The Jensen family has a long tradition of hosting an authentic Louisiana crawfish boil with live music for their family and friends in San Diego. The Crawfish Boil became a fundraiser in 2012 when Taylor Jensen and her young son, River, were diagnosed with myotonic dystrophy type 1 (DM1). The Jensen's learned first-hand how complex DM is and how it impacts an entire family. After struggling with the initial impact of the diagnosis, Taylor and Eric evolved the family tradition into a fundraiser to support Care and a Cure.

The Fundraiser has two ultimate goals: to raise awarness of the most common form of muscular dystrophy known as myotonic dystophy (DM); and to to raise funds to continue the research that will enable treatments and an eventual cure. This year marks the first time people living with DM are receiving a potential therapy. The first DM clinical trial began this year, evaluating a medication that targets not just disease symptoms but the genetic mutation that causes the disease.

This year the Jensen Family had their 5th Annual Crawfish Boil Fundraiser ("Pinching Tails for a Cure") hosted at the San Diego Harley Davidson Dealership. Thanks to the sponsors and donors, the Crawfish Boil was a success, raising over $30,000 - bringing that to a total of $110,000 over the last five years!

You can read more about their personal journey with DM in this letter from the Jensen family.

Are you interested in hosting a fundraiser for Care and a Cure? MDF is here to help.

Caroline Easterling, a former preschool teacher and mother of 11-year-old twin girls has been in two recent DM 1 studies. She’s learned a lot along the way and has solid advice for anyone who wants to make a contribution to the greater good by taking part in research.

1. Do Your Homework

Each study and trial has unique requirements. Find out exactly what those are before you get started. 

For example, drug trials may include side effects. You need to understand the potential consequences of side effects, including how they might impact your daily life during the trial.

Another issue to consider is the time commitment. One study Caroline participated in was close to home. That made it very easy to keep up with appointments. However, another was located more than an hour away. It even required some overnight hotel stays. This presented more of a challenge, especially with child care. With advance planning and family support, Caroline was able to make it work.

“You want to be able to see it through to the end, so find out all the information you can,” says Caroline. “You’ve got to make sure you can do the time commitment. Find out about any side effects ahead of time. You’ve got to be willing to deal with the side effects.”

2. Line Up Support

It’s great to have support when you try something new. Studies are no different, and your research team is there to support you. Don’t be afraid to ask questions, and let them get to know you. Caroline found that her team was a great source of support, not just for the study, but also for her DM concerns. 

“It gave me the insight that people really care,” she said of the researchers she worked with. “They were very willing to answer my questions and give me information. They were happy to help me with family life stuff that I was having issues with. They talked about what may be coming next for me down the line.”

Let your friends and family know what you will be doing and that it may require some changes to your usual shared routines. Caroline and her husband knew they would need to swap some household responsibilities in order for Caroline to participate. With her husband’s support, she was able to fit the studies into their family schedule.

“Make sure your family is OK with the time that you’re asking from them. My husband had to take the kids to school and pick them up. It’s not just you who has to deal with the time," says Caroline.

3. Get a Study Buddy

Having a friend to share an experience with always makes it better, and the buddy system applies to research too.

Caroline’s sister, Mary, also has DM1 and has been in both studies with her. “I lucked out to have someone like my sister to hang out with me,” Caroline says. “We accompanied each other to each appointment.”

Do you know someone who would also be a good candidate for a trial you are considering? Let them know about it, and see if you can participate together. Or maybe you have a friend or family member who can make time to share the drive and attend appointments with you.

Challenges to research participation can be minimized with education, support and advance planning to smooth the way. Caroline emphasizes the rewards. “Research studies are important, because they give us insights that we wouldn’t otherwise have,” says Caroline. “A research study will help the greater good, and I’m hoping one may help me.” 

Caroline took part in a study to find DM1 biomarkers (indicators of disease progression), through a site at the National Institutes of Health (NIH) in Bethesda, Maryland. She is also part of a trial by Ionis Pharmaceuticals to test the safety and tolerability of DMPKRx, an experimental drug that targets the underlying molecular defect in DM1, through a site in Baltimore. 

Find out about studies and trials you can participate in.

