Understanding cardiac and other myotonic dystrophy (DM) risk factors and planning for the known complications of DM that may affect you someday can help protect and maintain your quality of life and that of your loved ones. Cardiac complications are the highest-priority care consideration for doctors treating patients with myotonic dystrophy type 1 (DM1) (as identified by expert clinicians in the forthcoming care guideline, "Consensus-based Care Recommendations for Adults with DM1"). As a result, researchers have been trying to understand the factors that may increase the risks of cardiac disease for DM patients.

Dr. Caroline Chong-Nguyen at the Sorbonne Paris Cité University and her colleagues recently published a study in which they looked at DM1 repeat length and its relationship to the risk of cardiac disease. This was a large study of the data in the French patient registry, which tracks patients' symptoms and information over time to understand disease progression and other important information. Eight hundred fifty-five patients with genetically-confirmed DM1 were followed for an average of 11.5 years in order to gain insight into how repeat length could predict cardiac events. Importantly, the research team considered many other factors (such as age, sex, and presence/absence of diabetes) to ensure that their data was not confounded by other variables.

The research team showed that death, sudden death and other adverse cardiac events were linked to DM1 repeat length. Heart rate was higher and conduction system disease was more prevalent in subjects with larger repeats. They found that each 500 repeat increase was associated with 1.5-fold higher risk of death from all causes. Patients with longer repeat lengths also were more likely to have a permanently-implanted pacemaker. 

These findings support taking a more aggressive approach toward screening DM patients for adverse cardiac events, particularly for DM1 patients at the higher end of the range of repeat lengths. Knowing your repeat will help you have discussions with your physician about monitoring and managing your level of risk for cardiac disease.

DMPK CTG expansion length generally correlates with the severity of myotonic dystrophy type 1 (DM1), but is not fully prognostic of disease onset, course and severity. For congenital myotonic dystrophy (CDM), the apparent requirement for an epigenetic change upstream of the DMPK locus is apparently a co-requirement, along with a long CTG repeat. Moreover, the relationship between repeat expansion length and the cardiac phenotype in DM is a gap in our understanding of cardiac disease in DM1.

Multivariate Analysis of a Large Genetically Confirmed DM1 Cohort

Dr. Caroline Chong-Nguyen (Sorbonne Paris Cité University) and colleagues characterized the relationship between DMPK repeat expansion length and cardiac disease in a retrospective study of a cohort of 855 adult subjects from the DM1-Heart Registry. Subjects entered into the study had genetic analysis (Southern blot of peripheral blood) done at the time of their baseline cardiac investigations.

Genotyped patients were followed for a median of 11.5 years. The authors utilized a multivariate analysis that considered potential confounding factors, including age, sex, and diabetes mellitus.

Repeat Length is a Key Factor in Prognosis Even When Confounding Variables are Taken into Account

Survival of DM1 subjects was correlated with the quartile of CTG expansion size—37% mortality was reported in subjects with greater than 830 repeats. Across the range of repeat lengths studied, each 500 repeat increase was associated with 1.5-fold higher risk of death from all causes. Heart rate was higher and conduction system disease, left bundle branch block, and longer PR and QRS intervals were more prevalent in subjects with larger repeats. CTG length also associated with the presence of a permanently implanted pacemaker. Availability of extensive longitudinal data allowed the authors to report Kaplan–Meier estimates for survival, supraventricular arrhythmias, pacemaker implantation and sudden death.

This longitudinal study of a large cohort genotyped at the time of initial cardiac evaluation provides new insights into genotype-cardiac phenotype relationships in DM1. Overall, the authors showed that longer DMPK repeat expansions were correlated with the severity of cardiac involvement, including development of conduction defects, left ventricular dysfunction, supraventricular arrhythmias, the requirement for permanent pacing, sudden death and mortality. These findings support a more aggressive approach toward cardiac screening based on DMPK repeat length—the authors argue that care should be based on assessment of conduction system defects and other cardiac manifestations.

This peer-reviewed research article was accompanied by an editorial by Dr. Matthew Wheeler (Stanford University) in the same issue of the journal. This editorial is also referenced below.

References:

Association Between Mutation Size and Cardiac Involvement in Myotonic Dystrophy Type 1: An Analysis of the DM1-Heart Registry.
Chong-Nguyen C, Wahbi K, Algalarrondo V, Bécane HM, Radvanyi-Hoffman H, Arnaud P, Furling D, Lazarus A, Bassez G, Béhin A, Fayssoil A, Laforêt P, Stojkovic T, Eymard B, Duboc D.
Circ Cardiovasc Genet. 2017 Jun;10(3). pii: e001526. doi: 10.1161/CIRCGENETICS.116.001526.

