As a proximate mediator of the splicopathy that characterizes DM1, DMPK RNA carrying the toxic expanded CUG repeat sequence represents a potentially important target for therapy development. A candidate therapeutic with drug-like properties, including the ability to access the many affected target tissues in DM1, that specifically targets expanded repeat RNA, would represent an important compound for evaluation in interventional clinical trials. A new study has taken steps to establish preclinical proof of concept for such an agent.

Initial Development of Cugamycin

Ms. Alicia Angelbello (PhD graduate student) and Dr. Matt Disney at The Scripps Research Institute, Florida and their colleagues (at University of Florida and Iowa State) have developed a small molecule compound capable of cleaving DMPK expanded repeat RNA, as evidenced by data from studies in DM1 patient-derived myotubes and a DM1 mouse model (Angelbello et al., 2019). The candidate therapeutic has been named Cugamycin, because of its specificity/affinity for expanded, but not sub-disease threshold, CUG repeats.

The research team explored the idea that bringing specificity to a known RNA cleaving compound, bleomycin A5, represents a rationale path toward a DM1 therapeutic. By attaching bleomycin A5 to an RNA-binding molecule, the team could achieve a critical level of specificity and thereby advance both bioactivity/efficacy and safety of the resulting compound—Cugamycin. Target recognition and cleavage specificity of Cugamycin was established through studies showing in vitro binding and efficient cleavage of CUG^exp, but not DNA repeat hairpins.

Cell- and Animal-Based Support for Further Development of Cugamycin

In vitro analyses using DM1 patient-derived and control myotubes showed that Cugamycin was cell-permeable (overcoming a hurdle seen in large molecule development for DM1 muscle) and tracks to the nucleus. DMPK RNA cleavage efficiency in this model was 40%, with an EC₂₅ in high nanomolar range—notably, wild type DMPK RNA was spared. The research team also established that Cugamycin reduced nuclear foci and rescued defects in the splicing events tested in the cell model. Direct comparison of Cugamycin and antisense oligonucleotides (AONs) targeted to DMPK expanded repeat RNA showed higher specificity for the small molecule drug (AON sequence/chemistry used here failed to distinguish between expanded and subthreshold DMPK RNA).

Findings of subsequent in vivo evaluations of drug metabolism and pharmacokinetics (the other DMPK) of Cugamycin supported a move to mouse efficacy testing. Short-term dosing of 10 mg/kg ip every other day in adult HSA^LR mice was well tolerated and without side effects linked to the base bleomycin A5 compound. Short-term dosing also produced a 40% reduction in toxic DMPK RNA and reversal of splicing defects tested in hindlimb muscles, confirming systemic drug bioavailability and target engagement and modulation. Treated HSA^LR mice showed restoration of Clcn1 protein levels and reductions in myotonia. The high selectivity of the candidate therapeutic was confirmed in RNA-seq analyses of skeletal muscle samples from untreated wild type and vehicle only and Cugamycin treated HSA^LR mice.

The authors conclude that, as a preclinical candidate molecule, Cugamycin has limited liabilities, but do note the opportunities for further chemical analoging around its scaffold to continue to optimize and arrive at a development candidate for IND-enabling studies and entry into clinical trials.

Path Forward

Taken together, this new study provides a compelling case that small molecules can be developed to safely and effectively target toxic RNA cleavage in DM1. At the time of this writing, yet another reminder became available that efficacy in a mouse model may or may not translate into an effective drug in patients (Chakradhar, 2019 and justsaysinmice). Thus, while current findings are encouraging, they are in a model organism that cannot actually “have” the human disease—we look forward to further testing of Cugamycin and its analogs, and pursuit of all strategies for the development and regulatory approval of safe and effective drugs for patients living with DM.

