Medical Marijuana and Muscular Dystrophy

Patient advocacy has brought sweeping changes to laws regarding medical use of marijuana and its cannabinoid derivatives—at least 33 U.S. states have passed some form of enabling legislation. An increase in clinical evaluations has quickly followed. At present, ClinicalTrials.gov lists 399 clinical studies of cannabinoids across a wide variety of indications.

Patient, drug industry, and research communities have largely focused on vaporized cannabinoid derivatives as the best therapeutic approach—although recent acute lung complications with this delivery mechanism remain to be addressed. The value of medical marijuana for the muscular dystrophy community is largely presumptive, as putative benefits, including analgesia, immunomodulation, anti-inflammatory activity, and antioxidative activity, have attracted few carefully controlled studies to date. Findings from a pilot survey of cannabis use in DM confirmed interest of the patient community (Montagnese et al., 2019a), showing that 33% of U.S. DM patients regularly utilize cannabis or cannabinoids for symptomatic relief. While interest in cannabinoids, particularly for management of pain, in DM has been acute, evidence of efficacy in DM patients can best be characterized as anecdotal at best. Whether cannabinoids may have benefits for other symptoms of DM is unknown.

Clinical Testing of Cannabinoids in DM Patients

Dr. Federica Montagnese and colleagues at Ludwig-Maximilians-University Munich provided a cannabidiol and tetrahydrocannabinol (CBD/THC) cocktail to four patients with DM1 or DM2 and two patients with CLCN1-myotonia, through a compassionate use protocol (Montagnese et al., 2019b). Study duration was four weeks, and the weekly assessed endpoints included myotonia behavior scale (MBS), hand-opening time, visual analogue scales for myalgia and myotonia, and fatigue and daytime sleepiness severity scale.

Almost all patients reported improvement in myotonia and hand-opening time, and MBS values improved for all patients. Some improvement in myalgia was also noted. Significant improvement in GI symptoms was reported by those patients experiencing symptoms at the study start. The authors included more detailed case report data on the responsiveness of two study patients (one with DM2, one CLCN1-myotonia).

Path Forward

Here, the research team has taken initial steps in evaluating the potential for cannabinoids in the treatment of myotonia and myalgia in a cohort of patients with DM. While lacking the potential for statistical treatment of data, the study represents a pilot for conducting controlled interventional trials for this candidate therapeutic class and demonstrates its potential value. Given the small study, the use of primarily patient-reported outcome measures, and the heterogeneity of the DM population, considerably more work (controlled studies with objective outcome measures in particular) remains before we understand whether and how to use this compound class in patients with DM. There are, as yet, no studies of cannabinoids and DM listed in ClinicalTrials.gov. Yet, Nexien BioPharma Inc. has announced their intent to seek a pre-IND meeting with FDA and to pursue a clinical development program in DM with “specific cannabinoid formulations.”

References:

Cannabis use in myotonic dystrophy patients in Germany and USA: a pilot survey.
Montagnese F, White M, Klein A, Stahl K, Wenninger S, Schoser B.
J Neurol. 2019a Feb;266(2):530-532. doi: 10.1007/s00415-018-9159-2. Epub 2018 Dec 15.

A role for cannabinoids in the treatment of myotonia? Report of compassionate use in a small cohort of patients.
Montagnese F, Stahl K, Wenninger S, Schoser B.
J Neurol. 2019b Oct 26. doi: 10.1007/s00415-019-09593-6. [Epub ahead of print]

Risk Factors for Falls in DM

Falls are a well-recognized risk factor for patients living with DM. Factors previously linked to falls in DM1 patients include muscle weakness, altered gait properties (including impairment of walking speed), and impaired balance and confidence in balance (Wiles et al., 2006; Hammarén et al., 2014; Hammarén et al., 2015; Radovanović et al., 2016; Jiménez-Moreno et al., 2018). A recent study estimated the risk ratio for falls and associated fractures as 30%-72% and 11%-17%, respectively (Jiménez-Moreno et al., 2018). Data on falls in DM2 patients does not appear to be available. Overall, a better understanding of the incidence, circumstances, and consequences of falls is essential for improving quality of life of those living with DM1 and DM2.

