University of Florida - Sanofi Collaboration Receives DM Drug Screening Grant

Published on Fri, 03/04/2016

In a collaboration with pharmaceutical company Sanofi-Aventis, University of Florida investigators Dr. Andrew Berglund, Dr. Eric Wang and Dr. Kausiki Datta have been awarded $200,000 by MDF to screen for new drugs to treat DM1 and DM2.

The group will first optimize an assay designed to identify compounds that inhibit the transcription of the repeats in the DM1 and/or DM2 genes, and then will work with Sanofi to conduct a high throughput screen to identify drug candidates. By targeting transcription of the repeats, the group hopes that a variety of potential downstream toxic effects will be corrected, from protein sequestration to improper signaling to protein production through RNA translation.

This work builds on a previous discovery by Dr. Berglund and colleagues that the antibiotic Actinomycin D can block transcription of CUG repeats at nanomolar concentrations.


Actinomycin D Specifically Reduces Expanded CUG Repeat RNA in Myotonic Dystrophy Models.
Siboni RB, Nakamori M, Wagner SD, Struck AJ, Coonrod LA, Harriott SA, Cass DM, Tanner MK, and Berglund JA.
Cell Rep. 2015 December 22. 


Multi-Disciplinary Approach Needed for Congenital and Childhood DM Care

Published on Thu, 02/11/2016

Poor communication, fatigue and gastrointestinal problems worry parents most.

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

Frequency of Symptoms

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

Impact of Symptoms

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

Additional Factors

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

Take Home Messages

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

The Impact of Pregnancy on Myotonic Dystrophy: A Registry-Based Study

Published on Thu, 02/11/2016

Dr. Nicholas Johnson and a research team from the Universities of Utah and Rochester partnered on a study commissioned by MDF to study how women with myotonic dystrophy (DM) are impacted by pregnancy. Data for the study were drawn from the Myotonic Dystrophy Family Registry and the National Registry for DM and FSHD. Previous studies have shown that women with DM may have pregnancy complications in excess of what is normally seen in women without DM. For example, pregnant women with DM1 experience more spontaneous abortions, polyhydramnios (excess amniotic fluid), ectopic pregnancies (fertilized egg implants outside the uterus), placenta previa (placenta covers the cervix) and early labor. Other studies focusing on DM2 showed that 21% of women with DM2 had their first symptom during pregnancy, and women with DM2 experienced more urinary tract infections and preterm labor.

This new study recruited 152 women from the two registries and collected data on their 375 pregnancies. Women with DM1 and DM2 had miscarriage rates of 32% and 37%, respectively, which is higher than the national average of 17%. All women with DM combined had a 10% rate of preeclampsia (high blood pressure and protein in urine) and a 14% rate of peripartum hemorrhage (bleeding before, during or after delivery), both of which are well above the national average of 3%. Many common symptoms of DM progressed during pregnancy, including mobility limitations, activity limitations, pain, emotional issues and myotonia. After delivery many of these symptoms reportedly did not return to the level experienced before pregnancy.

The authors summarize their findings by suggesting that “this research may be utilized by DM patients and family members seeking to better understand the risks and outcomes associated with pregnancy and DM.”


The Impact of Pregnancy on Myotonic Dystrophy: A Registry-Based Study.
Johnson NE, Hung, M, Nasser, E, Hagerman, KA, Chen, W, Ciafaloni, E, and Heatwole, CR.
Journal of Neuromuscular Diseases. Oct 7, 2015.

Myotonic Dystrophy Anesthesia Guidelines

Published on Thu, 01/28/2016

Myotonic Dystrophy Anesthesia Guidelines

Please know that the use of anesthesia raises special risks to those living with myotonic dystrophy (DM), as the disease results in heightened sensitivity to sedatives and analgesics. Pay particular attention to the serious complications that can arise in the post-anesthesia period, when risk of aspiration and other complications increase. 