References:

Precise small-molecule cleavage of an r(CUG) repeat expansion in a myotonic dystrophy mouse model.
Angelbello AJ, Rzuczek SG, Mckee KK, Chen JL, Olafson H, Cameron MD, Moss WN, Wang ET, Disney MD.
Proc Natl Acad Sci U S A. 2019 Mar 29. pii: 201901484. doi: 10.1073/pnas.1901484116. [Epub ahead of print]

It’s just in mice! This scientist is calling out hype in science reporting.
Chakradhar, S.
STAT. April 15, 2019
 

The muscular dystrophy field provides case studies of how flawed assumptions about the mechanistic understanding of a disease can lead therapeutic discovery and development efforts astray. One should never assume that we “already know” all key aspects of disease pathogenesis and thus have identified all feasible targets for therapeutics.

While the DM field certainly has developed a strong disease understanding, including of molecular targets that are tractable for drug and biologic development, there are many nagging questions remaining, such as the role of RAN translation in DM1 and DM2 and that of the epigenetic modifications upstream of the DMPK locus in CDM. In addition to these known unknowns, there likely are unknown unknowns in DM biology to worry about. Therapeutic efforts certainly need to go forward for rationale targets. But, as the NINDS concluded several years ago, there will always be a need for the novel findings that originate only from continuing basic and mechanistic research.

Might RNAi Machinery Play a Role in DM1?

A new article (Qawasmi et al., 2019) from Drs. Susana Garcia (University of Helsinki), Yuval Tabach (The Hebrew University of Jerusalem), and colleagues explores an alternative gain-of-function mechanism, that expanded CUG repeats in the DMPK transcript serve as templates for gene silencing via RNA interference (RNAi). This work utilized a novel C. elegans model of DM1.

The research team used the worm model they had developed previously, expressing 123 CUG repeats in the 3’UTR of a GFP transcript driven by a skeletal muscle promoter. Phenotypically, this model is characterized by motility and heat shock survival response defects.

To show that RNAi could be activated by expanded CUG repeats independent of other RNA mechanisms known to be operative in DM1, wild type worms were fed plasmid expressing RNA with 50 CTG repeats—this RNA is known to be cleaved and the resulting short CUG fragments activate RNAi. Data showed the development of motility defects similar to that of their 123 CUG DM1 model and a heat shock survival defect.

Consistent with findings in wild type worms fed expanded CUG plasmid, the 123 CUG repeat DM1 model showed, over time, a decay of the exogenous CUG repeat transcript and its protein product. By silencing RNAi pathway genes, the team showed that gene silencing was responsible for disappearance of the 123 CUG repeat. In the next series of experiments, they tested whether CUG repeats in their DM1 model were similarly processed and act as non-coding RNAs to silence expression of other endogenous CUG-bearing genes via RNAi. In these studies, expression of endogenous genes bearing at least 4 repeats was reduced by 1.6-fold. This suggests that expanded CUG repeat transcripts activate RNA silencing followed by the downregulation of endogenous CUG-bearing transcripts. Using RNA-seq of entire worms, a total of 982 genes were found to be downregulated by ≥ 1.5x; because some of the knocked down genes are not expressed in muscle, the overall effect apparently involves non-cell-autonomous RNA silencing in adjacent tissues. Finally, knocking down genes comprising the RNAi machinery rescued expression of genes that were otherwise affected in the 123 CUG repeat model.

Connecting the Dots

Collectively, these studies support the conclusion that expression of CUG expanded repeats triggers an RNAi-mediated repression of multiple endogenous genes that normally contain CUG repeats in their transcript. Thus, RNAi pathways may contribute towards the pathogenesis of DM1 and thus may represent a potential target for therapeutic intervention in the disease. Future studies should evaluate the potential operation of RNAi driven pathology in mammalian models of DM1 and determine its relative contribution to disease.

Reference:

Expanded CUG Repeats Trigger Disease Phenotype and Expression Changes through the RNAi Machinery in C. elegans.
Qawasmi L, Braun M, Guberman I, Cohen E, Naddaf L, Mellul A, Matilainen O, Roitenberg N, Share D, Stupp D, Chahine H, Cohen E, Garcia SMDA, Tabach Y.
J Mol Biol. 2019 Mar 14. pii: S0022-2836(19)30121-4. doi: 10.1016/j.jmb.2019.03.003. [Epub ahead of print]

Recent announcements from three biotechnology and pharmaceutical companies reflect the increasing interest in and tractability of myotonic dystrophy for therapy development. Short summaries and links to the press releases are provided here.