Repeats and Survival in Myotonic Dystrophy Type 1.
Wheeler MT.
Circ Cardiovasc Genet. 2017 Jun;10(3). pii: e001783. doi: 10.1161/CIRCGENETICS.117.001783

A recent review article makes the case that DM is a brain disease and that better understanding of and treatment strategies for the neurological consequences of DM are essential.

Considerable Gaps Exist in Understanding of the CNS in DM

The central nervous system (CNS) consequences are arguably among the least understood aspects of myotonic dystrophy (DM) and certainly have received only modest attention in drug development, yet:

• Grant applications—or at least successful ones—in this niche are few. The National Institutes of Health’s (NIH) categorical spending database reports that approximately $1.6 million of the $8.8 million awarded for DM in fiscal 2016 is for grants focused solely on the CNS (just one R01 and one P01 that is in its last year);
• Savvy industry researchers recognize the considerable contribution that CNS sequela make toward the overall burden of disease;
• Exploration of the CNS in has produced sparse natural history data and few insights into biomarkers that can provide early indications of target engagement and modulation and clinically meaningful endpoints.

A Status Report

Drs. Genevieve Gourdon (French National Institute of Health and Medical Research) and Giovanni Meola (University of Milan) have published a provocative review article addressing current status of understanding of CNS-related symptoms and the development of tools and therapeutic strategies to address them in DM.

An overall premise of this review, while acknowledging the considerable skeletal and cardiac muscle involvement, is that DM is a brain disease. The authors do acknowledge an essential barrier in moving forward toward CNS-targeted therapies—that the current level of understanding of how repeat expansion-triggered molecular changes link to CNS phenotypes in DM is only a shadow of the mechanism-to-phenotype understanding that we have for skeletal muscle.

The authors review current knowledge of the neuropsychological, cognitive and other CNS signs in CDM, DM1 and DM2, based on available functional and imaging methodology. A gap in longitudinal data, understanding how CNS symptoms progress with age, was identified as particularly acute. To drive interventional studies, it is necessary to establish strong correlations between CNS functioning and endpoints (such as imaging) that can be easily and reproducibly assessed in clinical trials of manageable duration. While we are not yet to this point, the authors note that small studies linking skeletal muscle and neurologic changes are suggestive of common disease mechanisms and highlight the potential that further data may support the linkage of muscle and CNS endpoints in the same clinical trial.

While the invasive splicing biomarkers developed for skeletal muscle-targeted drugs are not available for the CNS, assessment of proteins or exosomal RNA in blood or CSF may provide insights into patient neurological status. The authors’ literature review suggests that correlations between biomarkers and CNS functional status may be weak, at least for studies reported thus far. Instead they point to the value of cell and animal-based models as a means to develop sufficient scientific rationale to drive human clinical trials.

Finally, Drs. Gourdon and Meola give their assessment of putative strategies to therapeutically target the CNS in DM: the primary DNA mutation, toxic RNA, mediator proteins, or the variety of downstream targets arising from specific gene mis-splicing events. Nearly all of the data supporting these various strategies has been developed in studies of skeletal muscle, while conceptually applicable to the CNS, but will encounter both drug delivery and potentially different toxicity questions.

Taken together, the difficulties of assessing the CNS in DM, identifying meaningful endpoints for clinical trials, and ultimately establishing the effectiveness of CNS targeted therapies is captured in the author’s observation of the complex interrelationship of neurological, psychological and social factors in DM. Yet it is essential that we find ways to address the critically important neurological sequela of DM.

Steps to Address the Problem

The authors point to knowledge gaps—longitudinal natural history studies, linkage of imaging and other biomarkers to CNS phenotypes, and better-powered studies focused on more homogeneous cohorts—as important to the path forward. For its part, MDF has organized a forum, Bringing the Patient Voice to CNS-Targeting Drug Development in Myotonic Dystrophy, to bring in the invaluable patient perspective at the IDMC-11/MDF Annual Conference in San Francisco, on September 9, 2017.

Reference:

Myotonic Dystrophies: State of the Art of New Therapeutic Developments for the CNS
Gourdon G, Meola G.
Front Cell Neurosci. 2017 Apr 20;11:101. doi: 10.3389/fncel.2017.00101. eCollection 2017.

