The Myotonic Dystrophy Clinical Research Network (DMCRN) sites are currently conducting a critically-important research study designed to help drug developers successfully design clinical trials and understand how to assess the efficacy of potential therapies. The research study, entitled, “Establishing Biomarkers and Clinical Endpoints in Myotonic Dystrophy Type-1 (END-DM1)", is being conducted at 20 sites around the world. Researchers are trying to learn more about what causes the muscle weakness and stiffness (myotonia) in myotonic dystrophy. This study will enroll 700 people, ages 18-70, with myotonic dystrophy type 1 who are willing to travel, up to 4 times, to one of the centers below and complete the study requirements. Subjects may be asked if they would like to participate in the muscle biopsy sub-based on the study team’s assessment.

The information collected in this study will help scientists design new treatments for myotonic dystrophy, find the best way to measure whether myotonic dystrophy is getting better or worse, and determine how it changes over time. There is no cost to you to participate.

Study Details

Enrolled subjects will be asked to undergo the following procedures at each visit:

• Physical examination
• Electrocardiogram (EKG)
• Muscle strength and myotonia testing
• Some patients will need to have a needle muscle biopsy to obtain a small amount of muscle tissue (smaller than a pea)
• Provide blood samples
• Complete a set of questionnaires
• Complete cognitive testing

If you are selected for the muscle biopsy sub-study, the first biopsy will be obtained from the lower leg, next to the shin (tibialis anterior muscle). The second biopsy will be obtained 3 months later, from the opposite leg, next to the shin (tibialis anterior).

Additional follow-up visits will be at month 3 (if you provided a muscle biopsy), month 12 and month 24.

Ready to Participate?

If you are interested in this project, please contact one of the recruiting study coordinators listed below or Jeanne Dekdebrun at Jeanne_Dekdebrun@urmc.rochester.edu or Jessica St. Romain at Mary.StRomain@vcuhealth.org.

• University of Kansas, Kansas City, Kansas
  Rebecca Clay, rclay@kumc.edu
• University of Rochester, Rochester, New York
  Jim Hilbert, James_Hilbert@URMC.Rochester.edu
• Virginia Commonweatlh University, Richmond, Virginia
  Carino Jennings, Carino.Garza@vcuhealth.org
• Ohio State University, Columbus, Ohio
  Kaneshia Hives, Kaneshia.Hives@osumc.edu, 614-685-5661
• University of Florida, Gainesville, Florida
  Whitney Miller, Whitney.Miller@neurology.ufl.edu
• Houston Methodist, Houston, Texas
  KaDeesia Brown, Kbrown5@houstonmethodist.org
• University of Iowa, Iowa City, Iowa
  Maegan Tyrrell, maegan-tyrrell@uiowa.edu

• Centro Clinico NEMO, Milan, Italy
  Erica di Natale, erica.dinatale@centrocliniconemo.it

• Radboud University, Nijmegen, Netherlands
  Monique Plieger, Monique.Plieger@radboudumc.nl
• München, Germany
  Corinna Wirner-Piotrowski, Corinna.Wirner@med.uni-muenchen.de
• University College London, London, United Kingdom
  Nikoletta Nikolenko, n.nikolenko@nhs.net
• St. George’s University, London, England, Claire Gilmartin, Claire.Gilmartin@stgeorges.nhs.uk
• University of California Los Angeles, Los Angeles, California
  Dennis Fernando, DeFernando@mednet.ucla.edu
• Stanford University, Stanford, California
  Sarah Ismail, sismail@stanford.edu
• University of California San Diego, San Diego, California
  Mariah Stechschulte, mastechschulte@health.ucsd.edu
• University Colorado Denver, Aurora, Colorado
  Alyssa Avilez, alyssa.avilez@cuanschutz.edu
• UT Health San Antonio, San Antonio, Texas
  Marlon Tamayo-Muradas, tamayomurada@uthscsa.edu
• University of Auckland, Auckland, New Zealand
  Sarah Nagar, sarah.nagar@auckland.ac.nz
• Université de Sherbrooke, Sherbrooke, Quebec
  Camélia Dubois, CameliaDubois@cegepjonquiere.ca
• Aomori – Osaka, Japan
  Eri Ikeda, eri.ikeda@verlieben.jp

The Need for Respiratory Guidelines

Due to the multisystemic nature of myotonic dystrophy type 1 (DM1), the studies and rigorous evidence needed to drive the creation of an evidence-based guideline for the respiratory clinical care of myotonic dystrophy patients were not available. In order to improve and standardize care for DM1, 12 leading DM1 pulmonologists in Western Europe, the UK, Canada, and the US joined together to create the Consensus-based Care Recommendations for Pulmonologists Treating Adults with Myotonic Dystrophy Type 1. The project was organized and supported by MDF.