Data from a New Prospective Study

Dr. Corinne Horlings (Radboud University Medical Center and Medical University Innsbruck) and colleagues have completed a prospective study designed to ascertain the properties and consequences of falls in a cohort of DM1 patients (n = 102), DM2 patients (n = 42), and healthy controls (n = 65) (Berends et al., 2019). Data on self-reported falls during the previous year were collected prospectively, while new falls were assessed over a 100-day interval—sample size and study interval were informed by a power analysis.

The research team found that DM1 and DM2 patients both exhibited an increased frequency of falls, falling at rates 7x and 8x that of healthy controls, respectively. Roughly one-third of both DM groups fell at least once, with approximately 17% of each group falling at least twice during the 100-day prospective study period. The majority (two-thirds) of falls occurred inside.

Circumstances and Consequences of Falls

Assessment of the circumstances of falls showed that what the team defines as extrinsic factors—slippery floors or objects on the floor—were associated with the majority (55% in DM1, 46% in DM2) of falls. Most other falls were attributed to intrinsic factors—light-headedness, fatigue, weakness, or stiffness.

For nearly half of falls (40% in DM1, 46% in DM2), patients required assistance to regain standing position. Moreover, injuries resulted from 50% of falls, although most were minor (four patients suffered head trauma). DM1 patients suffering falls profiled as generally older, weaker, had less confidence in balance (often using a walking aid), and had lower DM1-Activ scores. Regression analysis showed that only the DM1-Activ score was associated with increased risk of falling. Profiles of falling versus non-falling DM2 patients could not be differentiated.

Synopsis

The current Clinical Care Recommendations for Adults with Myotonic Dystrophy Type 1 provide this guidance pertinent to falls:

• Moderate- or low-intensity aerobic and resistance exercise, minimizing sedentary activities, if possible. Consider a cardiac evaluation prior to starting a new exercise routine;
• Assistive and adaptive devices such as orthoses, braces, canes, walkers, hand-splints, etc.; and
• Home and environmental modifications as necessary.

The research team described falls as both prevalent and clinically relevant in DM and provided data in support of the Clinical Care Recommendations. They found a substantially increased incidence of falls among DM1 and DM2 patients versus healthy controls, with most falls occurring indoors, in a familiar environment. The high rate of injuries from falls reinforces the risks faced by DM patients. A key gap in the current study is the absence of data on cognitive impairment, potentially a key contributor to falls. The authors acknowledge that the study was not designed to substantiate risk factors for falls. Efforts are needed to develop strategies to mitigate the risks of falls in DM.

References:

Falls and stumbles in myotonic dystrophy.
Wiles CM, Busse ME, Sampson CM, Rogers MT, Fenton-May J, van Deursen R.
J Neurol Neurosurg Psychiatry. 2006 Mar;77(3):393-6. Epub 2005 Sep 30.

Factors of importance for dynamic balance impairment and frequency of falls in individuals with myotonic dystrophy type 1 - a cross-sectional study - including reference values of Timed Up & Go, 10m walk and step test.
Hammarén E, Kjellby-Wendt G, Kowalski J, Lindberg C.
Neuromuscul Disord. 2014 Mar;24(3):207-15. doi: 10.1016/j.nmd.2013.12.003. Epub 2013 Dec 15.

Muscle force, balance and falls in muscular impaired individuals with myotonic dystrophy type 1: a five-year prospective cohort study.
Hammarén E, Kjellby-Wendt G, Lindberg C.
Neuromuscul Disord. 2015 Feb;25(2):141-8. doi: 10.1016/j.nmd.2014.11.004. Epub 2014 Nov 13.

Comparison of temporal and stride characteristics in myotonic dystrophies type 1 and 2 during dual-task walking.
Radovanović S, Perić S, Savić-Pavićević D, Dobričić V, Pešović J, Kostić V, Rakočević-Stojanović V.
Gait Posture. 2016 Feb;44:194-9. doi: 10.1016/j.gaitpost.2015.12.020. Epub 2015 Dec 20.

Falls and resulting fractures in Myotonic Dystrophy: Results from a multinational retrospective survey.
Jiménez-Moreno AC, Raaphorst J, Babačić H, Wood L, van Engelen B, Lochmüller H, Schoser B, Wenninger S.
Neuromuscul Disord. 2018 Mar;28(3):229-235. doi: 10.1016/j.nmd.2017.12.010. Epub 2017 Dec 27.