Many of you have seen posts on social media about treatments they have received in other countries or heard about through friends, that include everything from dietary aids to gene therapy, and want to know how you can assess the possible benefits and risks of these "treatments." In this complicated therapy environment, how can patients make decisions about whether an available treatment or therapy is safe and effective? How can you tell the quacks from the cures?

In Pursuit of a Cure

MDF is committed to the pursuit of improved Care and a Cure for people living with myotonic dystrophy (DM). We’re a non-profit advocacy organization and there is no other reason for our existence. In pursuit of a cure, we fund research, support infrastructure projects for therapy development, recruit investigators to work on DM, educate drug regulatory agencies, and work with companies to help them see the opportunities and potential for investments in a new therapy for myotonic dystrophy.

Patients and their families know well that the search for a cure, or even a treatment that can mitigate symptoms of DM, is a long and arduous process. We have recently seen the development of IONIS-DMPK-2.5Rx ended because the oligonucleotide drug did not reach its target tissue (skeletal muscle) in concentrations adequate to have a meaningful effect. Fortunately, Ionis has reported that it has alternative compounds that appear to have better tissue-targeting and we hope to see these move toward clinical trials.

Sometimes it’s Complicated

More broadly, we have seen significant recent controversy and lack of agreement regarding therapies developed for other rare diseases, with insurance companies refusing to reimburse for drugs they claim do not have enough scientific evidence to demonstrate a clinically-meaningful effect for patients. We also know that the ‘placebo effect’ where patients report significant therapy benefit when actually on a placebo (a non-active substance with no therapeutic effect), can also complicate the discussion, particularly when a given therapy has a relatively small demonstrable impact. 

Stick with What Works

Oligonucleotide drugs can succeed as therapeutics. Biogen and Ionis collaborated on the development of Spinraza for spinal muscular atrophy. The two companies exercised considerable care in development of these drugs and sought FDA approval only after obtaining results from two international, placebo-controlled clinical trials. The key here is that considerable drug effect was demonstrated in a large cohort of patients enrolled in the clinical trials. As a consequence, the drug is now marketed for all types of spinal muscular atrophy and, while the cost of the drug is very high, many families are getting insurance coverage for Spinraza. The evidence had to be there for both therapy approval and insurance company reimbursement.

Achieving a drug that is proven to have a considerable level of effect on measures that are clinically-meaningful to DM patients is a central requirement for both drug approval and reimbursement. 

The therapies that we hope to achieve for DM will come only from this evidence-based drug development and approval process. MDF regularly meets with biotechnology and pharmaceutical companies—including ten companies in the last two months—providing information and making the case that DM represents a good investment with a clear pathway to drug approval. Any legitimate clinical trial will be listed in ClinicalTrials.gov, and information about legitimate DM studies and trials will always be circulated by MDF.

Dangers lie in the pursuit of quack “therapies.” A brief Google search will reveal fabulous claims of cures for just about any disease, if the patient will only travel to a developing country, with less regulatory oversight, for the ‘breakthrough’ therapy. Most often, the claims of effectiveness lack substantiation. These “therapies” have certainly not gone through any drug regulatory agency for approval, and often supportive data has not even been published in a reputable scientific or medical journal. They are, to put it bluntly, quack “therapies” that are potentially harmful because safety data is often not there.

To the safety point, even in the U.S., unproven “therapies” that bypass FDA regulations have caused harm. Three women were recently blinded in Florida after receiving stem cell “therapy” injections for macular degeneration.

Do Your Homework

So, to steal from an old saying, ya can’t tell the quacks from the cures without a scorecard. If a DM therapy sounds too good to be true, the people behind it are probably just after your money. The reliable scorecard here is the physician who is knowledgeable of DM. If your doctor or any other reputable physician with an understanding of DM won’t prescribe the treatment, you probably should not be taking it. 

MDF is also happy to help you understand whether something is in a legitimate clinical trial, an approved therapy…or not. Browse the resources and tools available on the MDF website or call the MDF Warmline at 415-800-7777.

The AHCA

In March, Republican Members of the U.S. House of Representatives’ Committee on Ways and Means and the U.S. House Committee on Energy and Commerce introduced legislation, entitled the American Health Care Act (AHCA), that would repeal and/or replace major parts of the Affordable Care Act (ACA). The ACA (also known as Obamacare) expanded health care coverage for more than 20 million vulnerable Americans and prohibited health insurance plans from discriminating against individuals with pre-existing conditions like myotonic dystrophy (DM). MDF is committed to advocating to help ensure that all persons with DM have affordable, comprehensive health insurance.