To promote the development of pulmonary care guidelines for myotonic dystrophy, MDF solicited the input of care experts and organized the drafting of these recommendations. A group of neuromuscular experts in DM1 including pulmonologists, respiratory physiotherapists and sleep specialists created the Consensus-based Care Recommendations for Pulmonologists Treating Adults with Myotonic Dystrophy Type 1 through an iterative process. All authors contributed content to create the first draft and leading author Valeria Sansone, M.D., Ph.D. was in charge of managing further editing cycles. The process began in 2017 and concluded in April 2020, with the article published on Respiration’s website on 4/17/20 and in print in Volume 99, Number 4.

Share this with your Pulmonologist

In patients with DM1, respiratory muscle weakness frequently evolves, leading to respiratory failure as the main cause of death, followed by cardiac complications. These guidelines provide a more detailed outline on the diagnostic and management protocols which can guide pulmonologists who may not have experience with DM1 or who are not part of a neuromuscular multidisciplinary clinic. The 7-page document provides detailed respiratory care recommendations for the management of patients living with DM1, including respiratory testing and management at baseline and during follow-up visits. The resulting recommendations are intended to improve respiratory care for the most vulnerable of DM1 patients and lower the risk of respiratory complications and mortality by providing pulmonologists with practical indications on which tests and when to perform them, adapting the general respiratory knowledge to specific issues related DM. The guidelines represent an exciting step in the respiratory treatment and management of DM1 and MDF is thrilled to support this vital educational effort.

During the COVID-19 Pandemic, please be sure to share the Respiratory Care Recommendations for Myotonic Dystrophy Patients During the COVID-19 Pandemic with your doctor as well!

Resources

You can access the full article online via Respiration and Karger Publishers at https://www.karger.com/Article/Abstract/505634.

Click here to download a copy of the Consensus-Based Care Recommendations for Pulmonologists Treating Adults with Myotonic Dystrophy Type 1!

If you would like a hard copy of the article or the guidelines mailed to you, please contact us at info@myotonic.org with your mailing address.

Evidence-based Guidelines

Due to the multisystemic nature of myotonic dystrophy type 1 (DM1), it has been a challenge to conduct the studies and collect the rigorous evidence required to create an evidence-based guideline for the cardiac clinical care of patients with myotonic dystrophy type 1. In order to improve the quality of life and standardize care for people living with DM1, MDF organized and supported 10 leading DM1 cardiologists in Canada, Japan, Western Europe, the United Kingdom, and the United States to create the Consensus-based Care Recommendations for Cardiologists Treating Adults with Myotonic Dystrophy Type 1.

Publication Preparation

To promote the development of cardiac care guidelines for myotonic dystrophy, MDF solicited the input of care experts and organized the drafting of these recommendations. The 10 leading DM1 cardiologists created the Consensus-based Care Recommendations for Cardiologists Treating Adults with Myotonic Dystrophy Type 1 through an iterative drafting process. All authors contributed content to create the first draft and leading author Elizabeth McNally, M.D., Ph.D. was in charge of managing further editing cycles. The process began in 2017 and concluded in February 2020, with the article published on the Journal of the American Heart Association website on 2/6/20 and in print on 2/18/20 in Volume 9, Issue 4.

Tell Your Cardiologist

The guidelines review cardiac management of myotonic dystrophy, including surveillance for arrhythmias and left ventricular dysfunction, both of which occur in progressive manner and contribute to morbidity and mortality. Other topics reviewed in the guidelines include heart imaging, cardiomyopathy treatment and stroke risk, concluding in 15 summary recommendations. The recommendations represent expert consensus opinion from those with experience in the management of myotonic dystrophy, in part supported by literature‐based evidence where available.

The guidelines are intended for use by cardiologists but individuals diagnosed with DM1 are encouraged to provide a copy of the recommendations to their cardiologists. The guidelines represent an exciting step in the cardiac treatment and management of DM1 and MDF is thrilled to support this vital educational effort to standardize care.

