There has been relatively little research on quality of life for DM2 patients, and DM2 is often considered “less severe” than DM1. However, a new study identified a subset of DM2 patients who are impacted as severely as those with DM1.

Dr. Dusanka Savic-Pavicevic and colleagues recently published a comparison of genetically confirmed DM2 and DM1 patients using a variety of quality of life measures.

The research team found no differences between DM2 and DM1 in the overall and physical composite scores of the survey.

Emotional and mental composite scores were typically better in DM2 patients, as were independence and body image scores. Disease impact on cognition, strength, heart function, breathing and cataracts were also less severe in DM2.

The DM2 patients who reported worse scores were typically older, weaker, and had higher fatigue levels than the DM2 patients who scored better on certain segments of the surveys. Lower quality of life scores were also associated with lower cognitive achievement, memory impairment and lower educational levels.

A deeper understanding of the correlation of age, strength, and fatigue with quality of life in DM2 is needed to facilitate better patient outcomes. More DM2 studies like this will pave the way for higher quality care.

Reference:

Quality of life in patients with myotonic dystrophy type 2.
Rakocevic Stojanovic V, Peric S, Paunic T, Pesovic J, Vujnic M, Peric M, Nikolic A, Lavrnic D, Savic Pavicevic D.
J Neurol Sci. 2016 Jun 15. 

“CRISPR-Cas9" (pronounced "crisper") is an acronym for the full name of a new cutting edge, gene-editing technology: “Clustered Regularly Interspaced Short Palindromic Repeat - Cas9". 

CRISPR-Cas9 has garnered wide research interest for its capacity to target and correct disease-causing mutations. A naturally occurring gene editing technology, it was first identified in bacteria, which use it to protect against invasive viruses. 

CRISPR and DM 

DM is a disease of RNA processing, and understanding RNA binding proteins is at the core of understanding DM. It is the reduced availability of the RNA binding proteins muscleblind and CUGBP1 that cause the alterations in RNA splicing leading to many, if not all, of the signs and symptoms of DM.  

New Breakthroughs in Targeting RNA from University of California

Dr. Gene Yeo’s lab at University of California, San Diego focuses on how gene expression is controlled at the level of RNA, the intermediary step in the DNA to RNA to protein pathway by which genes produce proteins. 

His lab is specifically interested in RNA processing, RNA binding proteins, and how defects in RNA binding proteins cause neurological and neuromuscular diseases like DM.

In a recent publication in Cell and a more detailed commentary on technology development in Bioessays, Yeo and colleagues show that incorporating a fluorescent tag into the CRISPR-Cas9 system allows them to target and track the movements of RNA within individual living cells.  

Importantly, the binding of the CRISPR-Cas9 tracker did not appear to influence the level of RNA or its function, letting it function as an inert tracking tool. We know that proper RNA localization and movement within the cell is essential to faithfully transmit the genetic code into protein synthesis.  

This latest publication offers an opportunity to better understand the disease mechanisms in DM (through precise tracking of intracellular movement of RNA), an essential step in therapy development. 

CRISPR for DM Mouse Models 

Another important use of CRISPR-Cas9 technology is in the development of better DM mouse models to support studies of disease mechanisms and developing therapies. 

This novel gene editing approach allows triplet repeat expansions to be precisely inserted into the mouse DMPK and ZNF9 genes in the same locations the expansions occur in the human genes. MDF is currently working with researchers to improve DM models, including mouse models, and make them available to our research community through this strategy.

The Future of CRISPR

Although there are considerable hurdles to overcome, we will likely see CRISPR-Cas9 technology in clinical trials in the next several years as a novel, potentially disease-mitigating approach.  

Since editing of the genome is involved, unintended consequences could be severe, so the first uses of CRISPR-Cas9 in humans will draw considerable attention from national regulatory authorities like the Food and Drug Administration (FDA) in the US, and the European Medicines Agency (EMA) in Europe.

We look forward to gene editing progress on the use of CRISPR-Cas9 to treat disease, and learning more about the potential for this approach to edit the CTG and CTTG expansions in DM1 and DM2. 

References:

For more information on CRISPR, see a recent New Yorker article, The Gene Hackers.

Programmable RNA Tracking in Live Cells with CRISPR/Cas9.
Nelles DA, Fang MY, O'Connell MR, Xu JL, Markmiller SJ, Doudna JA, Yeo GW.
Cell. 2016 Apr 7. Epub 2016 Mar 17.

Applications of Cas9 as an RNA-programmed RNA-binding protein.
Nelles DA, Fang MY, Aigner S, Yeo GW.
Bioessays. 2015 Jul. Epub 2015 Apr 16.

Dr. Matt Disney brings an unusual and increasingly valuable skill to therapy development for DM—he’s a chemist. 

Dr. Disney’s background, position and interests give him the flexibility to do exploratory work that leverages the latest advances in RNA biology in order to target the unique disease mechanisms of DM. By focusing on small molecules, his work has the potential to target all organ systems affected by DM and move toward practical applications in treating DM.

Medicinal chemists working on rare diseases at universities or non-profit research organizations, like his home base at The Scripps Research Institute, Florida, are rare, as they usually are based in the Pharma/Biotech sector.  