MDF Response and Your Opportunity to Act

MDF has reviewed the legislative proposal and identified significant concerns about how the proposed changes would limit access to affordable, quality health insurance coverage and vital medical care, especially for individuals living with rare, complex and costly conditions like DM. As Congress debates repealing and replacing the ACA, we urge our community to inform their elected Representatives and Senators to carefully consider any significant changes to health care and ensure that the interests of all Americans needing health care, especially those with special needs, including persons with DM and their families, are fully protected.

Potential AHCA Impacts to DM Families

The Congressional Budget Office (CBO) AHCA Cost Estimate released on March 13, 2017, estimated that, in 2018, the AHCA legislation would change the number of people who obtain federally-subsidized health insurance through Medicaid, the nongroup market and the employment-based market—an estimated 14 million more Americans would be uninsured under the AHCA legislation than under the current ACA law.

The Congressional Budget Office estimates that the AHCA would tend to increase average premiums in the nongroup market prior to 2020 and lower average premiums thereafter, relative to projections under current law. Medicaid enrollees, according to the CBO estimates, would decrease by $880 billion over the 2017-2026 period, as the result of lower enrollment culminating in 14 million fewer Medicaid enrollees by 2026. Under the legislation, beginning in 2020, the federal government would no longer share in the open-ended financing of Medicaid. The AHCA would establish a limit on the amount of reimbursement it provides to states, with states bearing all of the burden for increased costs. 

Specifically, MDF is concerned about the following AHCA provisions:

• Insurance Subsidies. For individuals and families seeking health insurance who do not have group-based/employer-based coverage, AHCA would provide tax credits that would vary on the basis of age (not household income) between $2,000-$4,000 for individuals (more families) that could be used to purchase health insurance. These tax credits will be significantly lower than those currently offered under the ACA and could make it more difficult for lower-income individuals and families to afford health insurance. 
   
• Continuous Coverage Penalty. The AHCA requires nongroup or small-group market health plans to impose a substantial late enrollment fee (a surcharge equal to 30 percent of their monthly premium for up to 12 months) for individuals who reapply for coverage after going more than 63 days without health insurance coverage. 

The likelihood of having interrupted coverage is greater for those changing jobs, including people living with DM who may change or lose employment due to the significant physical and cognitive impairments. The AHCA thereby penalizes individuals with DM and other chronic conditions.

• Medicaid Expansion & Caps. Under the ACA, many states expanded eligibility for Medicaid coverage that was supported by additional federal funding. This would end in 2020 under the proposal, and many individuals currently receiving Medicaid coverage would lose coverage. Medicaid currently requires coverage for persons who qualify based on their income and their disability status. 

MDF is concerned that eliminating expansion funding and capping the federal contribution to state Medicaid programs could result in persons with DM losing coverage, and those who keep their Medicaid coverage could see a reduction in covered medical services and higher out-of-pocket costs. 

• Age Rating Rules. Beginning in 2018, AHCA would increase the limits on how much insurers in the nongroup and small-group markets can vary premiums on the basis of age. For example the premium for a 64-year-old could be three times to five times higher than the rate a 21-year-old is charged. This could adversely affect the adult-onset DM population.

MDF is pleased that the AHCA retains the following ACA provisions:

• Pre-Existing Condition Protections. Health insurers would still be prohibited from denying critical insurance coverage to individuals who have a “pre-existing” medical condition like DM, heart disease, diabetes and cancer. 
   
• Young Adult Coverage. Parents could keep children up to age 26 on their health insurance policies. 
   
• Lifetime & Annual Caps. Insurers would continue to be prohibited from setting annual and lifetime limits on health insurance expenditures they cover.

Next Steps - Get Involved

MDF will continue to advocate in a bipartisan manner to help ensure that all persons with DM have affordable, comprehensive health insurance with access to high quality medical care and therapies. Since it is anticipated that AHCA will be amended as it advances on its legislative journey to become a law, we will continue to closely monitor the evolving bills and offer our expertise. However, it is imperative that members of the MDF community become actively involved in advocating for ensuring access to affordable quality medical care for individuals with DM in their local areas as ACHA will likely include greater state-based choices.

Questions?

Contact MDF for more information at 415-800-7777, or info@myotonic.org.

When Dr. Thurman Wheeler was a resident in neurology, he remembers a senior physician telling him that myotonic dystrophy would probably be one of the most difficult diseases to treat because it involves so many body systems. But thanks to unprecedented advances in laboratory and clinical research since then, “it looks like it might turn out to be fairly straightforward,” Dr. Wheeler says. Now an assistant professor of neurology at Harvard Medical School and a clinical neurologist at Massachusetts General Hospital, Wheeler has spent more than a decade caring for patients with myotonic dystrophy (DM) and conducting lab-based DM studies using mouse models.