MDF has published two versions of its Anesthesia Guidelines:

  • A one-page summary of the anesthesia guidelines to share with your clinician and anesthesiologist.
  • The complete "Practical Suggestions for the Anesthetic Management of a Myotonic Dystrophy Patient".

Download an electronic copy of the latest versions of both documents on the Toolkits & Publications page.

New to DM? Click here for more information.

Common Symptoms of DM2 and Their Impact on Daily Living

Published on Wed, 12/02/2015

While symptom themes such as inability to do activities, mobility limitations and weakness were the most common, fatigue was the symptom that had the greatest impact on patients' lives. This research will help focus developing treatment strategies on the most important issues reported by people with DM2.

These findings are similar to those from a previous study from the same authors that examined symptoms in DM1, where fatigue was also ranked as the most burdensome symptom but not the most common.

More on the study:

In this study, researchers interviewed and sent surveys to people across the USA with DM2, asking respondents to report what symptoms they were experiencing, and what impact those symptoms had on their daily living.

Symptoms were grouped into themes, and researchers found that the most commonly reported symptom themes were:

  • Inability to do activities (94%)
  • Limitations with mobility or walking (89%)
  • Hip, thigh, or knee weakness (89%)
  • Fatigue (89%)
  • Myotonia (83%)
  • Pain (80%)

When the themes were broken down into individual symptoms, the most commonly experienced symptoms included difficulties getting up from the floor, squatting, walking hills, rising from a seated position, and other issues stemming from leg weakness.  These symptoms were experienced by at least 97% of the respondents.

Aside from assessing symptoms, this study also gathered information on employment, age, duration of symptoms, and gender. This allowed the researchers to break down their DM2 respondents into groups to determine whether there were any subsets of the population that had a different experience with DM2 than others.

They found that the significant differences between subsets of the population came when patients were grouped by employment status. Unemployed respondents more commonly reported mobility or walking issues, problems with shoulders or arms, emotional issues, decreased satisfaction in social situations, and many other symptomatic themes.

The researchers believe that “employment status is highly dependent on a patient’s overall disease burden,” and also found that employed respondents had better satisfaction in social situations. While this study was not designed to determine cause and effect, the authors hypothesize that many symptoms of DM2 may make obtaining employment difficult or impossible. They further hypothesize that unemployment may also potentially lead to increased disease burden in DM2.

To read an abstract of this article, click here

MDF SAC Member Profile: Dr. Kathie Bishop

Published on Wed, 12/02/2015

MDF is pleased to welcome Dr. Kathie Bishop, Ph.D., to its Scientific Advisory Committee(SAC). Dr. Bishop, who joined the SAC in summer 2015, is a seasoned expert in neurological and neuromuscular research and drug development.

She received her Ph.D. in neurosciences from the University of Alberta (Canada) in 1997 and then completed a postdoctoral fellowship in molecular neurobiology at the Salk Institute in La Jolla, Calif.

From 2001 to 2009, Dr. Bishop was at Ceregene, a San Diego biotechnology company developing gene therapies for neurological disorders. At Ceregene, where she was Director of Research and Development, she worked on preclinical and clinical programs in Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, retinal degenerations, and amyotrophic lateral sclerosis (ALS).

In 2009, Dr. Bishop moved to Ionis (formerly Isis) Pharmaceuticals in Carlsbad, Calif., a biotech company specializing in antisense oligonucleotide-based therapeutics. While at Ionis, she led programs within the neurology franchise, including leading development for programs for spinal muscular atrophy, amyotrophic lateral sclerosis, type 1 myotonic dystrophy (DM1), and other rare genetic neurological disorders. She left Ionis Pharmaceuticals in 2015, as Vice President of Clinical Development.

She is now Chief Scientific Officer at Tioga Pharmaceuticals, a San Diego biotechnology company developing treatments for chronic pruritus. We talked with Dr. Bishop in October 2015:

MDF: What prompted your decision to move from academia to industry?