High incidence of falls in patients with myotonic dystrophy type 1 and 2: A prospective study.
Berends J, Tieleman AA, Horlings CGC, Smulders FHP, Voermans NC, van Engelen BGM, Raaphorst J.
Neuromuscul Disord. 2019 Aug 28. pii: S0960-8966(19)31103-4. doi: 10.1016/j.nmd.2019.08.012. [Epub ahead of print]

Value of Registries?

The existence of patient registries is essential to establishing clinical trial readiness for any rare disease. Without the ability to identify and characterize patients, it is virtually impossible to develop and validate biomarkers and clinical outcome measures necessary for decision-making in interventional clinical trials. Any advances in a highly heterogeneous disease such as DM require standardized, longitudinal data collection and analysis from as well-powered a cohort as possible. While safe and effective therapies are under development, an understanding of disease progression and assessment of the efficacy of existing care management strategies gained through well-powered registry studies can make a meaningful difference in patient care. It then is important to capture lessons learned from all existing DM patient registries, as well as those ongoing for other neuromuscular diseases, to both improve patient care now and gain knowledge to guide the development of novel, life-changing therapies.

The DM-Scope Registry Model

Over the last several years, the Myotonic Research News has highlighted several important new findings in DM from the French national registry, DM-Scope. These have included identification of gender as a phenotypic modifier in DM1, establishment of a more detailed DM1 classification scheme, and the characterization of pediatric DM1 subgroups and their potential use in improving evidence-based care.

In the process of their studies to improve understanding of the DM patient, leadership of DM-Scope realized an opportunity to “promote DM epidemiology, clinical research and patient care management simultaneously.” Dr. Guillaume Bassez (Pitié-Salpêtrière Hospital and INSERM/Sorbonne University) and his 10 co-authors and 82 collaborators in DM-Scope have articulated this concept and their progress over the 11 years since the registry's founding in a new publication (De Antonio et al., 2019).

The authors describe the development and implementation of an information technology platform that facilitates clinical research in DM using data collected in regular, routine clinical visits by DM1 (n = 2828) and DM2 (n = 142) patients at 55 neuromuscular centers throughout France. Details are provided as to the governance and oversight of research studies, ethical/legal considerations, data breadth/depth/quality control/security, and design of the database, user interfaces, and statistical package.

DM-Scope Accomplishments and Lessons

DM-Scope has established nationwide coverage for annual visits and data input from the nearly 3,000 DM enrollees (enrollment continues to increase linearly since 2009), >77% with genetic diagnosis, at the pediatric and adult clinical sites, facilitating 10 published clinical studies to date. Capability and efficiency of DM-Scope to support clinical trials was demonstrated in the recruitment of 71 patients for OPTIMISTIC in the timespan of six months. Patient demographics, clinical presentation, and education/employment data suggest that a broad spectrum of clinical data is being captured. Kaplan-Meier survival analysis identified heterogeneity between the 20 DM-Scope centers that recorded death status.

The authors conclude that DM-Scope has been able to overcome key challenges that are generally experienced by rare disease registries, including optimizing the standardization and comparability of patient data, patient retention and longitudinal follow-up, facilitating interoperability across existing registries, limiting gaps in data, and improving data quality. This model both facilitates critical research efforts and, through longitudinal comparisons of outcomes, provides practitioners with knowledge to optimize patient care.

Reference:

The DM-scope registry: a rare disease innovative framework bridging the gap between research and medical care.
De Antonio M, Dogan C, Daidj F, Eymard B, Puymirat J, Mathieu J, Gagnon C, Katsahian S; Filnemus Myotonic Dystrophy Study Group, Hamroun D, Bassez G.
Orphanet J Rare Dis. 2019 Jun 3;14(1):122. doi: 10.1186/s13023-019-1088-3.

SAN FRANCISCO, CA (May 2, 2019): MDF is pleased to announce the publication of the first-ever Consensus-based Care Recommendations for Congenital and Childhood-onset Myotonic Dystrophy Type 1 and Myotonic Dystrophy Type 2. The Quick Reference Guides to the full Consensus-based Care Recommendations were published in Neurology Clinical Practice online April 24th. The articles will be published in the NCP print journal in Summer 2019. MDF is working internationally to help ensure that the care recommendations are disseminated and adopted broadly.

