MDF is pleased to announce that Dr. Melissa (“Missy”) Dixon, a Research Associate in the Deptartment of Neurology at the University of Utah, has been awarded a 2016-2017 postdoctoral fellowship.

Dr. Dixon’s research proposal is titled “Evaluation of Functional Connectivity as a Brain Biomarker in Congenital Myotonic Dystrophy.” In this study, she and her colleagues will use magnetic resonance imaging (MRI) to evaluate connectivity networks in the brains of children with congenital-onset myotonic dystrophy (CDM) to see if they differ from those of children without CDM, whether they change over a one-year time period, and whether the MRI results correlate with data from neuropsychological testing.

Dr. Dixon has an extensive background in clinical psychology, neuropsychological testing and clinical trial coordination. She received her doctorate in counseling psychology from the University of Utah in December 2015. We recently talked with Dr. Dixon to learn more.

MDF: There was a time when most children with CDM didn’t survive very long. Do they have a better prognosis now?

MD: Oh, absolutely. I would say that kids with this disorder have a better prognosis than they did a decade ago. We now know that respiratory and feeding problems can be life-threatening, and we’re better equipped to work with those issues from the start.

MDF: What is known so far about the neuropsychology and the brain abnormalities in children with congenital-onset myotonic dystrophy?

MD: Networks in the brain are kind of like a highway system. You can get from Illinois to Colorado by taking Interstate 80, but if there’s a block in that road or a piece of the road that’s missing, you have to take a different route to go around it. 

I don’t know if there are fewer “interstates” in the brains of children with CDM compared to those of children without CDM, but it may be that they’re using more roundabout pathways for getting from one place to another. I think the networks are different [from those in unaffected children.]  

People have used resting-state functional MRI [fMRI] during the resting state [without an attentional focus] to look at brain connectivity in kids who have autism, and they’ve found that it’s sensitive enough to show that there are differences in their connectivity networks. 

Earlier DM studies relied on structural imaging techniques. These can demonstrate a wide range of changes, but they’re not well correlated with clinical outcomes, such as IQ.

We think that by using fMRI we’ll be able to look at connectivity differences in these brain networks and see if they change over time in kids with CDM. 

MDF: Will this study be helpful in telling parents what to expect as their child matures?

MD: We’re hoping to be able to demonstrate changes over time by looking at blood flow in the brain using resting-state fMRI, at baseline and then at a year from baseline.

We’ll be tracking neuropsychological measures, such as executive function and IQ assessment. We’ll also look at adaptive behavior, at how a child is functioning, through a questionnaire that a parent or caregiver will fill out.  At the completion of the study, we would hope to tell parents where a child may have the most learning difficulty, and design interventions to approach those learning difficulties.  

MDF: If you do see abnormalities in connectivity in the brain, what are the possible implications?

MD: We know that cognition is impacted in CDM, but there is not a very sensitive way to see how this changes during the course of a short period of time, like during a drug trial. This technique could become an endpoint for a clinical trial to test the effect of a potential drug or therapy.

MDF: Is it possible that something like, say, DMPKRx, which is being developed by Ionis Pharmaceuticals, could have an effect on the brain, if it could be made to cross the blood-brain barrier?

MD: If not that particular therapeutic, then perhaps another, could potentially slow or halt the progression of the brain changes in this disease as we learn more about them.

MDF: Can you say more about the fMRI study?

MD: We’ll be enrolling 20 participants with CDM, ages 7 to 14, and we already have a control group for comparison. We’re not recruiting yet for the fMRI study; we’re still at the IRB [institutional review board] stage, applying for study approval. We hope to start recruiting in June 2016, and we’ll be posting that on the MDF site when we do. [Studies are listed at the MDF Study and Trial Resource Center under the Current Studies and Trials tab.]

We do, however, have an ongoing study of the natural history of CDM here at the University of Utah, and we hope to recruit some participants for the fMRI study from that group. [The natural history study, which is open, is Health Endpoints and Longitudinal Progression in Congenital Myotonic Dystrophy. Read more about it at the MDF Study and Trial Resource Center under Current Studies and Trials.]

We’ve done neuropsychological testing with the children in the natural history study. The children are all different, and that’s what makes CDM so interesting. The cognitive piece is fascinating. That profile for them is definitely varied, and I think that some of the measures that we’ve been using are just not sensitive enough to understand what’s going on.

I chose 7-year-olds as the lower cut-off age, because they have to stay in the fMRI scanner for 20 to 30 minutes. That can be difficult or scary for any child, and children with CDM sometimes have sensory issues. They’ll have something that’s like a fish tank for them to watch during the scan. It’s not like a movie, where they’d be actively thinking about things, but they’ll be looking at something.