07/27/2016

The annual Biotechnology Innovation Organization's (BIO) International Convention was held in San Francisco, CA earlier this summer. BIO represents more than 1,100 biotechnology companies and other organizations, and the annual Convention usually attracts more than 15,000 attendees. BIO is the trade organization that represents biotechnology and pharmaceutical companies, academic institutions, and biotechnology centers and organizations dedicated to innovation in biotechnology. The annual BIO Convention provides unprecedented partnering opportunities, and thus is a critically important forum for MDF to both learn from and educate potential partners in drug development for myotonic dystrophy.

The BIO Convention provided MDF with myriad opportunities to meet with industry partners that are already working in drug development for DM, have potential interest in DM, or are developing technology that MDF believes could be used to create potential therapies for DM patients. 

MDF staff and board member Dr. Woodie Kessel met with senior representatives of 11 different biotechnology companies at BIO, who are either existing partners with drugs in preclinical or clinical development for DM (including AMO Pharma and Amorchem/Roche), or currently in early stage development efforts. 

Staff also used the face-to-face meetings to evaluate the applicability of technologies such as gene therapy via companies experienced in cell line development as potential DM treatments. MDF used the meetings to describe the comprehensive infrastructure, data collection, funding and other efforts put in place by DM stakeholders (including MDF) to lower the risks to new DM drug development, to help ensure that the DM drug development pipeline continues to expand.

Drug discovery and development programs are inherently high-risk investments for pharmaceutical and biotechnology companies. Engagement and recruitment of new companies to work on DM, as well as continuing efforts to foster companies already working in the area, are critically important goals for MDF. 

Myotonic dystrophy is characterized by considerable variability in signs and symptoms that involve multiple body systems. In addition to variations resulting from repeat length and tissue-specific somatic repeat expansions, we know that gender can influence disease phenotype. Yet, there is a general lack of understanding of factors underlying heterogeneity of the DM phenotype. This warrants further studies of genetic factors, including the potential for additional disease genes and genetic modifiers.

Dr. Simone Rost and his colleagues at the University of Würzburg have explored the potential involvement of genetic variants in determination of DM-like phenotypes and recently published their results in the European Journal of Human Genetics. The team started with a cohort of 5,280 patients with a primary clinical diagnosis of DM evaluated in the Würzburg molecular genetics lab over a 10-year period. Of the cohort, 38% had repeat expansions in DMPK or CNBP, while a relatively small portion of the cohort (< 0.5%) was found to have mutations in genes associated with other types of muscular dystrophy (e.g., FSHD1, LMNA, PABPN1). 

A subset of the patients lacking the traditional DM1 and DM2 repeat expansions, but with DM symptomology verified by neurological exam, underwent further genetic analyses. No additional pathologic variants were identified in DMPK, CNBP, or CUGBP; patients were also free of mutations in 27 other muscle disease genes. The study identified three unrelated patients with potentially pathogenic variants in MBNL1.

Mice with mutations in Mbnl1 appear to phenocopy mice containing large DMPK repeat expansions, consistent with the known role of Mbnl1 in the pathogenesis of DM. To evaluate potential splicing changes due to the MBNL1 variants, the Würzburg team performed splicing assays for six genes that are mis-spliced in DM1, using peripheral blood leukocytes from the three patients. The authors failed to identify splicing alterations, but acknowledge the potential tissue specificity of DM mis-splicing.  

Taken together, Dr. Rost and colleagues have linked MBNL1 variants to a DM phenotype. However, despite careful analysis of thousands of patients with DM-like symptoms, only a small number of MBNL1 variants were identified. These findings suggest that MBNL1 mutations may not be more than a minority contributor to DM, and thus other potential gene variants or modifiers should be prioritized for population studies.

Reference:

Identification of variants in MBNL1 in patients with a myotonic dystrophy-like phenotype.
Larsen M, Kress W, Schoser B, Hehr U, Müller CR, Rost S.
Eur J Hum Genet. 2016 May 25. doi: 10.1038/ejhg.2016.41.

Endpoint Award

Dr. Donovan Lott, of the University of Florida, has successfully competed for support of his project, “Development of Magnetic Resonance Imaging as an Endpoint in Myotonic Dystrophy Type 1.” The award is for one year, at $150,000. 