Currently no evidence-based guidelines exist to establish standards of care for myotonic dystrophy, and comprehensive care guidelines will not be available until a number of studies are conducted to establish the rigorous evidence needed to create them. As a result, patients and caregivers report difficulty accessing informed clinicians and quality care.

To develop the recommendations, eleven international clinicians experienced in the care of infants and children living with congenital and childhood-onset DM1, and fifteen international clinicians experienced in the care and treatment of adults with DM2 worked collaboratively for over a year to develop consensus regarding care strategies for over 20 different body systems. The resulting clinical care recommendations are intended to help standardize and elevate care for people living with myotonic dystrophy, improving quality of life for affected families and reducing variability in clinical trial and study environments.

The publications and clinical care recommendations are accessible via the links below.

Consensus-based Care Recommendations for Adults with Myotonic Dystrophy Type 2

• Publication - Consensus-based Care Recommendations for Adults with Myotonic Dystrophy Type 2
• Comprehensive document and Quick Reference Guide - Consensus-based Care Recommendations for Adults with Myotonic Dystrophy Type 2

Consensus-based Care Recommendations for Congenital and Childhood-onset Myotonic Dystrophy Type 1

• Publication: Consensus-based Care Recommendations for Congenital and Childhood-onset Myotonic Dystrophy Type 1
• Comprehensive document and Quick Reference Guide - Consensus-based Care Recommendations for Congenital and Childhood-onset Myotonic Dystrophy Type 1

Adults with Myotonic Dystrophy Type 1

Clinical care recommendations for adults with myotonic dystrophy type 1 were published in Fall 2018. Access the comprehensive document and Quick Reference Guide here.

About Myotonic Dystrophy

Described as “the most variable of all diseases found in medicine”, myotonic dystrophy (DM) is an inherited disorder that can appear at any age and that manifests differently in each individual. The most common form of adult-onset muscular dystrophy, DM1 population-based prevalence is 1:2,300 people worldwide (Johnson 2018), and can cause muscle weakness, atrophy and myotonia, as well as problems in the heart, brain, GI tract, endocrine, skeletal and respiratory systems. There is currently no treatment or cure for DM.

About MDF: 

MDF is the world’s largest DM patient organization. Its mission is My Cause. My Cure: is to enhance the lives of people living with myotonic dystrophy, and advance research efforts focused on finding treatment and a cure for this disorder through education, advocacy and outreach.

For additional clinical resources offered by MDF, click here.

Muscle metabolic defects have been suspected as contributors toward the pathogenesis of DM. Recent studies have suggested that cellular/molecular mechanisms underlying reduced insulin sensitivity in skeletal muscle of both DM1 and DM2 may be more complex that has been appreciated. Specifically, prior findings suggested that perturbations of post-INSR signaling may be a key factor in development of insulin resistance (Renna et al., 2017). A new publication builds on these data to better establish the link between DM splicopathy and the development of insulin resistance and skeletal muscle atrophy.

Linking DM Molecular Biology to Metabolic Dysfunction

Drs. Laura Renna, Giovanni Meola, and Rosanna Cardani and colleagues (IRCCS-Policlinico San Donato and University of Milan) investigated events downstream from DM-associated mis-splicing of the insulin receptor (INSR) to identify pathways underlying insulin resistance and skeletal muscle wasting (Renna et al., 2019). Specifically, the team asked whether a lack of insulin pathway activation could contribute to skeletal muscle atrophy. Dr Renna was the recipient of an MDF Fellowship in support of this work.

The research team evaluated muscle biopsies from 8 DM1 and 3 DM2 genetically confirmed patients enrolled in a national registry. Biopsies were assessed for muscle fiber type and morphometrics, insulin receptor protein expression, INSR alternative splicing, and signaling pathway response to insulin stimulation.