KB: I’ve always been interested in genetic neurologic diseases. My original degree was in genetics, and my Ph.D. is in neuroscience. While at the Salk Institute for my postdoctoral fellowship, I worked on development of the brain and spinal cord and found I wanted to apply the science to drug discovery and development.

MDF: What kinds of drug development programs have you worked on?

KB: At Ceregene, we were developing gene therapies for Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and ALS [amyotrophic lateral sclerosis].

When I moved to Ionis, my first program was developing antisense against SOD1 for ALS. We did a phase 1 clinical trial administering IONIS-SOD1Rx into the CSF [cerebrospinal fluid] in patients with the genetic form of ALS, and no safety issues were found. [See Miller et al., Lancet Neurology, May 2013.] At the time, we were concentrating on whether the CSF delivery of antisense drugs would be feasible and safe, which it was

I led the SMA [spinal muscular atrophy] program at Ionis from the preclinical stage through the phase 1 and phase 2 trials and up to trial design and initiation of phase 3 studies. IONIS-SMNRx acts on the SMN2 gene to change SMN2 splicing so that a functional protein is made. It acts right on the disease mechanism. This antisense [ASO] drug is the same chemistry as IONIS-SOD1Rx, but it doesn’t downregulate the SMN protein the way IONIS-SOD1Rx downregulates the SOD1 protein. The ASO doesn’t have a gap for an enzyme to bind that would downregulate the SMN RNA. It’s now in phase 3 studies in infants and in children with SMA.

I was also involved with developing IONIS-DMPKRx, an ASO against the DMPK RNA to treat type 1 myotonic dystrophy [DM1]. We completed a phase 1, single-dose study in healthy volunteers, and a multiple-dose study in adults with DM1 is ongoing. IONIS-DMPKRx destroys the DMPK RNA, which is thought to be the cause of DM1. It also affects the wild-type DMPK allele, but it may have a preference for the [abnormally expanded] DMPK RNA that’s stuck in the nucleus.

MDF: Do you see other therapeutic avenues for DM?

KB: Yes, absolutely. I think any one therapy, even one which acts on the genetic mechanism in DM, might not work perfectly in longstanding disease and might not work on all aspects of the disease or in all patients. We may need other compounds, such as muscle-enhancing drugs, to supplement it and be taken together with it. We will also need additional drugs that work on other aspects of DM, such as drugs that help stop degeneration in smooth muscle and heart, as well as CNS [central nervous system] drugs. Antisense drugs such as IONIS-DMPKRx do not penetrate into the CNS when given systemically, and particularly in the congenital and juvenile-onset forms of the disease, the CNS effects need treatment.

MDF: What do you see as the main challenges to drug development for DM and other rare disorders? For example, how can small companies meet the demands of patients for expanded access to compounds in development while pursuing full regulatory approval for these compounds?

KB: I think it’s the responsibility of people like me, who work in drug development, and of drug companies to communicate effectively about the development process and the risks involved to patients, their families, and their caregivers. We have to make it clear that experimental treatments could be harmful, and we have to be realistic and honest about the potential benefits. There is a lot of hope, but we also need to communicate better with the patient community about the drug development process.

That said, I would like to see the drug approval process be more efficient and go faster for diseases where the drug has a clear mechanism that acts directly on the underlying genetic cause of the disease. I think the FDA [U.S. Food and Drug Administration] is on board with this, but they aren’t going to come up with solutions. The drug developers have to do that.

MDF: What particular challenges do you see with drug development for DM?

KB: The clinical outcome measures used in this disease change very slowly, so you need long trials to measure decline. We need molecular markers, such as those reflecting splicing changes downstream of the mutant DMPK RNA that are linked to clinical changes. These are known as surrogate markers, and companies have to provide the data on these markers and clinical outcomes to the FDA.