Resources

Digitally access the full article on the Journal of the American Heart Association website.

You can download the full Consensus-based Care Recommendations for Cardiologists Treating Adults with Myotonic Dystrophy Type 1 as well as other critical care resources to share with your doctor on our Toolkits & Publications page.

If you would like a hard copy of the article or guidelines mailed to you, please email us at info@myotonic.org.

References:

Clinical Care Recommendations for Cardiologists Treating Adults With Myotonic Dystrophy
McNally EM, Mann DL, Pinto Y, Bhakta D, Tomaselli G, Nazarian S, Groh WJ, Tamura T, Duboc D, Itoh H, Hellerstein L, and Mammen PPA
JAHA. 2020 Feb 6. doi 10.1161/JAJA.119.014006 [Epub ahead of print]

CNS Matters

At times in past decades, pharmaceutical companies considered CNS sequelae of disease to be difficult, potentially untractable, targets. Even in areas where both the burden of disease and socioeconomic costs have been high, say, in Alzheimer’s Disease, drug discovery and development pipelines are littered with failures. There are a variety of explanations for failure to demonstrate efficacy in CNS indications—including the slowly progressive nature of some diseases, lack of meaningful animal models, low drug bioavailability at target, difficulties of biomarker discovery and validation, and the clarity provided by available outcome measures.

The burden of CNS symptoms is considerable, as evidenced by patient and caregiver information such as that from MDF’s Voice of the Patient report. Publications and workshops have addressed the question, do we treat DM as a brain disease? The answer lies in the criticality of CNS symptoms for many living with DM1, yet is the CNS becoming tractable in these patients?

Generally, CNS targets now appear more tractable, with recent approvals of drugs/biologics for multiple sclerosis, cystic fibrosis, seizures, and spinal muscular atrophy, and the robustness of pharma/biotech pipelines suggests more approvals are on the horizon.

But Do We Have Sufficient Knowledge to Target the DM1 CNS?

There is increasing focus on the CNS in DM1 that is evident from PubMed searches or conference agendas, although many studies to date have not been sufficiently powered to gain broad insight into a heterogeneous disease. This is a gap that must be addressed to help justify the growing interest in drug development for DM1.

Dr. Peggy Nopoulos and colleagues at the University of Iowa are in the process of conducting longitudinal assessments of brain structure and function in DM. The broad goal of these studies is to investigate the use of MRI measures of white matter health as biomarkers of CNS disease in DM1.

As part of their overall biomarker effort, the Iowa group has now published data on muscle properties, spinal reflexes, and transcortical long-latency reflexes in a cohort of 24 subjects with clinically mild/moderate DM1 in comparison with 25 matched controls (Shields et al., 2019). These data support the potential to expand the repertoire of neurologic instruments, beyond currently available behavioral tools, to both track the progression of DM1 and to provide clinical trial assessment tools.

In this study, DM1 subjects showed decreased tibial nerve H-reflex depression compared to controls, although this alteration did not correlate with either MIRS score or CTG repeat length. Following supra-maximal tibial nerve stimulation, single twitch and doublet forces generated in the soleus were lower than control in DM1. In contrast to controls, repetitive stimulation did not result in force potentiation in affected subjects.

DM1 subjects tested in the single-limb squat visual-motor task showed higher overall absolute error in both perturbation and non-perturbation trials. Finally, the team established a relationship between transcortical long-latency reflexes magnitude (when normalized to nonperturbed trials) and the magnitude of H-reflex depression in DM1 subjects—those subjects with the least robust long-latency reflexes exhibited the greatest loss of spinal H-reflex depression.

Implications for Understanding CNS Involvement in DM1

Because of the multi-organ system involvement in DM1, it is important to understand the etiology of functional deficits. Here, the team has established the operation of homosynaptic depression of spinal reflexes and spinal trans-cortical reflexes. Many of these differences are viewed as neural circuitry and contractile apparatus adaptations that, in turn, may undermine lower extremity dysfunction in the DM1 patient.

Taken together, the team presents a cogent picture of how DM1-altered excitation-contraction coupling and diminished spinal reflex and transcortical reflex functioning collectively contribute to the motor phenotype of DM1. If validated in larger cohorts, the measures used here have the potential for following disease progression and evaluating therapeutic efficacy in interventional trials.