Skeletal muscle atrophy was detected in nearly all DM1 (type 1 and/or type 2 fiber atrophy) and DM2 (type 2 fiber atrophy) patients. In contrast to the pattern seen in controls (including samples from unaffected controls, motoneuron disease, and type 2 diabetics), RT-PCR analysis showed predominance of the fetal insulin receptor isoform transcript in both types of DM. When examined by fiber type, DM skeletal muscle exhibited a lower expression of insulin receptor protein than all controls for type 1 (slow oxidative) muscle fibers. The team found a negative correlation between type 1 fiber insulin receptor protein level and level of fetal insulin receptor transcript.

A means of assessing insulin pathway activation was identified and validated by the research team. Their results showed that defective activation of insulin signaling led to lower activation of mTOR accompanied by increases in MuRF1 and Atrogin-1/MAFbx expression—all key regulators known to act through insulin signaling to modulate skeletal muscle mass.

Modeling the Impact on Skeletal Muscle in DM

Taken together, these findings further advance understanding of the linkage between insulin receptor mis-splicing, metabolic dysfunction, and skeletal muscle atrophy. In terms of the insulin receptor, predominance of the fetal insulin receptor isoform in DM was observed, and an overall reduction in insulin receptor protein level in DM skeletal muscles was linked to reductions in receptor expression in type 1 fibers.

Based on these data, the research team suggests that reduced insulin receptor levels are responsible for the observed defect in insulin pathway activation in DM and a metabolic imbalance in protein synthesis/degradation—these, in turn, indicate a potential link to skeletal muscle weakness and atrophy, but causality has not yet been established.

Finally, another recent publication (Vujnic et al., 2018) expands upon this theme of metabolic dysfunction in DM, reporting an increased incidence of metabolic syndrome (i.e., co-occurrence of at least 3 of 5 symptoms: central obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein) in DM2. Thus, there’s a clear case for increased research and patient management efforts directed toward metabolic dysfunction in DM.

References:

Receptor and post-receptor abnormalities contribute to insulin resistance in myotonic dystrophy type 1 and type 2 skeletal muscle.
Renna LV, Bosè F, Iachettini S, Fossati B, Saraceno L, Milani V, Colombo R, Meola G, Cardani R.
PLoS One. 2017 Sep 15;12(9):e0184987. doi: 10.1371/journal.pone.0184987. eCollection 2017.

Aberrant insulin receptor expression is associated with insulin resistance and skeletal muscle atrophy in myotonic dystrophies.
Renna LV, Bosè F, Brigonzi E, Fossati B, Meola G, Cardani R.
PLoS One. 2019 Mar 22;14(3):e0214254. doi: 10.1371/journal.pone.0214254. eCollection 2019.

Metabolic impairments in patients with myotonic dystrophy type 2.
Vujnic M, Peric S, Calic Z, Benovic N, Nisic T, Pesovic J, Savic-Pavicevic D, Rakocevic-Stojanovic V.
Acta Myol. 2018 Dec 1;37(4):252-256. eCollection 2018 Dec.

What is the Medical School Roadshow?

MDF designed this volunteer initiative to educate the next generation of medical professionals about myotonic dystrophy in order to improve clinical care and shorten the diagnostic odyssey. MDF is partnering with medical schools to educate students about DM before they graduate and begin clinical work.

MDF Needs You!

We need participation from the people who know DM best: you and those in your family affected by DM. MDF will provide you with training, support in contacting medical schools, and a packet of information and tips. You'll then visit medical schools near your home to speak to second- or third-year students about myotonic dystrophy, including the disease mechanism, symptoms and your personal experience. You can help future doctors learn about DM in the most compelling way possible - by telling your story and providing a real-life picture of the disease in all its variability and whole-body impact.

Get in touch

If you have contacts at medical schools in the US or Canada and are interested in educating future doctors about myotonic dystrophy, we need your help! For more information or to get involved, please contact us at info@myotonic.org.

Get more details on the MDF Medical School Roadshow here.

Although excessive daytime sleepiness and sleep disordered breathing are well documented for patients living with DM1, there is less clarity regarding these symptoms in DM2. A new review article in Current Neurology and Neuroscience Reports examines the literature on sleep and breathing disorders in DM2. Respiratory muscle weakness, myotonia, and alterations in central nervous system respiratory centers are believed to be causative.

