dr. Ashizawa through the Hunter Fund, an account named after her older son and established by Shannon and her husband Larry to support DM research projects. The grant was the start of a long-term friendship between Dr. Ashizawa, Shannon and Larry Lord, and ultimately led to a DM scientific meeting organized by Dr. Ashizawa and including the Lord family. "It was so powerful," said Dr. Ashizawa. "Before this meeting, many in the scientific community only saw DM through a microscope. Now investigators could see and understand the human face of the disease. It was a real morale booster for everyone and provided a great deal of momentum to move our work forward."

By then Dr. Ashizawa had also co-founded the International Myotonic Dystrophy Consortium (IDMC) to bring together scientists and clinicians focusing on DM. Shannon Lord attended the third biennial IDMC meeting in Kyoto in 2001, serving in the role of patient advocate and introducing patient advocacy to the IDMC research community. By the fourth meeting, about one hundred patients and families attended, and the participation of a large number of patients at these international meetings has since become routine. Today, IDMC meetings provide a unique opportunity for global researchers, clinicians and patients to come together; IDMC 10 will be held next June in Paris, France. "Without patient involvement, we wouldn't be able to push forward on the research frontier," Dr. Ashizawa said.

Research Moves Out of the Lab

By 2011, DM science had progressed significantly in the development of potential treatments for DM1. Seven research and clinical institutions around the country are currently preparing to launch the first clinical trial in affected patients to test the efficacy of an antisense oligonucleotide (ASO) therapy, DMPKrx, in people affected by DM1. The University of Florida (UF) will serve as one of these sites, with Dr. Ashizawa as the Primary Investigator for the institution.

Dr. Ashizawa has recently started a project looking at DM1 patient-derived, induced pluripotent stem cells (iPSCs), which can be developed into different cell types needed for research, e.g. muscle, heart, or even brain cells. These cells can help researchers understand how DM affects different body systems and causes disease symptoms. While the clinical use of these cells may be a long way off, iPSCs have a more immediate and critical function as a platform for the screening of compounds to find drugs that have therapeutic potential in DM1. "It's a very exciting time in DM research," Dr. Ashizawa says.

Providing Multidisciplinary Care in the Clinic

In addition to his research projects, Dr. Ashizawa oversees the clinical program at the University of Florida. Patients benefit from a multidisciplinary team of doctors that includes cardiologists, anesthesiologists and geneticists. "We help patients access any clinical trials for which they may be eligible," he says. "And when new treatments become available we are committed to helping our patients access them as soon as possible."

Dr. Ashizawa has published over 190 research papers and 35 book chapters. He is currently Executive Director at the McKnight Brain Institute at UF and Professor and Chair of the Department of Neurology at the UF College of Medicine, and he serves on MDF's Scientific Advisory Committee. With Drs. Maurice Swanson and S.H. Subramony, he has recruited Dr. Laura Ranum to UF and is in the process of recruiting a handful of other key DM investigators to build one of the strongest DM research teams in the world. "We are very hopeful about the research and treatment possibilities on the horizon. We have a distance to go and there are many questions to answer, but we won't stop working," says Dr. Ashizawa. "We are dedicated to our patients and to collaborating with them to find a cure."

12/09/2014

Dahlqvist et al
European Journal of Neurology

Dr. John Vissing and his colleagues at the University of Copenhagen recently tracked a group of 68 adults with myotonic dystrophy type 1 (DM1), measuring their endocrine function change over 8 years.  The authors examined bloodwork for many endocrine dysfunctions including diabetes (HbA1c blood test), hyperparathyroidism (PTH blood test), and androgen insufficiency (testosterone blood test in men), and found that these dysfunctions became more common over time in people with DM1.  The authors recommend that doctors treating people with DM1 should screen for endocrine functions regularly, as the dysfunctions occurs more frequently in DM1 than the general population.

Click here to read the abstract for this study.

Click here for a PDF of this paper.