AMO Therapeutics

AMO Therapeutics is in clinical testing of AMO-02 for treatment of congenital and childhood onset myotonic dystrophy. Their strategy is to target GSK-3β with a small molecule drug in order to address the considerable CNS burden of disease.

To date, the large majority of therapeutic development efforts in myotonic dystrophy have targeted skeletal muscle. The ease of accessing and evaluating splicing events in small muscle biopsies provides a drug developer with rather rapid insights as to drug bioavailability and molecular target modulation. Assessment of the CNS in myotonic dystrophy patients is more complex—the hurdles here include identifying appropriate drug targets and targetable CNS phenotypes and determining how interventional trials can best demonstrate the clinical effectiveness of drugs and biologics in patients. Because of the importance of the CNS phenotype in DM, MDF is devoting a workshop to this topic, scheduled for September 12, 2019.

In efforts to establish sensitive and effective CNS outcome measures for congenital myotonic dystrophy, AMO Therapeutics has developed the Clinician-Completed Congenital Myotonic Dystrophy Type 1 Rating Scale (CDM1-RS). The new scale builds upon prior efforts on clinical rating scales by DM researchers, Drs. Chad Heatwole and Nicholas Johnson. CDM1-RS is currently being validated in a natural history study in children and adolescents with DM1 and AMO plans using it as the primary outcome measure in their upcoming registration trial.

The full press release is available on the AMO website.

Audentes Therapeutics

Audentes Therapeutics has announced the licensing of AT466 from Nationwide Children’s Hospital (Drs. Kevin Flanigan and Nicolas Wein) to target DM1 via facilitated delivery of an oligonucleotide therapeutic. Efforts are currently in the preclinical stage; the company notes that IND filing is planned for 2020.

The development of large molecule drugs, such as oligonucleotides, has a critical barrier to overcome in muscle diseases—the rather poor uptake of these large molecules by intact skeletal muscle fibers. Under evaluation is a strategy to deliver and enhance oligonucleotide uptake via AAV vectors. Two categories of oligo will be tested to block accumulation of toxic expanded repeat DMPK RNA in cells—oligos to achieve RNA knockdown and others for exon skipping—to treat DM1.

The full press release is available on the Audentes website.

Dyne Therapeutics

Earlier this month, Dyne Therapeutics announced that they had raised $50M in Series A financing in support of their lead disease target, DM1. Funding will support advancing a development candidate into clinical testing—a putative timeline has not yet been provided.

The development of large molecule drugs, such as oligonucleotides, has a critical barrier to overcome in muscle diseases—the rather poor uptake of these large molecules by skeletal muscle fibers. Dyne proposes to address this hurdle by linking oligonucleotides to an antibody that tracks to and is internalized via muscle cell surface receptor binding. Once this facilitated uptake process gains entry of the oligonucleotide into muscle fibers, the Dyne oligonucleotide mechanism is degradation of toxic expanded CUG repeat RNA.

The full press release is available on the Dyne Therapeutics website.

First Grant in $1M DM Cure Development Project Awarded

MDF community members likely remember that in late 2017 very generous donors committed $1M to MDF to launch a gene editing development project to find a cure for myotonic dystrophy. MDF conducted a comprehensive scoping and discovery workshop, followed by a Request for Applications in mid-2018. We are delighted to announce that Dr. Vincent Dion was awarded the first grant for that project.

Dr. Dion's Approach

Dr. Dion was trying to understand why the size of the repeating piece of genetic code in the gene that causes myotonic dystrophy varied from cell to cell in patients with the condition and in so doing, he may have stumbled on a novel treatment for the disease.