Dr. Lott’s group has extensive experience in developing skeletal muscle MRI as an endpoint measure in neuromuscular disease, including their ongoing interactions with FDA to obtain biomarker qualification. There have been very few imaging studies of myotonic dystrophy skeletal muscle. Given the considerable potential of MRI, an assessment of the feasibility of the approach in DM is essential.

Drug development in myotonic dystrophy (DM) enjoys an important advantage—having the tools in hand to show that a drug candidate gains access to and modifies the primary cause of the disease. Since expanded repeats in DMPK (in DM1) and CNBP (DM2) sequester MBNL1 protein and cause easily assessable molecular (mis-splicing of a large set of genes) and physiological (myotonia) changes, we can get an early signal in Phase 1/2 trials that a candidate therapy engages and modulates a key drug discovery and development target.

The existence of clear endpoints for early stage clinical trials helps de-risk DM for investments by pharmaceutical and biotechnology companies. By contrast, the development of endpoint measures that either establish, or are surrogates for, a clinically meaningful benefit is a clear need for Phase 3 trials in DM, in order to gain regulatory approval for a drug or biologic.

With the objective of meeting this critical need, MDF issued a Request for Applications to identify and support a project with the objective of developing new, clinically meaningful endpoint measures or refining endpoint measures already in development. Dr. Donovan’s project received the highest rating from the MDF peer review panel and was selected for funding.

Dr. Donovan’s team will complete a project in 25 DM1 patients. In these studies, they will quantitatively assess upper and lower limb muscle status by MRI and relate findings to a battery of functional measures, thereby taking the first steps toward development and qualification of MRI as a sensitive and non-invasive biomarker for clinical trials in DM. A qualified endpoint measure, with established linkage to clinically meaningful outcomes for patients, will make each of our clinical trials considerably more efficient and informative.

UK Natural History Grant 

Professor Hanns Lochmuller and Newcastle University are being awarded a $125,000 grant to extend a natural history study of 200-400 adult DM1 patients. 

The Newcastle group is currently funded by the UK National Institute for Health Research to recruit and collect natural history data on the DM1 cohort for one year, through March 31, 2017. MDF funding will leverage this existing funding to allow Professor Lochmuller and colleagues to reach the upper end of their recruitment target and to extend the duration of data collection from this valuable cohort for an additional year. Data collection involves a wide variety of endpoints, with the aggregate data assisting in the planning, design, and recruitment of future clinical trials, as well as supporting identification of putative biomarkers of DM1.

Robust natural history studies are critical to the development of endpoint measures that reflect clinically meaningful benefit for use in registration trials. MDF and MDF UK are pleased to be able to leverage other grant funding to increase the value and impact of this study.

Dr. Yao Yao, a former MDF Fellow, has brought us a step closer to effective muscle stem cell therapies for muscular dystrophy.

Dr. Yao identified a cell signaling mechanism by which muscle stem cells are directed to aid muscle regeneration. His work was recently published in the prestigious research journal, Nature Communications.

Muscle stem cells are responsible for the growth and regeneration of skeletal muscles. They are located immediately adjacent to muscle fibers and divide and fuse with the muscle fiber to increase its size and strength, for example, when you exercise.

These stem cells are also the means by which damaged and weakened muscles are strengthened and repaired. The process is very similar, whether the muscle damage is due to an injury or a muscle wasting disease, like DM.

Because of their vital role in muscle regeneration, muscle stem cells are a potentially important target for developing therapies. Increasing their activity should improve muscle repair.

The development of cell therapies has been difficult, however, because we don’t sufficiently understand stem cell biology. Muscle stem cells participate in both muscle regeneration and the fatty deterioration of muscle. Understanding the regulation of muscle stem cell fate is a critical, early step in therapy development.

A better understanding of the properties of muscle stem cells (and the molecular and cellular mechanisms that control their fate) will be essential to using them in therapies. MDF is pleased to have supported Dr. Yao’s advances in the therapeutic potential for muscle stem cells.

Dr. Yao currently holds a faculty position in the College of Pharmacy at the University of Minnesota, Duluth. For more details on Dr. Yao’s lab, click here.

Reference:

Laminin regulates PDGFRβ(+) cell stemness and muscle development.
Yao Y, Norris EH, E Mason C, Strickland S. 
Nat Commun. 2016 May 3.

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.