MDF: You have a broad background in clinical psychology. What led you to study children with myotonic dystrophy?

MD: In 2013, when [neuromuscular disease specialist] Dr. Nicholas Johnson came here from the University of Rochester, I became interested in people who have myotonic dystrophy, particularly congenital myotonic dystrophy. I’m interested in understanding the neuropsychological differences in this population. There isn’t a whole lot of known information about congenital myotonic dystrophy and neuropsychological function.

MDF: Did you know that another MDF research fellow, Dr. Ian DeVolder, is doing a study of fMRI in adults with type 1 DM?

MD: Yes, I saw that. That was great to see that someone is doing something very similar in adults. I’m sure our paths will cross as we move forward in our careers. Hopefully, both of our efforts will better define the neuropsychological dysfunction throughout the life spectrum.

Thornton Receives Prestigious National Science Award

Dr. Charles Thornton, neurologist at the University of Rochester Medical Center and MDF Scientific Advisory Committee member, has been awarded a Javits Neuroscience Investigator Award from the National Institutes of Health (NIH) to further his research on muscular dystrophy. Congress established the Senator Jacob Javits Awards in the Neurosciences in honor of the late Senator Javits (R-NY), who was himself afflicted with amyotrophic lateral sclerosis (ALS).

Javits Neuroscience Investigator Award

The Javits Award (R37) is a conditional, seven-year research grant given to scientists for their superior competence and outstanding productivity. Javits Awards provide long-term support to investigators with a history of exceptional talent, imagination and preeminent scientific achievement. The award is initially for a period of four years, after which, based on an administrative review, an additional project period of three years may be awarded.

Investigators may not apply for a Javits Award. Nominations for this award are made by the National Institute of Neurological Disorders and Stroke (NINDS) staff and by members of the National Advisory Neurological Disorders and Stroke (NANDS) Council. These nominations are then reviewed by the Director, NINDS and the NANDS Council.

Particularly Deserving Investigator

MDF reached out to Charles' longtime collaborator, Dr. Richard Moxley, for his thoughts on Charles and the Javits Award. Dr. Moxley noted that his comments about Charles could go on at length. In brief he noted:

"Charles exemplifies the best in superb clinical research. He is a caring physician, a brilliant scientist with innovative insights, a meticulous, thoughtful investigator, and an excellent team builder -- a critically important component of productive translational research."

He also shared the email that he received from Dr. Glen Nuckolls, Program Director of Extramural Research Program at NINDS. Dr. Nuckoll's comments underscore those provided by Dr. Moxley about Charles:

"This is a much deserved award! The NINDS Advisory Council members were universally enthusiastic about [Charles'] scientific accomplishments, service to the research and patient communities and remarkable track record of peer reviewed applications."

MDF's board and staff join many others in extending our very enthusiastic congratulations to Dr. Thornton for this outstanding recognition, and thank him for his transformative work on myotonic dystrophy research.

Read the University of Rochester Medical Center announcement here.

The University of Iowa’s DM1 Brain Imaging Research Group is excited to announce that its study (previously in a pilot phase of data collection) has been awarded a grant by the National Institute of Neurological Disorders and Stroke (NINDS), a division of the National Institutes of Health (NIH), to fund a 3-year longitudinal study of adults with a family history of DM1. 

This study seeks to identify, measure and track over time common symptoms and changes in the brain that may be happening to individuals living with DM1 and those at risk for DM1. 

The study is looking for adults aged 18 through 65 years old and living in the US who either:

1)    Have been diagnosed with DM1 after the age of 21 OR
2)    Have not been diagnosed with DM1 but have a family history of DM1 (i.e. are “at-risk” for developing DM1)

Research participants will be invited to come to the University of Iowa, located in Iowa City, Iowa, for three yearly study visits, each lasting about 8 hours. Study participants will be compensated for their time and travel.  

Eligible persons interested in participating should contact Stephen Cross, the Research Associate for this study, directly at (319) 384-9391 or email. Learn more about research trials and studies, and read about Dr. Ian DeVolver's study on the brain. 

MDF has awarded a 2016-2017 postdoctoral fellowship to Dr. Ian DeVolder, Ph.D., a Graduate Research Assistant in the Department of Psychiatry at the University of Iowa Carver College of Medicine. 

Dr. DeVolder’s research proposal is titled “Structural and Functional Connectivity in the Brains of Patients with Adult- and Late-Onset Myotonic Dystrophy Type 1 (DM1): A Potential Biomarker for Disease Progression.” In this study, Dr. DeVolder and his colleagues will evaluate brain structure and function in DM1 and correlate these with measures such as neurocognitive functioning and disease duration. The investigators will study 30 patients with classic adult-onset or with late-onset DM1, ages 21 to 65 years old, and compare them to 30 age-matched healthy controls. 