MDF has awarded Dion a two-year grant totaling $250,000 to support his research to determine the feasibility of a gene editing treatment for DM. He will be helped by Drs. Geneviève Gourdon at the Imagine Institute in Paris, and Jack Puymirat at Université Laval.

Myotonic dystrophy is known as a trinucleotide repeat disorder because of an expanded repeat of a three-letter piece of genetic code CTG (cytosine, thymine, and guanine) found in the DMPK gene of people with DM1. It’s normal to have several repeats of this code in the DMPK gene, but people who have more than 50 repeats, can develop DM1. The greater the number of repeats, the more severe the disease tends to be.

A Surprising Finding

Dion, a professor at the UK Dementia Research Institute at Cardiff University, knew that the size of repeats in any person with the disease could vary greatly from cell to cell. He wanted to understand why. He was using the gene editing technology CRISPR-Cas9, a bacterial enzyme that allows users to make precisely-targeted cuts in genetic material, to see if he could test a theory that changes in the number of repeats was caused by DNA damage. He wanted to see if disrupting the repeat track by making cuts in a single track of the double-stranded genetic code to expose the repeat would influence whether expansion of the repeat occurred.

In a surprising finding, Dion observed that by making such breaks in the repeat track he had corrected the error. Enzymes that naturally repair damaged DNA healed the cuts to the repeat track. But instead of amplifying the repeat, it reduced its size.

In essence, his work suggested gene editing might prove to be a way to correct the toxic repeat and possibly arrest the mechanism of the disease.

“We stumbled upon this by chance,” said Dion, who earned his Ph.D. in molecular biology at Baylor College of Medicine in Houston and then completed a postdoctoral fellowship at the Friedrich Miescher Institute in Basel. “The question we were asking was completely different and we ended up using CRISPR to correct the mutation in human cells, and then we went from there.”

Accelerating Research with MDF

The MDF grant will allow Dion to continue his work, exploring the gene editing approach in a DM mouse model to see if it corrects the mutation.

The grant will also be used to see how precise the approach will be within a living organism and to make sure that the CRISPR cuts the expanded repeat in the DMPK gene as intended, and not elsewhere, which could lead to severe off-target effects.

Dion does have some tricks to ensure the CRISPR targets the genetic material correctly at the desired point. He uses RNA to target the repeat track he wants it to cut. That’s not without its challenges, as he needs to package the CRISPR and RNA into a viral vector to carry it into the cell.

The other issue any gene editing therapy will face is the need to deliver it into the central nervous system (the brain) to address the neurological effects of the condition. That would likely require some means of direct delivery. In the mouse model, Dion will be injecting directly into the brain. If all of that works, Dion then hopes to move the gene editing work to a larger DM animal model.

For now, Dion hopes to demonstrate that the approach works. Even if he is successful with the experiments he'll be conducting over the next two years, he believes it would still be several years before the approach could advance to human testing.

“The hope is that we'll know whether it works. We'll know whether it's specific enough for the repeat track and whether it might cause other mutations,” said Dion. “If those questions are answered successfully, then I think we're looking at another five years or so after that to do a clinical trial.”

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.