MDF: What particular skills and insights will you bring to the MDF Scientific Advisory Committee?

KB: I plan to advise MDF on DM drug development and on incorporating science into drug development. I hope to help with encouraging and supporting new drug discovery and development programs for treatments for DM, advising on clinical trials, developing surrogate markers in DM, and having an effective working relationship with the FDA.

MDF SAC Member Profile: Dr. Laura Ranum

Published on Tue, 12/01/2015

MDF is pleased to welcome Dr. Laura Ranum, Ph.D., to its Scientific Advisory Committee (SAC). Dr. Ranum, who joined the SAC in summer 2015, is an internationally known investigator of disorders that result from repeat expansion mutations, such as those that cause type 1 and type 2 myotonic dystrophy (DM1 and DM2). More recently, she discovered that repeat expansion mutations can produce unexpected RNAs and proteins. These discoveries were big surprises and have changed the understanding of how expansion mutations work. 

Dr. Ranum received her Ph.D. in cell biology from the University of Minnesota in 1989 and carried out postdoctoral studies with Dr. Harry Orr in the Department of Laboratory Medicine and Pathology at that institution. In 1994, she joined the faculty of the University of Minnesota Department of Neurology as an assistant professor.

From 2003 to 2010 Dr. Ranum was a professor in the Department of Genetics, Cell Biology and Development at the University of Minnesota and the research director of the Paul and Sheila Wellstone Muscular Dystrophy Center.

In 2010 She moved to the University of Florida in Gainesville, to become the founding director of the Center for NeuroGenetics and a professor of Molecular Genetics and Microbiology and Neurology in the university’s College of Medicine. We spoke with Dr. Ranum in October 2015:

MDF: When did you first become interested in nucleotide repeat expansion disorders?

LR: I was working on spinocerebellar ataxia type 1 – SCA1 – as a postdoc in Harry Orr’s lab at the University of Minnesota. In 1993, we identified a CAG repeat expansion mutation as the cause of SCA1. That came on the heels of the 1992 identification of the CTG repeat expansion [on chromosome 19] as the cause of type 1 myotonic dystrophy -- DM1. DM1 was the third repeat expansion disorder to be identified. SCA1 was the fifth, after the triplet repeat identification in Huntington’s disease [HD], which was also in 1993.

It was all very exciting. We had suspected that SCA1 could be an expansion mutation, and it was. It was a very electric time. 

The first discussions of spinal-bulbar muscular atrophy [SBMA] and fragile X syndrome [two other triplet repeat expansion disorders] started to open up the possibility that variability in neurological diseases such as DM1 and SCA1 could be explained by the length of the repeat expansion. 

Curiously, the triplet repeat expansions for HD and SCA1, which are both dominant diseases, were in protein coding regions. But the expansion in DM1, which is also a dominant disease, was in an untranslated region of the gene, so it didn’t fit the same pattern.

MDF: When did you first become involved with the search for a second DM locus?

LR: That was probably in 1995 or so, shortly after I started as a faculty member in the Department of Neurology at the University of Minnesota. Dr. John Day, a neurologist there, was seeing a family in the clinic with DM but without the expected CTG expansion. John knew I had worked on SCA1, and we decided to work together [to identify the cause of this family’s disorder].

We began by collecting blood samples from a large family in Minnesota and mapped that gene to chromosome 3 in 1998. At a meeting in Naarden in the Netherlands, we began a collaboration with Dr. Kenneth Ricker, who was one of the first investigators to describe families from Germany who had DM but without the expected CTG expansion. I was interested in studying DNA samples from the additional families Dr. Ricker had collected because I thought that this would help us pinpoint and find the DM2 gene. So we expanded the project, with Dr. Ricker, to Germany.