Reference:

Myotonic dystrophy type 1 alters muscle twitch properties, spinal reflexes, and perturbation-induced trans-cortical reflexes.
Shields RK, Lee J, Buelow A, Petrie M, Dudley-Javoroski S, Cross S, Gutmann L, Nopoulos PC.
Muscle Nerve. 2019 Nov 26. doi: 10.1002/mus.26767. [Epub ahead of print]

Defective Myogenesis and DM1

Considerable literature now supports the notion that impaired myogenic differentiation plays an important role in the pathogenesis of DM1, particularly CDM (for reviews, see Thomas et al., 2018 and André et al., 2018). In studies using patient isogenic cell lines with large CTG repeats at the DMPK locus, Muscleblind sequestration and consequent mis-splicing have been demonstrated as early as the myoblast stage (André et al., 2019a). Better understanding of the etiology of muscle defects in DM can provide insight into disease mechanisms and putative targets for therapy development.

Expanding Upon the DMPK (CTG)2600 Repeat Cell Line

Taking further advantage of their isogenic CDM line, (CTG)2600, Dr. Derick Wansink (Radboud University Medical Center) and colleagues have addressed the reversibility of the myogenic defects they identified previously in this model (André et al., 2019b). In this study, they compared myogenesis in (CTG)2600 with that of cells where the expanded repeat was removed using CRISPR/Cas9 genome editing.

While failed fusion results in arrested myotube development in the (CTG)260 CDM line, excision of the expanded repeat restored the myogenic program and myotube differentiation (improved fusion index nuclei/cell, and myosin expression), while not altering the chromatin configuration characteristic of CDM (i.e., unaltered CpG island methylation and DM1 locus gene expression patterns). Moreover, gene and protein expression patterns for various regulators of myogenic differentiation (e.g., MYOD, MYOG, and MYF5), molecular markers of myogenesis (e.g., DMD, MHCp, and MHCe), and MBNL expression and related splicing patterns were restored in the edited cell line. The research team noted that few and selective changes in the myogenic transcriptome/proteome were observed.

Molecular Events Underlying CDM Severity

The singular action of repeat excision, in the absence of alteration of CDM-associated epigenetic changes at the DMPK locus, restored the myogenic program in a CDM cell line. These data further support the hypothesis that altered myogenesis driven by exceptionally large repeat expansions represents a major contributor to the skeletal muscle phenotype in CDM. Finally, these data have implications for the development of genome editing strategies to therapeutically target DM.

References:

Myotonic Dystrophy and Developmental Regulation of RNA Processing.
Thomas JD, Oliveira R, Sznajder ŁJ, Swanson MS.
Compr Physiol. 2018 Mar 25;8(2):509-553. doi: 10.1002/cphy.c170002. Review.

Abnormalities in Skeletal Muscle Myogenesis, Growth, and Regeneration in Myotonic Dystrophy.
André LM, Ausems CRM, Wansink DG, Wieringa B.
Front Neurol. 2018 May 28;9:368. doi: 10.3389/fneur.2018.00368. eCollection 2018. Review.

(CTG)n repeat-mediated dysregulation of MBNL1 and MBNL2 expression during myogenesis in DM1 occurs already at the myoblast stage.
André LM, van Cruchten RTP, Willemse M, Wansink DG.
PLoS One. 2019a May 22;14(5):e0217317. doi: 10.1371/journal.pone.0217317. eCollection 2019.

Recovery in the Myogenic Program of Congenital Myotonic Dystrophy Myoblasts after Excision of the Expanded (CTG)n Repeat.
André LM, van Cruchten RTP, Willemse M, Bezstarosti K, Demmers JAA, van Agtmaal EL, Wansink DG, Wieringa B.
Int J Mol Sci. 2019b Nov 13;20(22). pii: E5685. doi: 10.3390/ijms20225685.

Diabetes, DM1, and “Fortuitous” Drug Effects

An important downstream consequence of the DM1 mutation is aberrant splicing of the insulin receptor (INSR) transcript, glucose intolerance, insulin resistance, and development of type 2 diabetes (T2D). Metformin, an established anti-diabetic drug, has been used for symptomatic treatment of T2D in DM1. For reasons that are, as yet, unclear, metformin may be valuable in addressing other consequences of DM1, including improving patient mobility in a randomized, placebo-controlled clinical trial (Bassez et al., 2018). Since DM1 is without an approved therapy that is targeted to the primary disease mechanism, understanding of such multi-systems drug effects is of vital importance to the management of those living with DM1.