• Kansas City, Kansas: Katie Roath / kroath@kumc.edu / 913-945-9928
• Rochester, New York: Jeanne Dekdebrun / jeanne_dekdebrun@urmc.rochester.edu / 585-276-4611
• Richmond, Virginia: Jodie Howell / Jodie.Howell@vcuhealth.org / (804) 828-6110
• Houston, Texas: Aramide Balogun / abalogun@houstonmethodist.org / 713-441-6947
• Stanford, California: Christina Frater / cfrater@stanford.edu / 650-374-9438
• Columbus, Ohio: Kaneshia Hives / Kaneshia.Hives@osumc.edu / 614-685-5661
• Gainesville, Florida: Calvin Thomas / Ashley.Thomas@neurology.ufl.edu
• Iowa City, Iowa: Nicole Kressin / nicole-kressin@uiowa.edu / 319-678-8596
• Paris, France: Guillaume Bassez, MD / guillaume.bassez@aphp.fr
• Milan, Italy: Luca Mauro / luca.mauro@centrocliniconemo.it / +39 02 91433264
• Nijmegen, Netherlands: Baziel vanEngelen, MD / baziel.vanengelen@radboudumc.nl / (024) 366 8374
• München, Germany: Stephan Wenninger / Stephan.Wenninger@med.uni-muenchen.de
• London, United Kingdom: Chris Turner, PhD / chris.turner7@nhs.net
• Los Angeles, California: Jennifer Huynh / JenniferH@mednet.ucla.edu / (310) 825-3264
• Aurora, Colorado: Brianna Blume / NeurologyResearchPartners@ucdenver.edu / (303) 724-4644
• Auckland, New Zealand: Miriam Rodrigues / MRodrigues@adhb.govt.nz / 021896662
• London, United Kingdom: Nikoletta Nikolenko / n.nikolenko@nhs.net / +44(0)7572310021
• Quebec, Canada: Valérie Gagné-Ouellet / Valerie.Gagne.Ouellet@USherbrooke.ca
• San Diego, California: Mariah Stechschulte / mastechschulte@health.ucsd.edu
• Dallas, Texas: Sean Evans / Sean.Evans@UTSouthweatern.edu / 214-648-2926
• London, United Kingdom (St George)

What is the Medical School Roadshow?

Myotonic 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. Myotonic is partnering with medical schools to educate students about DM before they graduate and begin clinical work.

Myotonic Needs You!

We need participation from the people who know DM best: you and those in your family affected by DM. Myotonic 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 Leah.Hellerstein@myotonic.org

Get more details on the Myotonic Medical School Roadshow here.

Over the last year, MDF has carefully examined the potential of genome editing strategies to address myotonic dystrophy, including hosting an expert workshop and a competition for research grant funding. In these efforts, the focus has been upon the need to evaluate various genome editing strategies, optimize reagents, identify an effective delivery vehicle, and establish systems to assess both safety and efficacy in preclinical models—as reported out from the workshop. Although genome editing is rapidly moving into the clinic for other disease indications, the technology likely is not yet optimized and the DM field will benefit from learnings from any first-in-man studies.

Progress in Genome Editing for Neuromuscular Diseases

Haris Babačić (now a Ph.D. student in proteogenomics at Karolinska Institute), Dr. Benedikt Schoser (Ludwig-Maximilians-University of Munich), and colleagues have conducted an intensive analysis of preclinical research publications in neuromuscular and repeat expansion disorders to ascertain key lessons for moving genome editing strategies forward. Their review was recently published in PLoS One (Babačić et al., 2019). Their review provides important perspectives obtained from one genome editing platform, CRISPR-Cas, so that learnings are not siloed within disease fields.

These authors utilized literature searches of MEDLINE and EMBASE databases (coverage up to the end of 2017) to identify publications focused on use of CRISPR-Cas genome editing systems in preclinical studies of at least one monogenic neuromuscular disease. In all, forty-two publications met all eligibility criteria and were reviewed. Like the MDF Genome Editing Workshop, this publication identified the efficient delivery of editing reagents and evaluation of their safety and efficacy as the salient issues in moving toward clinical testing of this therapeutic strategy.

The majority of studies reviewed here (n = 26) were in preclinical models of Duchenne muscular dystrophy (DMD); information was also obtained from publications in Huntington Disease (HD; 5 publications), Spinocerebellar Ataxia 2 (SCA2; 3 publications), Friedreich’s ataxia (FA; 1 publication), myotonic dystrophy type 1 (DM1; 3 publications), Fragile X syndrome (FXS; 2 publications), and three other types of muscular dystrophy (FSHD, MDC1A, and LGMD; 1 publication each).

Lessons from Studies of Genome Editing

The theme that the efficacy of genome editing is influenced by selection and delivery of guide RNAs (gRNA) and Cas was readily apparent among the publications focusing on DMD. Efficacy was shown for DMD in in vitro, ex vivo, and in vivo models. Delivery predominantly relied upon viral vectors, although use of gold nanoparticles has shown potential. Evaluation of the specificity of off-target editing (safety) largely focused on sequences predicted using bioinformatic models—an approach unlikely to be sufficient to support clinical development (as per the NIST Genome Editing Consortium).