In 2001, we published the identification of the gene defect in type 2 myotonic dystrophy – DM2. [The paper, Liquori et al., Science, Aug. 3, 2001, described the identification of the DM2 gene as a CCTG repeat in an intron of the ZNF9 gene on chromosome 3.]  We were very excited, and the scientific community as a whole was excited, that a CCTG tetranucleotide repeat located in an intron had been found to underlie DM2. The interpretation was that, because the DM1 and DM2 diseases were so similar and both were expansions in noncoding regions, these were both RNA gain-of-function disorders.

That was the interpretation at the time. We now have a collaborative Program Project grant [from the National Institutes of Health] to investigate RNA mechanisms and also to test if other mechanisms might be involved. Investigators on this multi-investigator grant include me, Dr. Maurice Swanson at the University of Florida, Dr. John Day at Stanford University, and Drs.Timothy Ebner and Brent Clark at the University of Minnesota.

MDF: So that 2001 paper gave a lot of support to the RNA toxic gain-of-function hypothesis for both forms of DM?

LR: Yes, especially after the findings that the CUGBP1 protein and the MBNL protein were affected by the DM1 and DM2 RNA expansions and that they in turn affected splicing of various genes.

MDF: When did you first begin to think about bidirectional transcription of expanded repeats?

LR: I had continued to work on SCA genes, and in 1999, we published that an untranslated CTG expansion underlies spinocerebellar ataxia type 8 -- SCA8. [See Koob et al., Nature Genetics, April 1999.] It was a controversial discovery, because the expansion mutation did not cause disease in all people who carried it.

Eventually, we developed a mouse model of SCA8 with the untranslated CTG expansion. The mice developed SCA8 disease features, but when we investigated the details, we found an unexpected result: In addition to the CUG expansion, there was a CAG expansion RNA made in the opposite direction, and it was translated into a polyglutamine expansion protein that accumulated in both our mouse model and human autopsy brains. We published that in 2006. [See Moseley et al., Nature Genetics, July 2006.]    

MDF: When did you first start to think about translation without the usual start codon?

LR: This discovery also came from our SCA8 work and was completely unexpected. To understand the contribution of the polyglutamine protein versus the CUG RNA in SCA8, we removed the ATG initiation codon. Surprisingly, we found that mutating the only ATG start codon did not, as had been expected, prevent polyglutamine from being made. At the time, the ATG initiation codon was thought to be essential to start translation and also that this start signal would ensure only one protein would be made. 

To make a long story short, we discovered in studies of cells that CUG and CAG expansion RNAs can make three different repeat expansion proteins each – meaning that, if a disease-causing expansion mutation expresses RNAs in both directions, up to six additional, unexpected proteins could be made. We named this novel type of protein production repeat-associated non-ATG translation, or RAN translation.

So, in SCA8, first we found a CUG expansion RNA. Then we found the gene mutation ran in both directions, producing CUG and CAG RNAs in both directions; and later, that each RNA can make three mutant proteins. It got really exciting, as we showed that these unexpected RAN proteins are made in mice and also in patients.

Initially we reported the discovery of RAN translation in SCA8 and in DM1. [See Zu et al., Proceedings of the National Academy of Sciences USA, Jan. 4, 2011.] We and others have now found RAN proteins in a growing number of additional expansion diseases including Huntington’s Disease [HD], C9ORF72 amyotrophic lateral sclerosis [ALS] and frontotemporal dementia [FTD], and in fragile X tremor ataxia syndrome [FXTAS].

Now we are investigating the impact of RAN translation in DM1 and DM2. We know DM1 can express a polyglutamine protein, but a lot of questions remain. How frequently is the polyglutamine protein found in patients? Are other RAN proteins also found in DM1? Does RAN translation also occur in DM2? Do RAN proteins substantially contribute to DM1 and DM2? We don’t yet know, but we’re working hard on these questions. 

MDF: Most therapy development in DM1 centers on antisense oligonucleotides to block or destroy the expanded CUG repeats in the DMPK RNA. If that were accomplished, could bidirectional transcription or RAN translation still have an effect on the disease course? Is getting rid of the CUG RNA expansion enough to treat the disease?

