Cognitive and Adaptive Development in Congenital/Childhood DM1

Published on Tue, 02/12/2019

A Gap in Understanding

The CNS consequences of early-onset DM1 represent critical components of the burden of disease. Cognitive impairment is considered to be one of the most common and challenging manifestations of childhood DM1. This patient group exhibits significant cognitive and adaptive impairments consistent with intellectual disability. Improving upon developmental knowledge of cognitive functioning and adaptive capability in this DM1 population would serve multiple purposes, including readiness for clinical trials, improving patient management, and aiding the transition from pediatric to adult medical care. To date, relatively modest attention has been given to these critical features of pediatric-onset DM1.

New Longitudinal Study of Congenital/Childhood DM1

Following up on their prior cross-sectional study (Ekström et al., 2009), Dr. Anne-Berit Ekström (Queen Silvia Children’s Hospital) and colleagues have completed a prospective longitudinal study of individuals with a genetic diagnosis of pediatric DM1 (Lindeblad et al., 2019), including severe congenital (n – 16), mild congenital (n = 17), and childhood (n = 18) subtypes. Mean elapsed time between initial assessment and follow-up was 8 2/3 years. The study focused on assessment of subject’s cognitive function (Wechsler scales) and adaptive skill (Vineland Adaptive Behavioral Scales).

Progression of intellectual disability in the severe CDM group was modest—19% showed decreased function over the study period, while 6% showed an improvement. Comparable intellectual function change values for the mild CDM and childhood groups were 35% decreased/12% improved and 22% decreased/22% improved, respectively. Regarding adaptive function, the research team observed longitudinal changes in scores reflecting the domains of communication, socialization, and daily living. Predictors of change over time were patient age and level of intellectual ability at the study's second time point. However, a critically important finding was that subjects did not exhibit an actual regression of any key adaptive skills over the ~8-year study period. By contrast, there was evidence for improvement in some aspects of adaptive functioning.

Patient management in congenital and childhood DM1 draws much from practices/experience in adult patients. Given the severity of the CNS phenotype in pediatric patients, advances in clinical practice must be informed by rigorous, longitudinal assessments of both the natural history of cognitive impairment as well as the adaptive capacity of these patients. A tendency toward decline in cognitive and adaptive ability was seen in severe and mild CDM, but not in childhood DM1. The researchers also offered insights into proper use and caveats of the Vineland Adaptive Behavioral Scales in pediatric DM1.

Taken together, this study highlights the slowed development of individuals living with congenital and childhood DM1, but also the lack of an absolute decline in cognitive and adaptive abilities over time. These data should aid design and implementation of CNS endpoints in interventional clinical trials and improvement of management of patients with pediatric-onset DM1. Going forward, measures capable of detecting changes over shorter timeframes should be explored in this patient population.


Cognition and adaptive skills in myotonic dystrophy type 1: a study of 55 individuals with congenital and childhood forms.
Ekström AB, Hakenäs-Plate L, Tulinius M, Wentz E.
Dev Med Child Neurol. 2009 Dec;51(12):982-90. doi: 10.1111/j.1469-8749.2009.03300.x. Epub 2009 Apr 21.

Cognitive and adaptive functioning in congenital and childhood forms of myotonic dystrophy type 1: a longitudinal study.
Lindeblad G, Kroksmark AK, Ekström AB.
Dev Med Child Neurol. 2019 Jan 31. doi: 10.1111/dmcn.14161. [Epub ahead of print]

A Novel Genome Editing Strategy for DM1

Published on Tue, 12/11/2018

Focusing on Genome Editing for DM1

MDF has reported out on a recently held workshop that focused on the opportunities and challenges of genome editing for DM1. The feedback received from that workshop went into the design of a Request for Applications, where MDF challenged academic investigators for innovative genome editing approaches to DM1. Applications from the RFA are now under review and award announcements are expected in early 2019. MDF continues to monitor new developments in genome editing technology in general, as well as the development of targeted strategies that are potentially applicable for DM1.

Disrupting Expanded CUG Repeats in DMPK Transcripts

There have now been several published studies that followed the strategy of removing the expanded CTG tract from DMPK. One concern that has emerged is the potential for increasing the repeat instability already inherent in pathological length CTG expansions (van Agtmaal et al., 2017). These authors did demonstrate that dual CRISPR/Cas9-cleavage at either side of the expanded repeat tract could achieve efficient editing and correct biomarkers of DM in DM1 patient myoblasts and in a mouse model. But, dual cuts can also produce a low rate of inversions at the targeted genomic locus. These earlier findings suggest that translation of a dual cleavage approach to DM1 patients would have to address both genome editing reagent delivery and inversion rate issues.