Studies in DM may need to overcome difficulties in removal of the long, expanded repeat tracts; yet a strategy of targeting and eliminating the toxic repeat RNA with dCas9 has also been tested. The review’s authors note that mRNA targeting would require life-long administration of the candidate therapeutic—potential consequences of that strategy are not yet known, although there is a more general concern about off-target and immunological consequences of continues expression of the Cas protein. These safety concerns may require use of a delivery system in which Cas protein can be switched off after editing is complete.

Analysis of the other indications addressed in this review led to few additional lessons, outside of therapeutic window considerations that are disease-specific. The authors do include an important section on ethical issues that accompany genome wide editing strategies, ranging from benefit-risk assessments to the societal issues raised by germline editing. Overall, the review’s authors acknowledge the rapid progress that has been made in moving a potentially game-changing therapeutic forward, but conclude that the evidence to move into clinical trials for neuromuscular diseases is insufficient. They argue for more basic research to optimize delivery systems, thoroughly assess off-target safety concerns, and create standards for efficacy determination before transitioning to clinical trials. These are goals that are consistent with the due diligence that MDF has done to assess the opportunities and challenges of using genome editing in DM.

Reference:

CRISPR-cas gene-editing as plausible treatment of neuromuscular and nucleotide-repeat-expansion diseases: A systematic review.
Babačić H, Mehta A, Merkel O, Schoser B.
PLoS One. 2019 Feb 22;14(2):e0212198. doi: 10.1371/journal.pone.0212198. eCollection 2019.

Despite their considerable burden in DM1, attention to respiratory complications has lagged behind that given to other organ systems. This pattern is not unique to DM1--it has been seen for other types of muscular dystrophy, with the slow recruitment of pulmonologists, and the clinical assessment measures they can bring to bear. In addition to improving respiratory management and reducing morbidity and mortality for those with DM1, increased attention to respiratory function may reveal outcome measures useful in interventional clinical trials. In a slowly progressive, neuromuscular disease like DM1, it is important to consider all endpoint measures with the potential to report on meaningful changes within the normal duration of an interventional clinical trial—respiratory dysfunction measures may meet this need.

This last month has brought the publication of a new original cross-sectional study and a detailed review article, both focused on respiratory dysfunction in DM1.

Publication of a Multicenter, Cross-Sectional Study in DM1

Dr. Gabriella Silvestri (Gemelli IRCSS and Catholic University of the Sacred Heart) and colleagues have published an analysis of respiratory function in a cohort of 268 genetically confirmed adult patients with DM1. Spirometric examinations included forced expiratory volume (FEV1), forced vital capacity (FVC), FEV1/FVC, total lung capacity (TLC), vital capacity (VC), maximum inspiratory pressure (MIP), and maximum expiratory pressure (MEP). Indication for and compliance with non-invasive ventilation (NIV) was also determined.

The study cohort presented with a wide spectrum of skeletal muscle involvement as measured by MIRS score. MIP and MEP values established that respiratory muscle fatigue is the major determinant of restricted lung function. Nearly 52% of patients assessed exhibited a restrictive syndrome detected by spirometry, with frequent reports of excessive daytime sleepiness, snoring, exertion dyspnea, and rest dyspnea. Males were at higher risk for restrictive syndrome. 36% of the cohort met clinical criteria to initiate NIV, but only 57% of those were compliant with treatment. The prevalence of mexiletine use was too low in this cohort to assess its value for treating respiratory dysfunction in DM1.

Based on univariant analysis, FEV1, TLC, VC, MIP, and MEP differentiated restricted from non-restricted patients. Restricted patients were also distinguished by CTG repeat length, MIRS score, obstructive sleep apnea, conduction abnormalities, and prophylactic pacemaker implantation. By multivariant analysis, only MIRS and CTG length were independently predictive of restrictive ventilation.