Dr. Wheeler recently received a one-year grant through MDF to develop new serum-based biomarkers in adults and children with type 1 and 2 myotonic dystrophy (DM1 and DM2) for use in therapeutic trials. (For more about MDF grants, see Fellows & Grant Recipients. Additionally, information about the Wyck Foundation and its related grantees is available).

Searching for DM Biomarkers in Body Fluids

Dr. Wheeler’s grant, which runs from November 2016 through October 2017, will allow him and his team to begin initial exploration of the viability of developing DM biomarkers that can be measured in blood and urine, reducing or avoiding the need for muscle biopsies – which are invasive and risky – to support data collection in clinical studies and trials.

Dr. Wheeler will examine differences in extracellular RNA that are associated with DM1 and DM2 compared with healthy controls, and look for possible changes in these RNA forms and levels that correlate with disease activity or treatment response.

"We’re looking for extracellular RNA in blood and urine," Wheeler says. "A few years ago, a colleague here found that blood has extracellular RNAs that can serve as biomarkers for brain tumors," Wheeler says. "We’re going to be adapting the approach of the study that looked for markers of brain tumors and use that for myotonic dystrophy. We’re examining gene expression, splicing, microRNAs, and things like that."

Dr. Wheeler and colleagues will be studying extracellular RNA in adults and children with DM1 and DM2, in collaboration with neurologist Basil Darras at Boston Children’s Hospital.

The collaboration with Dr. Darras, who sees more pediatric patients than does Dr. Wheeler, is important, Wheeler says, “because this enables us to expand the study in children. Muscle biopsies in children require general anesthesia, he notes, “and that’s something you want to avoid in myotonic dystrophy, because patients can have a difficult time coming out of it. So, if we’re successful, we may be able to include children [in clinical trials] much earlier than originally thought.”

Early Years in the Clinic and Lab

Wheeler, who graduated from the University of Washington School of Medicine in 1995 and then completed a neurology residency at that institution, first became interested in muscular dystrophy research during a fellowship in neuromuscular medicine at Johns Hopkins University.

He then moved to Stanford University to work with Tom Rando, M.D., Ph.D., on developing nonviral gene therapy for Duchenne muscular dystrophy. Then, as now, the potential for unwanted effects associated with using viral vectors as gene delivery vehicles was well understood, and the Rando lab was looking to reduce this downside.

"We were doing plasmid and oligo work," Wheeler recalls. "[Dr. Rando] was using a type of non-viral gene therapy called antisense for gene correction of point mutations in a mouse model of Duchenne muscular dystrophy.  It involves using an oligo that’s complementary to the region across the point mutation except it has the correct base."

After three years at Stanford, Wheeler took advantage of an opening at the University of Rochester (N.Y.) to switch gears and study DM. “I knew what myotonic dystrophy was," he says, “but I had never done any research on it. I moved to Rochester, took what I learned about nonviral gene therapy from Tom, and applied it to myotonic dystrophy.”

"We ended up getting antisense to work for exon skipping to eliminate myotonia [in a DM mouse model]. The chloride channel RNA is misspliced in myotonic dystrophy. There’s an exon included aberrantly in the disease state. So if you use antisense to induce skipping of that exon, that can potentially rescue the myotonia, because you’d be restoring the normal chloride channel RNA, and that leads to a normal chloride channel protein. We did that in mice, and it worked beautifully.”

Correction of chloride channel splicing wasn’t taken forward into drug development, Wheeler says, "because there’s much more to myotonic dystrophy than myotonia. You’d eliminate the myotonia, but ultimately you’d be doing nothing for the rest of the symptoms."

It did, however, provide evidence that antisense could be an effective therapy, setting the stage for therapy development to target the fundamental DM1 RNA defect – expanded CUG repeats in the DMPK gene. “In parallel, we were working on CUG targeting,” Wheeler says of his Rochester work. “We were doing them both at the same time, and we finished the chloride channel work first. But we knew that the CUG targeting was working in the mice and that that could be a long-term answer.”

Developing Antisense for DM1 Treatment 

At first, the Rochester team’s goal was to develop antisense against the CUG repeat expansion in the DMPK gene. "We originally were using antisense that was targeting the repeat expansion directly," Wheeler recalls, "and the concern was that there are other genes that have shorter CUG repeats where that could interfere. We didn’t really find that in mice, but it was a theoretical concern."