The NIH has recently awarded two research grants in support of Dr. Disney’s research.  

The first grant is an NIH Director’s Pioneer Award— a program that the NIH describes as supporting “individual scientists of exceptional creativity, who propose pioneering and transforming approaches to major challenges in biomedical and behavioral research.” 

The Pioneer program is extremely competitive, with only 13 Pioneer Awards issued by NIH in 2015. This five-year, $960,000/year award seeks to utilize the defective gene as a catalyst for the synthesis of highly selective therapeutic compounds directly in the affected cells. The approach ensures that the drug will be available in precisely the cells where it is needed, thereby entirely avoiding issues encountered by traditional drug development and delivery strategies.

The second grant award is a renewal of Dr. Disney’s current NIH funding, providing an additional 5 years and $2.5M of support. In this work, he is trying to overcome the limitations of oligonucleotide therapeutics traditionally used to target RNA through the design, synthesis, and evaluation of small drug-like compounds with potent RNA binding capacity. Dr. Disney and colleagues have recently described this novel platform in an article in Bioorganic & Medicinal Chemistry Letters.

Reference:

Comparison of small molecules and oligonucleotides that target a toxic, non-coding RNA.
Costales MG, Rzuczek SG, and Disney MD.
Bioorg Med Chem Lett. 2016 Jun 1. Epub 2016 Apr 11.

While it has been widely recognized by clinicians treating DM that gender plays an important role in determining disease heterogeneity and progression, there is little hard data to support differential response of males and females to DM.

Dr. Guillaume Bassez and a large team in France and Canada have recently published an analysis of gender as a modifying factor of the DM1 phenotype. In the study, they evaluated 1,409 adult DM1 patients in the French DM-Scope registry. Importantly, findings were validated using additional cohorts from the AFM-Telethon DM1 survey and the French National Health Service Database.

The research team identified clear differences in symptoms detected by gender. Adult males were much more likely to present with “traditional” DM1 signs and symptoms, including muscle weakness and myotonia, cognitive impairment, and cardiac and respiratory involvement. By contrast, adult females had symptoms that were less suggestive of “traditional” DM1, instead showing predominance of cataracts, obesity, thyroid signs, and GI symptoms.  

The differing constellation of symptoms in the two sexes led the research team to conclude that women were often less symptomatic of DM1 and thus often undiagnosed, although this was potentially offset by the finding that women appeared to more often seek specialist care for DM1 symptoms.

Gender matters in DM1. The biologic mechanisms underlying the gender differences that the French group has documented for DM1 are unknown. To improve diagnosis and management of DM1, as well as to better plan for inclusion of both genders in clinical trials, it will be important to understand the factors responsible for the very different onset and progression of DM1 in males and females.

The heterogeneity (variability) that characterizes the clinical manifestations of myotonic dystrophy type 1 (DM1) has been well recognized by physicians, patients, and family members. Although the length of CTG expansions in the DMPK gene correlates with age of onset and severity of DM1, knowledge of other factors that impact progression of DM1 currently is rather limited.  

Intensive analysis of large cohorts of DM1 and DM2 patients are underway to identify both genetic modifiers, gene variants that can speed or slow disease onset or progression, and biomarkers, measurable indicators in blood or other tissues that can be critical for studies of disease progression and clinical trials. 

MDF is partnering with the research community to identify biomarkers and move them toward qualification by the regulatory authorities as drug development tools.

Understanding of the biological factors behind heterogeneity of DM1 is critical to help patients better understand their disease, as well as to help drug developers design successful clinical trials. The studies necessary to identify the underlying factors require large cohorts of affected individuals—for this reason, it is essential that patients become involved in research efforts that build the requisite databases, such as the Myotonic Dystrophy Family Registry. 

Heart dysfunction is the second leading cause of death for DM patients and affects 80% of the population; yet very little is known about the molecular changes that alter the cardiac conduction system. A multi-disciplinary, international team, representing 25 different academic institutions, recently undertook a massive messenger RNA sequencing project to learn more about this. Their findings provide an important understanding of the molecular basis of cardiac dysfunction in DM and may have immediate implications for how DM patients are treated.

Using biopsy or post mortem samples from DM1 and DM2 patients, the team assessed the identity of mis-spliced genes and correlated the pattern of changes with the cardiac dysfunction seen in these patients. Considerable progress has been made in understanding the molecular events behind the skeletal muscle changes in myotonic dystrophy (DM). The CTG or CCTG expansions (“triplet repeat”) in the DNA of patients with DM1 or DM2, respectively, produce aberrant messenger RNAs that alter the expression of two proteins that regulate gene splicing, muscleblind and CUG-binding protein 1. These changes in splicing regulatory proteins, in turn, cause the mis-splicing of key skeletal muscle genes that, in turn, produce myotonia and muscle wasting.