10/16/2014

A Toxic RNA Catalyzes the In Cellulo Synthesis of Its Own Inhibitor

Researchers from Dr. Matthew Disney's lab at the Scripps Research Institute of Florida, including Suzanne Rzuczek, PhD, a 2013 MDF Fund-a-Fellow grant recipient, recently published an article describing a new chemical they designed to inhibit the unhealthy repeat-containing RNA molecule seen in myotonic dystrophy type 2. This project was supported by a postdoctoral fellowship awarded by MDF. The study describes the design of a pair of molecules that seek out the unhealthy repeat RNA and attach to it. When both of the molecules attach near each other on the RNA, they join together and permanently attach to each other, forming a strong inhibitor of the RNA. The authors state that they are "using the cell as a reaction vessel and a disease-causing RNA as a catalyst." By this they mean that only cells that have the large DM2 repeat-containing RNA will create their own chemical to inhibit the negative effects of the DM2 RNA. They were able to show that their chemicals reduced the number of unhealthy RNA clumps found in DM2 cells, and were able to partially reverse the improper processing that normally occurs in those with DM2 as a result of the unhealthy RNA.

Click here to read the full article. You can also view a presentation from the 2014 MDF Annual Conference by Dr. Rzuczek where she discusses this research.

09/25/2014

Dr. Katharine Hagerman, Research Associate at Stanford University Neuromuscular Division and Clinics, has prepared the following summary of the recently published study, "Parental Age Effects, But No Evidence for an Intrauterine Effect in the Transmission of Myotonic Dystrophy Type 1" in the Journal of Human Genetics. 

Researchers from the laboratories of Fernando Morales from the University of Costa Rica, and Darren Monckton from the University of Glasgow collaborated in a recent study examining how the DNA mutation causing myotonic dystrophy type 1 (DM1) worsens from one generation to the next. Previous studies have shown that the DM1 mutation behaves differently depending on whether it is passed on from the father or mother. However, there has been conflicting information regarding whether the age of the parent’s symptom onset or parent’s age at conception of their affected child can change the degree to which the child is affected by DM1.

The conflict in research findings is likely the result of using different methods to assess the size of the DM1 mutation, and failing to account for the age of the parent at the time the blood was collected, since the mutation grows throughout their lifetime. This study uses a newer technique called "small pool PCR" to assess the mutation size, and a complex statistical analysis to predict what the original size of the repeat was at birth. This method clarified the relationship between parent and child with regard to CTG repeat size and symptom onset, confirming that children born with DM1 have an inherited repeat that is larger than their parent’s repeat about 95% of the time, and symptom onset comes earlier in the child than their affected parent around 86% of the time. Furthermore, the parent’s age of onset is correlated with the child’s age of onset, but the correlation is much stronger in affected mothers than fathers.

What really stood out in this paper was a completely new finding that the age of the affected parent at conception correlates with the repeat size in their child. In other words, as people with DM1 age, the size of the repeat in their eggs or sperm grows larger. Basic genetic principles dictate that there is a 50% chance of an affected parent passing on the mutation to their child.

This paper found that if the child inherits the mutation from their mother and gets DM1, there is a 64% risk of the child’s DM1 being congenital if the mother’s repeat size is above 164 CTGs. There are very few cases of an affected father having a congenitally affected child, and none were found in this study. Unfortunately, current procedures for diagnosing DM1 do not use the same experimental method as in this paper and do not predict what the individual’s repeat was at birth. Therefore this predicted risk cannot be applied to mothers whose repeat was sized using conventional methods for diagnosis.

The authors estimate that the diagnostic test most women get to determine the size of their repeat would also predict that if their offspring inherit the expanded repeat, they would be congenitally affected 64% of the time when the mother's repeat length is over 284 CTGs.

Genetic counseling for families with DM1 can be very complicated, as many factors such as the repeat size and sex of the DM1-affected parent can alter any predictions as to how severely a child may be affected. Overall, this study clarifies how the growing repeat size in adults with DM1 can affect their children, and brings to light a new factor to be considered by genetic counselors when advising families of the risks of transmitting DM1.

Click here to view the article abstract. Click here for an interview on genetic counseling with Carly Siskind of Stanford University Hospital and Clinics.

08/20/2014