Cancer and DM1

Patients with DM1 are at elevated risk of cancer (Gadalla et al., 2011; Alsaggaf et al., 2018). In the general population, epidemiological studies have suggested that use of metformin for T2D also has beneficial effects for cancer prevention and treatment.

Connecting the dots—the common use of metformin in T2D in DM1, its potential anti-cancer activity, and the prevalence of cancer in DM1—Dr. Shahinaz Gadalla (National Cancer Institute/NIH) and colleagues explored putative cancer-preventative effects in DM1 patients receiving the drug for diabetes (Alsaggaf et al., 2019).

This study took advantage of a large UK National Health System medical record cohort with a substantial DM1 population—the completeness of this database allowed for control of multiple potentially confounding variables. In the cohort of 913 DM1 subjects, plus over 12,000 randomized, matched controls, the research team assessed cancer risk in T2D patients prescribed metformin versus those not receiving the drug. Cox regression modeling generated hazard ratios that established a higher prevalence of T2D in DM1 versus controls (8% vs. 3%); of note, those DM1 patients with T2D were more likely to have late-onset DM1 than those without T2D. Moreover, DM1 patients who also had T2D were at three-fold higher risk to develop cancer—this risk was reversed when DM1/T2D patients were treated with metformin. By contrast, in the control cohort, metformin use was not associated with decreased cancer risk.

Understanding, but Still Many Known Unknowns

This study makes clear that DM1 patients are at nearly three-fold enhanced risk of developing T2D, and suggests that those who do develop T2D are also at greater risk for cancer. Finally, the data raise the possibility that metformin significantly reduces cancer risk in DM1/T2D patients. This information may stimulate further research to asses T2D and cancer risk in DM1.

Reference:

Improved mobility with metformin in patients with myotonic dystrophy type 1: a randomized controlled trial.
Bassez G, Audureau E, Hogrel JY, Arrouasse R, Baghdoyan S, Bhugaloo H, Gourlay-Chu ML, Le Corvoisier P, Peschanski M.
Brain. 2018 Oct 1;141(10):2855-2865. doi: 10.1093/brain/awy231.

Cancer risk among patients with myotonic muscular dystrophy.
Gadalla SM, Lund M, Pfeiffer RM, Gørtz S, Mueller CM, Moxley RT 3rd, Kristinsson SY, Björkholm M, Shebl FM, Hilbert JE, Landgren O, Wohlfahrt J, Melbye M, Greene MH.
JAMA. 2011 Dec 14;306(22):2480-6. doi: 10.1001/jama.2011.1796.

Cancer Risk in Myotonic Dystrophy Type I: Evidence of a Role for Disease Severity.
Alsaggaf R, St George DMM, Zhan M, Pfeiffer RM, Wang Y, Wagner KR, Greene MH, Amr S, Gadalla SM.
JNCI Cancer Spectr. 2018 Nov;2(4):pky052. doi: 10.1093/jncics/pky052. Epub 2018 Dec 10.

Diabetes, Metformin, and Cancer Risk in Myotonic Dystrophy Type I.
Alsaggaf R, Pfeiffer RM, Wang Y, St George DMM, Zhan M, Wagner KR, Amr S, Greene MH, Gadalla SM.
Int J Cancer. 2019 Nov 20. doi: 10.1002/ijc.32801. [Epub ahead of print]

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]

Criticality of Small Molecule Assays

Small molecule drug development relies upon unbiased cellular, biochemical, or molecular level assays (screens) that read out the ability of test compounds to alter pathogenic mechanisms operative in the disease under study. Structure-activity relationships (SAR) of hits from such screens, along with established knowledge of how to improve the drug-like properties of such hits, can identify lead compounds for further non-clinical and clinical development.

Best practices in small molecule assay development have been codified by the National Center for Advancing Translational Sciences (NCATS) in their on-line Assay Guidance Manual. At the core of NCATS guidance is pilot development of assays that can easily transition into high throughput screening formats (HTS; >100K compounds per screen) and thus are valuable for iterative SAR efforts and collaborations with major pharmaceutical firm operations and their multi-million compound libraries. 