Then came involvement with Ionis Pharmaceuticals, a Carlsbad, CA-based biotechnology company specializing in RNA-targeted drug discovery and development. 

"We tried some of the Ionis drugs that they developed earlier, but they didn’t really work very well," Wheeler says. "Then Ionis suggested we try their gapmer approach, and that worked incredibly well." A gapmer, he explains, refers to the design of the antisense. “The antisense has modified RNA at the 3-prime and 5-prime ends, separated by a central gap of DNA. When the oligo binds to the target RNA, you get a DNA-RNA heteroduplex that is recognized by RNAse H, which cleaves it. When the cleavage happens, the rest of the transcript is degraded by exonucleases." Non-gapmer antisense compounds, he explains, "just bind to the target and kind of sit there."

Unlike earlier antisense approaches for DM1, the Ionis gapmer approach did not directly target the CUG repeat expansion. "It targets outside the repeats," Wheeler says, thus removing the risk of inadvertent binding to CUG repeats in other genes. And, since RNAse H is located in the nucleus, the strategy preferentially targets aberrant DMPK RNA transcripts, which get stuck in that location, while normal DMPK RNA quickly leaves the area. "Transcripts that have a prolonged dwell time in the nucleus appear to be more susceptible,” he notes, although “potentially, the gapmer still could target the pre-messenger RNA of DMPK alleles with non-expanded repeats [normal alleles], so that is one of the things we’ll be watching in the clinical trials."

A phase 1-2 trial of IONIS-DMPKRx-2.5 in adults with DM1, testing the gapmer antisense against DMPK RNA at multiple U.S. centers, opened in 2014. It ended in late 2016, with results reported in January 2017. “I know that Ionis has taken great steps to test the safety ahead of time, and it’s been very effective in mice and other preclinical models of DM1,” Wheeler says. While the Ionis clinical trial did not achieve sufficient drug levels in skeletal muscle, they are exploring two other antisense oligonucleotide molecules that show promise of greater potency.

Move to Harvard

As fruitful and exciting as his time at the University of Rochester was, Wheeler was eager to expand his lab-based research and begin clinical work in DM and other muscular dystrophies. With that in mind, in 2013, he relocated to Massachusetts General Hospital and Harvard Medical School.  “It was just a great professional opportunity,” he says. “It was a natural step. In Rochester, I was doing no clinical work. Here I have a research lab that focuses on developing new biomarkers, including this new clinical project [for biomarker identification], as well as studying the factors that make muscles weaker and identifying new treatments for myotonic dystrophy. I also have an all-ages clinic every week and a pediatric clinic twice a month where I see patients with both types of myotonic dystrophy and all other forms of muscular dystrophy.”

Improving and Expanding Clinical Trials

“I’m optimistic that [antisense oligonucleotide therapies] will be safe and have some therapeutic effects,” Wheeler says. “I guess the question is to what extent the knockdown of the expanded repeat RNA will reverse the symptoms. In someone with mild symptoms, the drug may have a tremendous effect and slow progression.  But how will it work for patients who have a greater degree of weakness, more muscle atrophy, or problems walking?  Will the drug be able to improve their function at all? Or will we need to develop second-line therapies, the way the Duchenne dystrophy field is doing?”

Downstream effects of the expanded CUG repeats that appear to contribute significantly to disease symptoms include functionally low levels of the MBNL proteins and abnormally high levels of the CELF1 protein. Increasing MBNL activity and reducing total CELF1, preferably with small molecules, might add a lot to antisense therapy, Wheeler notes. “A small molecule that you could take by mouth would be ideal,” he says. “Until we have something that is proven to be highly effective, I think we should continue developing new therapies that target the disease from different angles.”

Continuing clinical trials of new DM therapies, including those for children, will require reliable biomarkers of disease activity, preferably markers accessible in blood or urine rather than muscle markers that require biopsies. 

“The plan is to begin the process of identifying biomarkers,” Wheeler says of his new grant. “That was one of the goals described by MDF. They want to find a project that is working toward biomarkers that will be on track to get qualified by the Food and Drug Administration (FDA).  

“The goal that I have is to try and reduce the need for muscle biopsies by looking at biofluids, so that there’s no anesthesia, no incision, no scarring, and no bleeding risk. This would allow monitoring during the treatment trial instead of waiting until the end.

“We had our first contact with the FDA back when the grant was submitted, which was in June [2016]. I think that no one expects that we’re going to have a biomarker or a group of biomarkers by the end of the year, but we’re going to be working toward that goal.”