Dr. DeVolder received his doctorate in neuroscience from the University of Iowa in 2015 and is a graduate research assistant in the laboratory of Peg Nopoulos, M.D., at the University of Iowa Carver College of Medicine. His work at Iowa has focused on the structure and function of the brain in children with clefts of the lip or palate and in children at risk for Huntington’s disease.

“If we can know how and when myotonic dystrophy type 1 affects the brain,” DeVolder says, “we can better time treatment so as to have a neuroprotective effect and try to prevent these brain changes from happening in the first place.” We recently talked with Dr. DeVolder to learn more:

MDF: Your previous work was focused mainly on the brain abnormalities that can accompany clefting disorders, such as cleft lip and cleft palate. [See DeVolder, I., et al., Abnormal cerebellar structure is dependent on the phenotype of isolated cleft of the lip and/or palate, The Cerebellum, April 2013.] How did you move from there into myotonic dystrophy?

ID: It’s definitely been a shift in terms of the clinical population that I’ve been working with. Clefting abnormalities and myotonic dystrophy are not directly related. However, in terms of the basic practice, the basic study we did, they’re actually not that far removed. It’s the same type of imaging techniques, the same type of neuropsychological evaluation.

And, even though my thesis work was with the clefting community, I actually have had a large role in a number of different studies in my lab. Importantly, one of those was our study on Huntington’s disease, which can be thought of as a sister disease to myotonic dystrophy. They’re both trinucleotide repeat disorders, and both previously were thought of as primarily neuromuscular diseases. 

The Huntington’s study was focused on children who were at risk for developing HD. These children had either a parent or grandparent who was affected by the disease. We did a full neuropsychological evaluation, MRI and genetic testing. We were comparing children with the expanded repeat, who, in 30 years or so, will likely develop HD, with those who don’t have the expanded repeat. We were looking at Huntington’s from a developmental perspective to see whether, at an early age, there is something being set in motion in terms of neurodevelopmental changes. Results from this study should start being published within the coming year.

It’s been an interesting shift into myotonic dystrophy. We wanted to model our DM1 study after our Huntington’s study, looking at kids who were not yet showing symptoms but who were at risk for DM1. But we underestimated the role of anticipation in DM1. This is a phenomenon that is seen in Huntington’s but not nearly as frequently and not nearly as severely as in myotonic dystrophy.

We discovered that families with DM1 oftentimes don’t know that they have it or that their children are at risk until they have a child that’s born with an extremely expanded repeat and the congenital-onset or childhood-onset form of the disease. So it’s much harder to identify children with pre-DM1 than children with pre-HD. Therefore, we shifted our focus to adult-onset  and late-onset myotonic dystrophy.

There have been some neuroimaging studies in myotonic dystrophy, but they’ve typically focused on the childhood-onset, adult-onset and congenital-onset forms all together in one group.

We really wanted to focus on one type of DM1, because the congenital-onset and childhood-onset forms seem to be so different in terms of the symptoms they show. We wanted to completely remove that confounding factor. We’re looking at a pretty big age range – 21 to 65 – but it’s still adult-onset DM1. We cut off the age for this study at 65 because we didn’t want to introduce aging effects as confounding factors.

We’re combining concepts from a lot of previous neuroimaging studies. We’re using several neuroimaging techniques and we’re combining those with a neuropsychological evaluation. We’re also making it a longitudinal study, where participants will come back once a year for three years. The study is unique in that sense. It’s the first neuroimaging study in DM1 to combine all of these elements.

MDF: What kinds of brain abnormalities are you looking for?

ID: The brain changes in myotonic dystrophy have been primarily found to be white matter-related. We expect to find some of the things that have already been seen, such as increased numbers of white matter hyperintensity lesions. White matter refers to the myelinated fibers that connect different regions of the brain, and there are variants that you can see on an MRI scan. They’re a little bit unclassified, but basically they’re considered to be abnormal white matter.

We’re also using diffusion imaging, which looks even more specifically at white matter structural integrity. Diffusion imaging measures the movement of water molecules in tissues. It’s a way to see if water is moving along the axon versus going out. From that we can get an idea of the actual shape and structure of the white matter. Typically, white matter in the brain forms tight fiber bundles and tracts, so healthier and better-myelinated white matter would lead to an increase in water movement along the axons, rather than out into the brain. This can be measured by diffusion imaging.

There’s been a fair amount of neuroimaging work in myotonic dystrophy, but there’s been hardly any functional neuroimaging. That’s something I’ve worked with in our studies and something I’ve really wanted to focus on for this population as well.