Current Status of DM2 Research

One of the most significant gaps in understanding of myotonic dystrophy is the relative dearth of natural history studies in DM2. While there is not yet an approved, disease-mitigating therapy for myotonic dystrophy, clinical trial readiness has vastly improved for DM1, but not for DM2. It is critically important that DM2 cohorts be recruited and phenotyped in order to understand the longitudinal progression of the disease and thereby identify biomarkers and clinical assessment measures that will enable clinical trials in this patient population. If phenotypic data do not become available and DM2 is not perceived as ‘tractable’ by the pharma and biotech industry communities, it will be difficult to convince companies to address this disorder.

Sleep Complaints and Breathing Disorders in DM2

Dr. Andrea Romigi (IRCCS Neuromed, Italy) and colleagues recently published a review article looking at literature focused on breathing and sleep disorders in patients with DM2 (Romigi et al., 2019). Sleep disorders are important contributors to the morbidity and mortality of this disease and these findings are important in establishing clinical trial readiness for DM2.

Both skeletal muscle weakness and CNS dysfunction are believed to contribute to respiratory dysfunction characteristic of DM2, but careful assessments of lung function in DM2 have not been common. The most commonly reported sleep disorders in DM2 are sleep-disordered breathing (38–67%) and restless legs syndrome (50–60%). Sleep disordered breathing, in turn, appears to be the major cause of excessive daytime sleepiness in DM2. Claims as to the value of non-invasive ventilation appear to have an almost anecdotal basis and have not yet been sufficiently studied in DM2.

Restless legs syndrome has been viewed as significant in DM2, although this finding appears to have its basis only in studies of small cohorts. The authors of this review suggest that the prevalence of restless legs syndrome may be overstated by the frequent occurrence of myalgia and pain in this patient population, although they also note that the PRISM-2 study reported fatigue in 89% and excessive daytime sleepiness in 77% of DM2 patients.

Taken together, the authors of this review advocate for the inclusion of sleep studies in evaluation of patients with DM2. While data suggest that the frequency of hypoventilation and pulmonary restriction in DM2 is low, they also suggest that use of standard pulmonary examinations may improve upon disease morbidity. Finally, the potential correlation of pain, that is so characteristic of DM2, and sleep disruption has not been fully studied and should be an important component of future natural history studies of patients with DM2.

Reference:

Sleep Complaints, Sleep and Breathing Disorders in Myotonic Dystrophy Type 2.
Romigi A, Maestri M, Nicoletta C, Vitrani G, Caccamo M, Siciliano G, Bonanni E, Centonze D, Sanduzzi A.
Curr Neurol Neurosci Rep. 2019 Feb 9;19(2):9. doi: 10.1007/s11910-019-0924-0. Review.

Avoiding the Pitfalls of Tunnel Vision

In a reward system driven by grant dollars in hand and publication numbers/journal impact factors, it is only too easy to put on the blinders and succumb to tunnel vision. Single-minded focus is a prized career trait in academia. Yet the puzzle that is myotonic dystrophy may only be solved by modelling that benefits from diseases not within the focus of your current R01 or the publication track record that you’re building. The role that Repeat-Associated Non-ATG (RAN) translation plays in DM1/DM2 is likely one of those cases where insights can be defeated by excessive focus on just ‘your disease.’

A Cross-Disease Framework for Understanding RAN Translation

Although studies in DM1 contributed toward the initial identification and characterization of a new molecular phenomenon, RAN translation, its role in the pathogenesis of DM remains elusive. Evidence on RAN translation acquired from ‘other diseases’ may advance understanding of basic and conserved molecular mechanisms, but also may inform what specific role RAN translation plays in DM and whether this mechanism needs to be targeted by therapeutic strategies. A new publication by Dr. Laura Ranum and colleagues at the University of Florida (including a former MDF Fellow as lead author, Dr. John Cleary) sought to review current knowledge of RAN translation across multiple microsatellite expansion disorders of the nervous system (Cleary et al., 2018).