For more about Dr. Wheeler’s MGH-based research, see Wheeler Muscular Dystrophy Research Lab. For information about muscular dystrophy clinics for adults, call (617) 726-3642; for children, call (617) 643-4645. Recruitment for the biomarker study is being done through the clinics.

Construction of a conceptual framework that integrates phenotypic, cellular and molecular data in DM is a critical step in developing a robust and diverse pipeline of candidate therapies. Although basic science has mechanistically linked the inherited repeat expansions to DM1 and DM2 phenotypes, there are critical gaps in understanding of disease mechanisms. A recent publication extends our understanding.

Dr. Perrine Castets, Prof. Michael Sinnreich and colleagues at the University of Basel recently studied the notion that perturbation of skeletal muscle metabolic pathways, including those responsible for protein degradation (ubiquitin-proteasome system and autophagy), plays an important role in DM. Their results, published in the Journal of Clinical Investigation, establish that (a) DM1 muscle is characterized by an altered response to energy/nutrient deprivation and that (b) dysregulation of AMPK/mTORC1 signaling, at least in part, underlies the altered metabolic state and its role in the pathogenesis of DM1 skeletal muscle. Importantly, these findings suggest new targets for drug discovery and development.

In studies of the HSALR mouse model of DM1, the investigators showed that a normal molecular response to fasting, AMPK activation and mTORC1 inhibition, is compromised in HSALR mice. Consistent with these findings and the interrelated role of AMPK and mTORC1 in autophagy, experimentally induced autophagy was disrupted in HSALR muscle. Deprivation of energy and nutrient supply in DM1 patient myotubes also produced data consistent with dysregulated autophagy. Finally, targeting either AMPK (with AICAR) or mTORC1 (with rapamycin) signaling improved muscle strength, splicing and/or myotonia in HSALR mice.

While the AMPK agonist, AICAR, disrupted nuclear foci and reduced myotonia, along with partial normalization of splicing (correction of Clcn1, but not Atp2a1 and Camk2b) in HSALR mice, rapamycin’s, an mTORC1 inhibitor, normalization of muscle function was not accompanied by correction of mis-splicing.

Many of the therapeutic strategies under development for DM are based on restoration of dysregulated alternative splicing. The study by the University of Basel group further supports those strategies, but also characterizes a key metabolic defect in DM1 muscle and identifies the mTORC1 pathway as an alternative, splicing-independent target for therapy development.

Thus far, nearly all of the therapy development programs in DM address the muscle phenotype. Recent studies show that the mTOR pathway may be an important target in developmental intellectual disorders, and two mTOR inhibitors have regulatory approval for other indications (Novartis' Everolimus and Wyeth's Sirolimus (rapamycin)). Drugs targeting mTORC1 then may have efficacy for both the skeletal muscle and cognitive symptoms of DM1 and thus their potential should be explored via rigorous efficacy studies in appropriate preclinical models.

Reference:

Targeting deregulated AMPK/mTORC1 pathways improves muscle function in myotonic dystrophy type I.
Brockhoff M, Rion N, Chojnowska K, Wiktorowicz T, Eickhorst C, Erne B, Frank S, Angelini C, Furling D, Rüegg MA, Sinnreich M, Castets P.
J Clin Invest. 2017 Jan 9. pii: 89616. doi: 10.1172/JCI89616. [Epub ahead of print

Among the multisystem consequences of myotonic dystrophy, patients are at risk of renal dysfunction. A recent paper by Dr. Tsuyoshi Matsumura (National Hospital Organization Toneyama National Hospital, Japan) and colleagues evaluated circulating cystatin C (CysC) levels in patients with a variety of neuromuscular diseases and found the highest levels in DM1, potentially predictive of subsequent kidney damage and failure. These data stress that renal function monitoring, via CysC levels, should be an important component of care for individuals with DM1. The assessment of renal dysfunction in neuromuscular disease is complicated by the fact that creatinine, which increases in renal dysfunction, declines in parallel with skeletal muscle loss. By contrast, cystatin C (CysC) levels also represent an indicator of kidney function, but one that is not affected by changes variables such as muscle volume, food intake, or exercise.

Thus CysC, as well as the glomerular filtration rate of CysC (GFRcys), constitute superior biomarkers of kidney function when the disease process itself impacts serum creatinine levels. Dr. Matsumura and his colleagues retrospectively studied a cohort of 586 patients with neuromuscular disease (141 with DM1), using a variety of renal function measures to evaluate the relative risks for development of kidney disease. None of the subjects had signs of renal dysfunction at the time of analysis. After controlling for baseline age and gender differences, cross-disease comparisons showed that elevation in CysC and reduction in GFRcys were most pronounced in individuals with DM1, suggesting that they were at the highest risk for kidney failure.