Until now, we have had very little knowledge of these molecular level events regarding the DM heart. The altered synchronization of the heartbeat (arrhythmias) and altered heart rate (ventricular tachycardia) seen in DM are likely the result of alterations in sodium and potassium ion flux. The propagation of electrical impulses across the specialized heart muscle cells that comprise the heart’s conduction system is dependent upon the flux of sodium and potassium ions across the cardiac cell membrane. Among the DM-related splicing changes in the heart, the research team discovered that a sodium channel gene, SCN5A, was mis-spliced. Specifically, there was a switch from SCN5A messenger RNA containing the normal, adult 6B exon to the fetal 6A exon.

This finding was of particular interest since the 6A exon-containing SCN5A is known to exhibit reduced excitability when compared to the normal adult SCN5A. To establish a connection between the molecular event, the DM-related switch from adult to fetal SCN5A isoform, to cardiac dysfunction, the research team developed a mouse model expressing the fetal, rather than the adult, SCN5A isoform. Notably, these mice exhibited similar cardiac conduction system delays and arrhythmias to those characteristic of DM, thereby providing support for a causal relationship between mis-splicing of SCN5A and cardiac dysfunction.

The mis-splicing of SCN5A explains some important changes in the hearts of DM patients. Mutations in SCN5A have been linked to other cardiac diseases, and there is the potential for repurposing the therapeutic and management strategies used in those diseases to DM. Knowledge of the downstream molecular changes that are responsible for changes in heart function will yield important insights into development of novel therapies for myotonic dystrophy.

It should be recognized that this study would not have been possible without the partnership of DM patients and a large scientific team of investigators. The sharing of expertise and resources that lies behind the success of this study needs to be our continuing model for future progress in understanding and treating DM. For information on other scientific studies currently recruiting, please see the Study and Trial Resource Center.

Reference:

Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy.
Freyermuth F, Rau F, Kokunai Y, Linke T, Sellier C, Nakamori M, Kino Y, Arandel L, Jollet A, Thibault C, Philipps M, Vicaire S, Jost B, Udd B, Day JW, Duboc D, Wahbi K, Matsumura T, Fujimura H, Mochizuki H, Deryckere F, Kimura T, Nukina N, Ishiura S, Lacroix V, Campan-Fournier A, Navratil V, Chautard E, Auboeuf D, Horie M, Imoto K, Lee KY, Swanson MS, Lopez de Munain A, Inada S, Itoh H, Nakazawa K, Ashihara T, Wang E, Zimmer T, Furling D, Takahashi MP, Charlet-Berguerand N.
Nat Commun. 2016 Apr 11;7:11067. doi: 10.1038/ncomms11067.

Since its discovery almost 25 years ago, researchers have been working to try to understand the DNA mutation causing myotonic dystrophy type 1 (DM1).

The mutation is known by many names, including “CTG repeat,” “triplet repeat,” “trinucleotide repeat,” “expansion mutation” and many more. Over the years researchers have determined that the mutation is unstable, and most often grows larger in size. Not only does the repeat usually get larger each time it is passed on to children, it can also get larger inside an individual person. 

For example, a common blood test for DM1 taken from the same person several times over many years reveals that the repeat grows slowly over time. It is important to note that a repeat size reported on a genetic test most often reflects an average size, or the most commonly found size of the repeat, it does not represent the size found in every single blood cell. 

Furthermore, the repeat size in the muscles of an individual with DM1 will often be many times bigger than the repeat size found in their blood, making the study of DM1 repeat size a very complicated research field. 

Researchers have puzzled over why the repeat is so unstable, and what drives the repeat to expand so much in some types of cells, and in some people more than others. In order to understand this better, researchers from the University of Costa Rica and the University of Glasgow teamed up to examine the DNA from 199 individuals with DM1 in order to determine what might be driving the repeat to grow. 

This team had previously developed a way to mathematically predict the original repeat size found in an embryo at the time of fertilization, and determined that this predicted repeat size could more accurately predict the age someone with DM1 would first experience any symptoms. In fact, this predicted repeat size was calculated to be responsible for 89% of the variability seen in blood over time. However the remaining forces driving repeat instability were unknown. 

In this recent publication, the same team explored whether there were other genetic factors aside from the repeat that might be inherited, and driving instability. They found that one variation in the genome, inside a gene called MSH3, was strongly connected to an increased amount of instability. 

This gene has previously been connected to the instability of DNA repeats, however this is the first time a naturally occurring variation has been connected to driving instability in people with DM1. Researchers call this variation a “modifier,” because it modifies how the DNA repeat behaves over time. 

Since larger DNA repeats have been previously associated with more severe symptoms, it is possible that future research might show that symptoms can be worse or better depending on which of the two variations of the MSH3 gene you inherit from each of your parents.  

However, that type of study would likely require many more patient samples than this preliminary study of 199 individuals. Interestingly, a study on cancer risk found that this same variation was linked with an altered predisposition to cancer, but the variant that had negative consequences when it came to cancer risk was the variant that saw less instability in DM1. Therefore, this variant can have both positive and negative consequences in humans.

Reference:

A polymorphism in the MSH3 mismatch repair gene is associated with the levels of somatic instability of the expanded CTG repeat in the blood DNA of myotonic dystrophy type 1 patients.
Morales F, Vasquez M, Santamaria C, Cuenca P, Monckton DG.
DNA Repair (Amst). 2016 Mar 8.

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. 

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:

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.