I was really excited and somewhat surprised when I saw the 2014 paper on functional brain connectivity in DM1. [See Serra, L., et al., Abnormal functional brain connectivity and personality traits in myotonic dystrophy type 1, JAMA Neurology, May 2014.]

They found that in patients with DM1 there was increased functional connectivity in certain parts of the brain compared to the control group. Specifically, they found increased network connectivity between the left and right posterior cingulate cortex and the left parietal node when the participant was in a resting state – in other words, not engaged in any specific task. They also found that the DM1 group was more likely to show certain personality traits, such as the presence of fixed ideas, rigidity of thought, and an acute sensitivity to anger or hostility in others, than the control group.

In our study, we’re looking at the resting state, and we’re looking at functional connectivity, but we’re also looking at the developmental component, whether these networks are changing over time and with disease duration.

In resting-state functional connectivity analyses, we’re examining low-level changes in blood flow throughout the brain. You can look at the time course of these blood-flow changes at each individual voxel [volume element] in the brain, and then can compare that time course to all other voxels of the brain. From this you can discover areas of the brain that are showing the same levels of blood-flow changes, with the idea being that those areas that are functionally connected to each other would show a more similar type of pattern to each other in terms of blood-flow. With this data we can examine functional networks in the brain, and how they may be changing in DM1.

In some of the questionnaires that we’re administering, we’re also looking for personality traits that may be typical. We’ll see whether or not we capture the same types of findings as the 2014 study.

MDF: If you do find brain abnormalities, are they necessarily the cause of the cognitive and personality differences sometimes seen in DM1? Could it be that focus on certain thoughts or activities could change the brain? Or could it be that respiratory or cardiac impairment associated with DM1 affect the brain?

ID: I think that if there’s a common pattern of brain abnormalities seen in a population, I would argue that it’s more neurobiologically based rather than the other way around. But it’s a hard thing to parse out. 

In another part of your question, you asked about whether what we’re seeing might not be primary but secondary to some of the respiratory or cardiac issues. It’s an issue that we’ve run into, particularly in the clefting studies that I’ve been involved in. 

A fair critique of that study is that some of the changes we measured may actually be secondary, a response to the things these kids experience at really young ages – like anesthesia during reparative surgeries when they’re not even one year old yet. They are facing these environmental insults at this critical developmental time point. It’s a potential caveat to some of our studies.

I think with myotonic dystrophy it won’t be quite as big an issue. In our screening process, we automatically exclude individuals who have a pacemaker installed, because they can’t go into the MRI scanner. As a result, I think those individuals who would be the most severely affected in terms of the cardiorespiratory symptoms are automatically being excluded from the study.

I think it’s going to be more reasonable in this study to really try and parse out the abnormalities that are directly caused by the gene expansion as opposed to other factors.

Also, we do get a pretty extensive medical history from all our study participants, so potentially we could create within the myotonic dystrophy group some separate subgroups, such as those that are most severely affected by arrhythmias, and see whether or not we are getting the same patterns of brain changes.

MDF: Would finding brain abnormalities in study participants with DM1 have therapeutic implications?

ID: We’re focusing on the longitudinal aspect in these studies. What we’re hoping to find is essentially biomarkers for the disease. These do have important therapeutic implications, but they’re not going to be immediately obvious. 

As for the current drug trials that are going on with Ionis, they potentially could have a lot of therapeutic benefit. However, the drug they’re testing cannot cross the blood-brain barrier unless delivered intrathecally -- via spinal infusion. Right now, the potential drug treatments, which are delivered subcutaneously, won’t actually get into the central nervous system. [Ionis Pharmaceuticals is testing its antisense-based drug IONIS-DMPK-2.5Rx, which targets the abnormally expanded RNA from the DMPK gene in DM1.]

The thing is, we don’t have a good idea of the developmental component of the brain abnormalities in terms of the disease progression itself. Before drug discovery can start moving into that area, we have to know what’s actually happening in the brain. If we can get a better idea of when these changes are occurring and what the changes actually are, we can track disease progression much better, potentially having much better timing of when drug delivery should happen. With optimal timing of drug delivery, these drugs could have a neuroprotective effect and ideally prevent these brain changes before they happen.

MDF: Is your study still open to recruitment?

ID: The study is well under way, but yes, it’s still open. We will continue to recruit new participants over the next few years.

Note: For details about this and other DM studies, go to MDF’s Study and Trial Resource Center and select the Current Studies and Trials tab. The study discussed in this article is Brain Structure and Function in Adults with a Family History of DM1.

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.

Reference:

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.

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.”

Reference:

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

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.

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 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.