Dr. Guangbin Xia (University of New Mexico) and colleagues recently compared two distinct genome editing strategies for feasibility in addressing DM1: (1) the “traditional” targeted deletion of the expanded CTG repeats in the DMPK gene and (2) a novel targeted insertion of a polyadenylation signal in the 3’ UTR to block formation of toxic CUG expanded repeats. This work was published in Molecular Therapy (Wang et al., 2018).

The research team tested the dual cut approach in DM1 neural stem cells derived from patient iPSCs, using S. pyogenes Cas9 and guide RNAs targeted up- and down-stream of the DMPK CTG repeat tract. This approach yielded a deletion frequency of < 10%, but also resulted in further instability/expansion of CTG repeats in the neural stem cell model. Higher editing efficiency (~53%) was seen with S. aureus Cas9, but further studies showed that this approach yielded inversions of the expanded CTG repeats at a rate as high as ~23%.

By contrast, insertion of a polyadenylation signal upstream of the DMPK repeat tract, using a S. pyogenes Cas9 nickase system, resulted in premature termination of transcription upstream of the repeats and elimination of nuclear foci in a subset of DM1 iPSC-derived neural stem cells. In additional studies, the research team showed that the modified DMPK transcript was stable, underwent post-transcriptional processing, and was normally exported to the cytoplasm in neural stem cells and cardiomyocytes. Similar results were obtained in studies of DM1 iPSC-derived skeletal myocytes, including loss of nuclear foci and retained ability to differentiate into myofibers in vitro.

Lessons for Therapeutic Development in DM1?

Advancement of an in vivo genome editing approach for any systemic disease faces a series of challenges, many of which were documented in the MDF workshop referenced above. This latest study shows that an S. pyogenes Cas9-directed dual editing approach in DM1 iPSC-derived neural cells and cardiomyocytes may suffer from several drawbacks, including low editing efficiency and inability to be packaged into AAV delivery vectors (due to size constraints). S. aureus Cas9 does not have the same AAV packaging constraints and was more efficient in deletion of repeat tracts, but, in the hands of this team, produced inversions leading to DMPK transcripts with expanded CAG repeats; RAN translation of these CAG tracts was not tested in the study but represents a concern due to known protein product toxicity. These findings suggest that the specific genome editing strategies tested here lack potential to move forward as a candidate therapy for DM1.

Alternatively, the study team demonstrated the potential of altering transcription of DMPK CTG repeat tracts via upstream insertion of a polyadenylation signal. This strategy results in generation of a DMPK pre-mRNA from mutant genes that is lacking the expanded repeat tract and appears to be processed normally, thereby avoiding any potential (although not yet discerned) consequences of DMPK haploinsufficiency.


CRISPR/Cas9-Induced (CTG⋅CAG)n Repeat Instability in the Myotonic Dystrophy Type 1 Locus: Implications for Therapeutic Genome Editing.
van Agtmaal EL, André LM, Willemse M, Cumming SA, van Kessel IDG, van den Broek WJAA, Gourdon G, Furling D, Mouly V, Monckton DG, Wansink DG, Wieringa B.
Mol Ther. 2017 Jan 4;25(1):24-43. doi: 10.1016/j.ymthe.2016.10.014. Epub 2017 Jan 4.

Therapeutic Genome Editing for Myotonic Dystrophy Type 1 Using CRISPR/Cas9.
Wang Y, Hao L, Wang H, Santostefano K, Thapa A, Cleary J, Li H, Guo X, Terada N, Ashizawa T, Xia G.
Mol Ther. 2018 Sep 11. pii: S1525-0016(18)30444-1. doi: 10.1016/j.ymthe.2018.09.003. [Epub ahead of print]

Corticospinal Tract Involvement in DM1

Published on Tue, 11/06/2018

Value of CNS Imaging in DM1

Brain imaging has shown potential to assess progression of DM1 and thus may prove to be an important biomarker or outcome measure to assess candidate therapeutics targeted to the CNS. Consistent with neuropathologic assessments, a recent systematic review of such studies (Okkersen et al., 2017) concluded that DM1 causes broad structural changes in both white and gray matter with little evidence of specific regional involvement or sparing. This imaging data also has been correlated with individual patient cognitive or neuropsychological findings. PET and SPECT imaging did identify patterns of specificity in cortical region involvement. However, data have not yet been available to evaluate links between brain pathology and motor function in DM1. Understanding such structural/functional associations is critical to the design, conduct, and interpretation of interventional clinical trials targeting the CNS in DM1 patients.

Identification of Pathway-Specific Involvement and Linkage to Motor Function

To determine the relationship between cerebral cortical changes and motor function, Dr. Yongmin Chang (Kyungpook National University) and colleagues studied a cohort of 18 adult DM1 patients (mean CTG repeat length of 360) and 20 age-matched healthy controls using voxel-based quantitative MRI (including DTI) in conjunction with motor functional assessments (hand grip, 6-minute walk test (6MWT), and MRC sum score (MRCSS)).