The review article gives a nice synopsis of the discovery and initial characterization of RAN translation in neurological disorders. Initial discovery was in Spinocerebellar ataxia type 8, but the mechanism was also rapidly found in DM1 as appropriate control experiments were included to ensure that RAN proteins could not arise from another mechanism. Discovery and characterization in other diseases rapidly followed, often expanding the potential pathological mechanisms operative in a disease—FXTAS being a prominent example where the field had pushed a toxic RNA gain of function mechanism, but now toxic RAN proteins had to be considered as well. By contrast, toxic polyglutamine proteins have been a leading pathogenic mechanism in Huntington’s disease, but it was soon discovered that CAG repeats in canonical open reading frames yielded multiple RAN proteins. RAN translation was subsequently discovered in other diseases where MBNL sequestration had been linked to the disease mechanism—DM2 and Fuch’s Endothelial Corneal Dystrophy. Finally, the authors devote space to the extensive work in C9orf72 ALS/FTD, where the literature now implicates RAN translation in specific molecular roles that may contribute to disease.

The authors of this review also discuss targeting of the RAN translation mechanism in drug discovery and development efforts. They note that such strategies may facilitate the determination of the differential roles of RNA gain-of-function versus RAN translation proteins.

Lessons Learned

It’s encouraging that many DM researchers have ties to the broader microsatellite expansion disorder community and attend conferences with that distributed agenda. Thus, there’s already a strong inclination to avoid the blinders and seek understanding of how similarities and differences across this > 40 neurological disease class with repeat expansions (8 of which have now been reported to exhibit RAN proteins) can provide insights into the individual diseases. Finally, it’s important to remember that both laser-like focus on DM and attention to lessons from the broader neurological disease class that invokes similar mechanisms may represent the optimal path forward to help patients living with DM.

Reference:

Repeat associated non-ATG (RAN) translation.
Cleary JD, Pattamatta A, Ranum LPW.
J Biol Chem. 2018 Sep 13. pii: jbc.R118.003237. doi: 10.1074/jbc.R118.003237. [Epub ahead of print]

The Reality: Clinical Trial Readiness Determines Tractability and Pharma/Biotech Interest

Ensuring clinical trial readiness is critical for any rare disease. If the patients to participate in clinical trials can’t be identified (function of registries), disease progression is not well understood (function of natural history studies), measures of target engagement and modulation aren’t available (function of pharmacodynamic biomarkers), and clinically meaningful measures are not available and validated (function of validated clinical outcome measures), then it is difficult to convince drug developers that a disease is tractable. The myotonic dystrophy field and MDF have been working toward checking these boxes to de-risk the disease for development of drugs and biologics. Yet, the majority of the efforts and accomplishments in achieving clinical trial readiness have been for DM1. There is a clear need to further invest in trial readiness for DM2.

What is the Status of Clinical Outcome Measures for DM2?

A systemic review has just been published, assessing one aspect of clinical trial readiness for DM2—the status of functional tests and patient-reported outcome measures that have been used in clinical studies and trials of DM2 patients. Drs. Emanuele Rastelli and Benedikt Schoser, and their colleagues at University of Rome Tor Vergata and Ludwig-Maximilians University, report their assessment and the critical need to invest further effort and resources into identification and validation of clinical outcome measures for DM2.

In their meta-analysis, the research team identified outcome measures used in studies of genetically confirmed DM2 subjects that were published before April 2018 (identified via key word searches of PubMed, EMBASE, Cochrane Reviews, and Cochrane trials databases). A similar search was conducted for the broader neuromuscular disease literature in order to identify and evaluate other outcome measures that could potentially be used for DM2.

The systematic process of identifying, screening, and determining eligibility resulted in inclusion of 10 studies of DM2 and 48 studies of outcome measures used in other neuromuscular diseases.

The most significant conclusion from this study is that none of the measures considered (either clinical function or patient-reported) have yet been validated in DM2. Utilization and pros/cons of each of the outcome measures in the studies evaluated here are reported in tabular form in the  paper.

INQoL, SF-36, MPQ, and BPI were the most frequently used patient-reported measures. It appeared that none of these were particularly effective in assessing the mild myotonia that characterizes DM2. MPQ showed value in differentiating characteristics of a prominent DM2 symptom, pain, while BPIsf exhibited difficulty in distinguishing pain in DM1 vs. DM2. Data on assessment of pain with a pressure algometer showed its potential as an outcome measure. The research team also identified liabilities in the broader patient-reported indices, INQoL and SF-36.