Given the variety of hurdles presented by the multi-system involvement in DM1, small molecule drugs are likely to play a significant role in reducing burden of disease. Thus, development and optimization of HTS assays utilizing expertise residing in academia will attract expertise and capacity of industry to the benefit of DM patients.

A Screen for Compounds Targeting Expanded CTG Repeats

 A paper describing a new drug screening assay for DM1 has been published in Proceedings of the National Academy of Sciences by Dr. Andy Berglund (University of Florida College of Medicine and University of Albany) and colleagues, including Dr. Kaalak Reddy, recipient of a 2017 MDF Postdoctoral Research Fellowship (Reddy et al., 2019). The team’s new assay is CTG repeat-selective, targeting the production and/or stability of construct containing a 480 CUG repeat tract in the context of a human DMPK segment, in a HeLa cell model. The model also contains a control, non-expanded CUG and uses a ratio-metric qRT-PCR readout of expanded repeat to non-expanded repeat levels. Cell lines generated by the team were evaluated for formation of nuclear foci and MBNL-dependent splicing events consistent with a DM1 phenotype.

After generating and selecting for optimal properties among several DM1 HeLa cell lines, properties of the selected line were evaluated using a pilot screen of the publicly available LOPAC¹²⁸⁰ small molecule library; actinomycin D was included as a positive control (Siboni et al., 2015). Top hits from the screen included three microtubule inhibitors, a DNA intercalator, and a purine nucleoside analog. Based upon further characterization of hits in an MBNL-dependent splicing assay, one of the microtubule inhibitors, colchicine, was carried forward into testing and subsequently validated in both DM1 mice (HSA^LR) and a DM1 patient cell line. Studies of the mechanism of action for colchicine support selectively reduced transcription of the CTG expansion. While known toxicity of colchicine might preclude its further development for DM1, this work has identified a novel potential therapeutic target (microtubule dynamics as a means of reducing DM1 expanded repeat transcription) and provides proof of principle for the new screening assay.

Going Forward

The research team has established a cell-based small molecule drug screening assay that reads out the selective reduction of the expanded trinucleotide repeat that is pathogenic in DM1. Moreover, their pilot screen establishes the feasibility of the assay to identify putative small molecule drug hits and to identify potentially new mechanisms of action for therapeutic development in DM1. The next steps are translation of the assay into a concerted drug discovery and development effort.

At a minimum, this new assay has importance as a secondary screening tool for validating HTS screening assay hits and for conducting SAR using analogs of primary screen hits. Key properties that are essential for HTS assays (see NCATS’ Assay Guidance Manual) are not reported out by the research team in this particular publication, thus its value for use in the large format (e.g., 1536-well) screens needed with very large (> 1M) pharmaceutical company compound libraries is not yet known.

References:

A CTG repeat-selective chemical screen identifies microtubule inhibitors as selective modulators of toxic CUG RNA levels.
Reddy K, Jenquin JR, McConnell OL, Cleary JD, Richardson JI, Pinto BS, Haerle MC, Delgado E, Planco L, Nakamori M, Wang ET, Berglund JA.
Proc Natl Acad Sci U S A. 2019 Sep 30. pii: 201901893. doi: 10.1073/pnas.1901893116. [Epub ahead of print]

Actinomycin D Specifically Reduces Expanded CUG Repeat RNA in Myotonic Dystrophy Models.
Siboni RB, Nakamori M, Wagner SD, Struck AJ, Coonrod LA, Harriott SA, Cass DM, Tanner MK, Berglund JA.
Cell Rep. 2015 Dec 22;13(11):2386-2394. doi: 10.1016/j.celrep.2015.11.028. Epub 2015 Dec 10.

Gait and Quality of Life in DM1

Disturbances of gait are an important component of the burden of disease in DM1—a patient/family member survey conducted in conjunction with the Myotonic Dystrophy Voice of the Patient Report identified difficulty with mobility as the second most impactful symptom affecting quality of life. Quantitative assessment of gait disturbances is viewed as a means of improving patient management (Bachasson et al., 2016; Pucillo et al., 2018) and is being incorporated as an outcome measure in interventional clinical trials (Bassez et al., 2018). Given the multifactorial regulation of gait, the understanding of contributing mechanisms, functional consequences, and potential therapeutic strategies represents an important unmet need for DM1.