Additional Insights from a Literature Review

A literature review of major databases (PubMed, Embase, Cochrane, etc.) formed the basis of a new review article on respiratory dysfunction in DM1 by Dr. Aaron Hawkins (Griffith University) and colleagues (Hawkins et al., 2019). The review was carried out in accordance with PRISMA guidance for systematic reviews—the initial 1,432 publications (appearing between 1964 and 2017) were culled to 45 articles classified as of “strong” quality.

Nearly all studies reported abnormal respiratory function values in DM1 with restricted ventilation—FVC and VC were the most commonly impaired measures. Restriction was associated with with alveolar hypoventilation, chronic hypercapnia, sleep apnea and sleep disordered breathing. In contrast to the findings of Rossi et al. (2019), respiratory dysfunction was associated with BMI; this and other issues (e.g., differences in MIP vs. MEP) are discussed in the Rossi paper.

The literature review showed divergence in whether there was an association between expanded CTG repeat length and respiratory dysfunction, as was found by Rossi et al. (2019). Meta data also was inconclusive as to whether there was a progression of respiratory abnormalities over time—this confusion strongly argues for careful, longitudinal studies of respiratory function in DM1 and a determination as to whether respiratory measures have value as clinical endpoints in interventional clinical trials. The majority of studies assessed in this review reported significant prevalence of sleep apnea, sleep disordered breathing, or significant overnight oxygen desaturations in DM1.

Finally, although there is considerable speculation in the literature, the authors of the review assert that there is not yet clarity as to the mechanisms (central vs. peripheral) of respiratory dysfunction in DM1. Better understanding of the natural history of respiratory dysfunction and its causes is needed to inform the design and conduct of clinical evaluations of candidate therapies for DM1.

References:

Prevalence and predictor factors of respiratory impairment in a large cohort of patients with Myotonic Dystrophy type 1 (DM1): A retrospective, cross sectional study.
Rossi S, Della Marca G, Ricci M, Perna A, Nicoletti TF, Brunetti V, Meleo E, Calvello M, Petrucci A, Antonini G, Bucci E, Licchelli L, Sancricca C, Massa R, Rastelli E, Botta A, Di Muzio A, Romano S, Garibaldi M, Silvestri G.
J Neurol Sci. 2019 Feb 7;399:118-124. doi: 10.1016/j.jns.2019.02.012. [Epub ahead of print]

Respiratory dysfunction in myotonic dystrophy type 1: A systematic review.
Hawkins AM, Hawkins CL, Abdul Razak K, Khoo TK, Tran K, Jackson RV.
Neuromuscul Disord. 2018 Dec 9. pii: S0960-8966(18)30449-8. doi: 10.1016/j.nmd.2018.12.002. [Epub ahead of print] Review.

DM1-associated declines in quality of life, including changes in daily activity and social participation, have become an important focus for both clinical research and patient care. Recognizing this burden of disease for both patients and caregivers, the MDF-led Consensus-Based Care Recommendations for Adults with Myotonic Dystrophy Type I includes a section on psychosocial management. Moreover, the recently published OPTIMISTIC study concluded that cognitive behavior therapy could improve patient socialization and capacity for participation in daily activities (Okkersen et al., 2018).

A Descriptive Longitudinal Study in DM1

An understanding of the progression of participation restrictions in relationship to disease course is essential to help maintain the quality of life of DM1 patients and their caregivers. Doctoral candidate, Kateri Raymond, Dr. Cynthia Gagnon (Université de Sherbrooke), and their colleagues have utilized their natural history database to publish a report on daily and social activities in patients living with DM1 (Raymond et al., 2019). 200 adults meeting eligibility criteria were enrolled and assessed at baseline and 9 years later; 115 completed both assessments. The primary instrument used to assess level of and changes in participation was a 77-item Assessment of Life Habits questionnaire within the Human Development Model – Disability Creation Process (HDM-DCP) framework—both daily activities (nutrition, fitness, personal care, communication, housing, and mobility) and social activities (responsibilities, interpersonal relationships, community life, education, employment, and recreation) were assessed.