The study also showed that there was a modest correlation between expanded CTG repeat length and CysC levels. Finally, the authors reported findings from two DM1 autopsies, where nephrosclerotic changes were observed relatively early in disease course  (both subjects in their 40’s); although CysC levels were not available for these subjects, these data support the need for further study of the natural history of kidney dysfunction in DM1, to determine best practices for patient care.

Elevated CysC has previously been reported in neuromuscular disease patients with renal dysfunction or failure, and has been suggested as a safety biomarker for interventional clinical trials in these diseases. Findings by Dr. Matsumura’s team suggest that DM1 patients may be at greater risk for kidney dysfunction and failure than those with other neuromuscular diseases. Moreover, CysC levels may be an important biomarker for careful management of DM, as well as for safety assessments of interventions in DM1 clinical trials.

Reference:

"Renal dysfunction can be a common complication in patients with myotonic dystrophy 1."
Matsumura T, Saito T, Yonemoto N, Nakamori M, Sugiura T, Nakamori A, Fujimura H, Sakoda S.
J Neurol Sci. 2016 Sep 15;368:266-71. doi: 10.1016/j.jns.2016.07.036. Epub 2016 Jul 15.

A recent study corroborated increased susceptibility to cancer in DM1, for women in particular, and linked the elevated risk to depressed levels of a tumor suppressor microRNA (miRNA). The association between DM1 and increased risk of certain types of cancer was first recognized in 1965. Recent studies have validated these initial findings and suggested that cancer risks in DM1 were greater in women, but the causative mechanisms remained unknown. 

Dr. Adolfo López de Munain (Donostia University Hospital, San Sebastián, Spain) and colleagues have now corroborated gender differences in susceptibility to cancer and identified potential molecular mechanisms behind the cancer risk in DM1. In a publication in Neurology, Dr. López de Munain’s team quantified cancer risk in a well-characterized cohort of 424 patients with DM1, representing > 18,000 patient years of data, and explored the potential molecular links between DM1 and cancer prevalence.

All patients in the study had molecular confirmation of DM1 and substantial longitudinal phenotypic data available. The observed numbers of cancers in the DM1 cohort were compared against the numbers that would be expected, as calculated from the Basque region’s overall prevalence numbers, in order to determine standardized cancer incidence ratios. The investigators also performed gene expression analyses as a first step to understand molecular mechanisms behind the cancer prevalence data.

When compared to a general, geographically controlled population, DM1 patients showed a 2-fold increased risk of developing cancer. Mean age of malignant cancer detection in the DM1 cohort was 47 years. Gastrointestinal, genitourinary, skin and thyroid were the most frequent sites for malignant tumors. Increased risk was stronger in women with DM1.

In the overall DM1 population evaluated in this study, cancer represented the third leading cause of death, after respiratory and circulatory diseases. Analyses of molecular factors that may differentiate the at-risk DM1 population included CTG repeat length and genome-wide expression analysis of blood leukocytes using Affymetrix microarrays. The authors did not find a correlation between expanded CTG repeat length and cancer risk. Genome wide expression analysis did show differential expression of several genes that were previously linked to cancer (e.g., PDK4, DAPK1, CASP5, and PLA2G7).

Moreover, female patients with DM1 displayed significant down-regulation of the miRNA-200c/141 tumor suppressor family, while levels of this miRNA were elevated in men with DM1. Prior studies, in non-DM cohorts, have shown an association between declines in miRNA-200c and tumor progression/poor prognosis. Although further studies will be needed to mechanistically link changes in the DM1 transcriptome to increased cancer risk, the data from the San Sebastián group supports a compelling hypothesis linking reduction in tumor suppressor genes to cancer risk in women with DM1. The gender-specific differences in susceptibility to cancer, and the linkage to reduced levels of miRNA-200c, are particularly compelling findings for validation in independent DM1 cohorts and further mechanistic analyses.

Reference:

"Cancer risk in DM1 is sex-related and linked to miRNA-200/141 downregulation."
Fernández-Torrón R, García-Puga M, Emparanza JI, Maneiro M, Cobo AM, Poza JJ, Espinal JB, Zulaica M, Ruiz I, Martorell L, Otaegui D, Matheu A, López de Munain A.
Neurology. 2016 Aug 24. pii: 10.1212/WNL.0000000000003124. [Epub ahead of print]

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.