LR: An antisense oligo, such as Ionis Pharmaceutical's DMPKRx, is a great idea because it is designed to destroy the CUG RNA, and this would also get rid of any possible CUG RAN proteins. I am hopeful that this will be enough to make a big impact on the disease. But there could still be additional problems caused by remaining RNA and proteins not removed by the drug, such as CAG RNA [resulting from bidirectional transcription of the CTG repeat] and RAN proteins. We don’t yet know the impact that the CAG RNAs or RAN proteins have on DM1 at this point, but we’re working hard on this problem and will need to keep this in mind.

MDF: Is there a mouse model for DM2?

LR: Yes. We’ve developed a mouse model of DM2 and presented it at IDMC 10 [the 10th International Myotonic Dystrophy Consortium, held in Paris in June 2015]. The model overexpresses CCUG RNA conditionally. We’re working on publishing this DM2 mouse model.

MDF: What special contributions do you expect to make to the MDF Scientific Advisory Committee?

LR: I have a lot of research experience in DM1 and DM2 and a broad perspective from working on these and other expansion diseases. There’s a lot you can learn from looking across diseases, and I can bring this perspective to the table.

Benefit/Risk Study Results: Focus on Muscle Weakness

Published on Mon, 11/16/2015

As part of our investment in the development of effective treatments for myotonic dystrophy, we are trying to better understand how people with DM weigh the benefits of new treatments against the risks.  To do this, we worked with a company called Silicon Valley Research Group to develop a survey that presented a series of hypothetical new treatments and asked that people choose the side-effects that concerned them the most and the least for.  This type of analysis is called “Max-Diff Analysis” or sometimes “Best-Worst Scaling” and has been used in other benefit-risk studies and by the Food and Drug Administration (FDA).  The method generates robust statistics to determine, on average, what risks people are or are not willing to accept for a given benefit.  The FDA has indicated that it is very interested in this type of information.  

The survey showed that reversing, stopping or slowing the progression of muscle weakness were the most preferred benefits, in that order.  The side effects people were most willing to tolerate overall for any benefit were loss of appetite and a small increase in tiredness. 

People in the study also completed the short version of the Myotonic Dystrophy Health Index (MDHI) to rate the severity of their myotonic dystrophy.  Scores were grouped into mild, moderate and severe categories.  For the majority of benefits, those with all levels of severity were similar in their willingness to tolerate side effects except that those with more severe myotonic dystrophy were less willing to risk liver failure for any type of therapeutic benefit.  Also, those with the highest severity rating for their myotonic dystrophy were more willing to tolerate an increase in tiredness if the drug could stop or reduce myotonia.  The data reported here are based on the survey responses from those with DM1.  The responses from those with DM2 are being analyzed now.

These results were presented on September 17th at the MDF-sponsored regulatory workshop on therapeutic development for myotonic dystrophy, which was attended by FDA staff.  Next steps will likely include an in-depth follow-on study that looks at the benefit-risk preferences of caregivers and younger people with myotonic dystrophy.  We are also investigating ways to collect “qualitative” data, such as stories and open-ended comments, on the benefit-risk preferences of those with myotonic dystrophy.  Ultimately this information will be made available to FDA reviewers through various mechanisms with the goal of incorporating the view of those with myotonic dystrophy and their families into the decision-making process about new therapies. 

MDF SAC Member Profile: Dr. Thomas Cooper

Published on Wed, 11/04/2015

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Experts Participate in DM Regulatory Workshop

Published on Sat, 10/10/2015

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


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

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

Living with Myotonic Dystrophy

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

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

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

Session One: Real World Patient Data

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

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

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

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

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

Session Two: Myotonic Dystrophy Trial Endpoint Selection

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

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

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

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

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

Session Four: Candidate DM Biomarkers

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

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

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


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

Meeting agenda and presentation links.