Over the course of the study, a decline in participation was observed for the overall instrument score, as well as for nutrition, fitness, personal care, mobility, community life, and recreation domains. Increases in disease duration were associated with increased disruption of daily personal and social activities. 10% of the study population was severely affected, with declines in almost all of the participation scores.

Although the study revealed similar progression of restrictions in both genders, there was a trend toward greater decline in each domain for men. Comparison of the study cohort with an age-matched typical control group, showed similar instrument scores at baseline, but lower values in the DM1 cohort at follow-up. One limitation identified by the study authors was ‘survival bias,’ in that many older patients, typically those with greater disease severity, died between the baseline assessment and 9-year follow-up.

Data Utilization and Next Steps

The authors suggest that these data may support improved targeting by health care professionals and family members of DM1-linked declines in participation. Data from this study should also inform the design and evaluation of interventions to address this aspect of the burden of disease. Finally, the authors note the importance for future studies of taking into account both baseline participation status and use of shorter intervals between assessments.

References:

Cognitive behavioural therapy with optional graded exercise therapy in patients with severe fatigue with myotonic dystrophy type 1: a multicentre, single-blind, randomised trial.
Okkersen K, Jimenez-Moreno C, Wenninger S, Daidj F, Glennon J, Cumming S, Littleford R, Monckton DG, Lochmüller H, Catt M, Faber CG, Hapca A, Donnan PT, Gorman G, Bassez G, Schoser B, Knoop H, Treweek S, van Engelen BGM; OPTIMISTIC consortium.
Lancet Neurol. 2018 Aug;17(8):671-680. doi: 10.1016/S1474-4422(18)30203-5. Epub 2018 Jun 19.

Progressive decline in daily and social activities: A 9-year longitudinal study of participation in myotonic dystrophy type 1.
Raymond K, Levasseur M, Mathieu J, Gagnon C.
Arch Phys Med Rehabil. 2019 Mar 1. pii: S0003-9993(19)30148-0. doi: 10.1016/j.apmr.2019.01.022. [Epub ahead of print]

Dr. Melissa Dixon at the University of Utah Department of Pediatrics is conducting this study. Dr. Dixon is a psychologist whose clinical interests include understanding cognitive function and the psychological and neurobehavioral symptoms associated with neuromuscular disorders in children and adults.

She is also interested in understanding psychological distress in children with chronic medical illness. Her research focuses on longitudinal assessment of cognitive function and brain connectivity and function in children with neuromuscular disease. (Get more information on Dr. Dixon’s credentials.)

Study Purpose

Cognitive Function and Neuroimaging in Myotonic Dystrophy (IRB_001116528)
The purpose of this study is to learn more about how congenital myotonic dystrophy and childhood-onset myotonic dystrophy affects thinking, memory, attention, brain function, and how these processes change over time. Dr. Dixon and her research team want to find out how the brains of children and adolescents with CDM and chDM1 are connected together through fibers that are like cable connections called white matter tracts, and how these connections may change with time, be related to age, and differ from the brains of children and adolescents without CDM or chDM1.

Study Design and Eligibility Criteria

Male and female children and adolescents (age 7 to 16 years) diagnosed with CDM or chDM1 are invited to participate. Participation includes two visits to the University of Utah. All study procedures will be conducted during a single-day outpatient visit at baseline (year 1) and 12 months (year 2). Study procedures include the consent/assent process, physical exam, completing questionnaires about how myotonic dystrophy affects behavior and quality of life, neuropsychological testing, and a MRI. The testing is approximately 4-6 hours per visit.

To Follow Up and Enroll

If you interested in participating or learning more about this study, please contact Melissa Dixon, PhD, MS, Department of Pediatrics, University of Utah, 15 North 2030 East, Room 2160A, Salt Lake City, Utah 84112. Dr. Dixon is also available by phone (office) 801-585-7606 or by email.