For evaluation of muscle strength, the team noted the frequent use of both MMT and QMT in assessment of DM2 subjects. While QMT was regarded as having higher potential to evaluate changes in strength over time (e.g., in longitudinal natural history studies or clinical trials), they suggest that inter-rater reliability has not yet been established in DM2. No publications came through the selection and screening process for clinical evaluation of myotonia in DM2; the authors noted the low reported disease burden of myotonia in DM2, thus quantitative testing may have little value for clinical trials in this patient group. Finally, the research team list in tabular fashion a total of 21 other outcome measures gleaned from the literature on other neuromuscular diseases that they deem as “suitable” for use in DM2. Assessment and validation of these measures would have to be performed in a DM2 cohort.

Path Forward

Taken together, the take-away from this systemic review is that availability of reliable and validated outcome measures represents an important gap in trial readiness for DM2. That is not to say that some measures already identified in studies of DM2 and other neuromuscular diseases might ultimately prove to be very adequate for use in natural history studies and interventional clinical trials.

Reference:

Towards clinical outcome measures in myotonic dystrophy type 2: a systematic review.
Rastelli E, Montagnese F, Massa R, Schoser B.
Curr Opin Neurol. 2018 Oct;31(5):599-609. doi: 10.1097/WCO.0000000000000591.

Human iPSCs as Disease Models and Drug Screening Tools

The ability to program human iPSCs derived from patients with genetic disorders into affected cell types has provided a better understanding of pathogenic mechanisms and a tool for early stage evaluation of putative drug development targets and therapeutic strategies. In conjunction with relevant animal models, iPSCs provide a platform to achieve preclinical proof of concept and the scientific rationale to move into clinical evaluation of candidate therapeutics. Given the involvement of the CNS in myotonic dystrophy, the availability of patient iPSC-derived neuronal cells would represent an important resource for therapy development.

Neuronal Differentiation of DM2 iPSCs

Establishment of patient-derived neural cell lines can provide an important tool for mechanistic studies and therapy development in neurodegenerative diseases, providing access to otherwise inaccessible brain tissues. For DM1, Dr. Tee Ashizawa and colleagues previously established DM1 iPSC lines and showed that iPSC-derived neural stem cells could be differentiated into neurons and glia with intranuclear RNA-MBNL foci (Xia et al., 2013).

In a recent report, Dr. Paola Spitalieri (University of Rome Tor Vergata) and colleagues have generated two DM2 and two wild type human iPSC lines from skin biopsies and differentiated these into cells expressing neuronal markers (Spitalieri et al., 2018). Established hallmarks of DM2 were conserved in differentiated neural cells—CNBP CCTG expansion length and number of CCUG-MBNL nuclear foci increased during neuronal differentiation. Assessment of various neuronal markers over the 25-30 days required to achieve neuronal conversion showed the differentiated population to contain an admixture of neurons, astrocytes, and oligodendrocytes.

Utility of DM2 iPSCs

The temporal pattern of expression of neuronal markers suggests that the time course of neurogenesis could be evaluated in vitro in DM2 versus wild type cells in an assessment of the suspected disease impact upon neurodifferentiation. Moreover, DM2 iPSCs may provide a renewable cell population for rapid screening of candidate therapeutics that address primary disease mechanisms in DM2. MDF has been working with RUDCR Infinite Biologics to establish DM iPSC cell lines that are available to all investigators without intellectual property constraints. RUDCR already has human iPSC lines established and quality controlled for DM1 and now available for distribution. We anticipate that human DM2 iPSC lines will be available soon.

References:

Generation of neural cells from DM1 induced pluripotent stem cells as cellular model for the study of central nervous system neuropathogenesis.
Xia G, Santostefano KE, Goodwin M, Liu J, Subramony SH, Swanson MS, Terada N, Ashizawa T.
Cell Reprogram. 2013 Apr;15(2):166-77. doi: 10.1089/cell.2012.0086.

Generation and Neuronal Differentiation of hiPSCs From Patients With Myotonic Dystrophy Type 2.
Spitalieri P, Talarico RV, Murdocca M, Fontana L, Marcaurelio M, Campione E, Massa R, Meola G, Serafino A, Novelli G, Sangiuolo F, Botta A.
Front Physiol. 2018 Jul 27;9:967. doi: 10.3389/fphys.2018.00967. eCollection 2018.