Moving Beyond Muscle Weakness in Understanding Gait Disturbances

In a new publication (Naro et al., 2019), it is posited that a ‘simple’ explanation for disturbances of gait and balance—that both are directly related to the degree of muscle weakness—is viewed as misleading.  Instead, Dr. Rocco Salvatore Calabrò (IRCCS Centro Neurolesi Bonino Pulejo) and colleagues have tested the hypothesis that gait disruptions in DM1 are a consequence of deterioration of CNS-skeletal muscle network, disrupting the synergy of muscle group activation.

In this study, the research team utilized time-frequency spectral coherence analysis of surface EMG readouts from eight lower limb muscles during walking. Using this approach, they could assess the status of multiple muscle group/network coordination as it relates to the disturbances in gait—muscle impairment versus CNS damage was evaluated. The group also assessed the link between postural control and gait disturbance using electronic baropodometry.

The research team assessed seven adult DM1 patients and ten controls. Assessment of muscle activation during ambulation was measured using surface emg recordings bilaterally from four proximal and distal lower limb muscles. A gait quality index was calculated from accelerometer data. Electronic baropodometer analysis informed quality of stance control.

All DM1 patients exhibited gait disturbances—gait cycles were longer, step cadence lower, and pace slower than controls—and disrupted balance. Muscle network pattern analysis showed disruption of the connectivity between distal muscles both within and between legs in DM1 versus healthy controls. Analysis of signal synergy in DM1 showed that muscle activation patterns varied from one gait cycle to another versus consistent activation patterns across cycles in controls. While muscle weakness correlated with stability of stance (postural control), there was no correlation between weakness and muscle connectivity or synergy data.

Modeling the Etiology of Gait Disturbances in DM1

Taken together, the research team utilized a novel muscle connectivity analytic approach and showed that patients with DM1 exhibit: deteriorated muscle network organization at temporal and spatial levels, reflecting disruption at a central neural network level; greater network integration but reduced network segregation, which they suggest may reflect reduced CNS ability to segregate signals to distinct motor control modules; and, overall, a reduced availability of motor repertoires resulting in greater gait cycle variability.

Importantly, the team found no correlation between muscle weakness and a disruption of muscle connectivity characteristic of DM1—instead DM1 appears to be characterized by deterioration of neuromuscular networks unrelated to the development of individual muscle weakness.

Based upon a model that is emerging from these studies, an understanding of neuromuscular network changes, particularly that originating from signal synergy deterioration in the CNS that underlie gait disturbances, is essential to development of effective rehabilitation programs for patients living with DM1. This understanding also may be critical to how we view DM1 in the development of candidate therapies and design of interventional clinical trials.

References:

Relationship between muscle impairments, postural stability, and gait parameters assessed with lower-trunk accelerometry in myotonic dystrophy type 1.
Bachasson D, Moraux A, Ollivier G, Decostre V, Ledoux I, Gidaro T, Servais L, Behin A, Stojkovic T, Hébert LJ, Puymirat J, Eymard B, Bassez G, Hogrel JY.
Neuromuscul Disord. 2016 Jul;26(7):428-35. doi: 10.1016/j.nmd.2016.05.009. Epub 2016 May 12.

Modified dynamic gait index and limits of stability in myotonic dystrophy type 1.
Pucillo EM, Mcintyre MM, Pautler M, Hung M, Bounsanga J, Voss MW, Hayes H, Dibella DL, Trujillo C, Dixon M, Butterfield RJ, Johnson NE.
Muscle Nerve. 2018 Nov;58(5):694-699. doi: 10.1002/mus.26331. Epub 2018 Sep 23.

Improved mobility with metformin in patients with myotonic dystrophy type 1: a randomized controlled trial.
Bassez G, Audureau E, Hogrel JY, Arrouasse R, Baghdoyan S, Bhugaloo H, Gourlay-Chu ML, Le Corvoisier P, Peschanski M.
Brain. 2018 Oct 1;141(10):2855-2865. doi: 10.1093/brain/awy231.

Paving the way for a better understanding of the pathophysiology of gait impairment in myotonic dystrophy: a pilot study focusing on muscle networks.
Naro A, Portaro S, Milardi D, Billeri L, Leo A, Militi D, Bramanti P, Calabrò RS.
J Neuroeng Rehabil. 2019 Sep 18;16(1):116. doi: 10.1186/s12984-019-0590-0.