The team showed that reductions in volume of specific gray matter regions correlated with CTG length, hand grip score, and disease duration. The broadest range of cortical involvement was seen in the correlation of hand grip score with pathology in specific gyri and sulci in frontal, parietal, and occipital lobes, including both precentral and postcentral gyri. DTI data established correlations between genetic and clinical parameters (CTG repeat length, MRCSS, and 6MWT) and abnormalities in the posterior limb of the internal capsule and middle section of the corticospinal tract. These white matter changes were accompanied by reduction in volume in both precentral and postcentral gyri, as measured by DTI—the authors argue that these data support a strong association between gray and white matter changes in DM1.

Overall, the research team noted strong relationships between the motor functioning of DM1 patients and abnormalities in the corticospinal tract, and specifically linked the degree of gray matter and descending motor tract changes, as measured by DTI parameters, to severity of hand grip performance. They reaffirmed prior calls for longitudinal imaging/clinical studies to better characterize the natural history of CNS changes and improve clinical trial readiness in DM1.


Brain imaging in myotonic dystrophy type 1: A systematic review.
Okkersen K, Monckton DG, Le N, Tuladhar AM, Raaphorst J, van Engelen BGM.
Neurology. 2017 Aug 2. pii: 10.1212/WNL.0000000000004300. doi: 10.1212/WNL.0000000000004300. [Epub ahead of print] Review.

Diffusion tensor imaging and voxel-based morphometry reveal corticospinal tract involvement in the motor dysfunction of adult-onset myotonic dystrophy type 1.
Park JS, Song H, Jang KE, Cha H, Lee SH, Hwang SK, Park D, Lee HJ, Kim JY, Chang Y.
Sci Rep. 2018 Oct 22;8(1):15592. doi: 10.1038/s41598-018-34048-9.

Challenges in Assessing the CNS in DM1

Published on Tue, 11/06/2018

Towards CNS Endpoints for Clinical Trials in DM1

CNS deficits represent an important component of the DM1 phenotype and play a key role in overall burden of disease. Yet, complex brain functional assessments may be complicated by the interaction of peripheral and central contributors, so it is important to understand any limitations imposed by such interactions.

The MDF Research News previously highlighted an important series of DM-focused reviews in Frontiers of Neurology. A new original research article in the same journal, by Mark Hamilton (Queen Elizabeth University Hospital, Glasgow) and colleagues (Hamilton et al., 2018), offers an important new perspective on developing clinical outcome measures for assessing CNS function in clinical studies of and interventional trials in DM1.

Deficits of Patient Motor and Cognitive Insight May Confound CNS Outcome Measures

The Glasgow-based research team assessed 45 adult or late-onset DM1 subjects and 20 controls using a battery of neuropsychological and symptomatic instruments, as well as assessments of CNS structure (by MRI) and CTG repeat length. Neuropsychological tests followed OMMYD recommendations, including Stroop test (controlled for reading speed), Trail Making tests (controlled for speed), Delis-Kaplan Executive Function System, and Block Design test. Study subjects also completed the Edinburgh Cognitive and Behavioral ALS Screen and the FAS controlled oral word association test. Self-reported instruments used assessed fatigue, daytime sleepiness, depression, pain, dysexecutive symptoms, as well as MDHI and DM1-ActivC. The overall test battery appeared to be well-tolerated by DM1 subjects.

Neuropsychological testing assessing multiple domains identified impairment in function of DM1 patients versus controls, although correction for reading or motor speed mitigated the magnitude of some of these differences. The researchers highlighted the impact that dysarthria and upper limb weakness could have upon some neuropsychological measures.

Self-reported assessments of cognitive function obtained data consistent with prior reports—that DM1 patients reported greater fatigue, lower mood, greater levels of pain, and executive dysfunction. However, findings of lower mood (including depression) strongly correlated with increased self-reporting of cognitive deficits. MRI gray and white matter measures correlated with various neuropsychological findings.

Selecting CNS Outcome Measures for DM1

The researchers concluded that muscle weakness interacts with and can potentially compromise the interpretation of data from cognitive assessment tools commonly used in studies of DM1. Moreover, they show that patient-reported assessments are subject to influence of mood and insight. The potential for peripheral physical limitations, mood, and/or insight (i.e., disease awareness) to influence CNS assessments should be considered in the choice of instruments for natural history studies or interventional clinical trials in DM1. Instruments not subject to limitations, or with known limitations that can be controlled for, of mood, basic speed of information processing or manual dexterity or dysarthria may be of greatest value in assessing CNS function in this multi-system disorder.


Outcome Measures for Central Nervous System Evaluation in Myotonic Dystrophy Type 1 May Be Confounded by Deficits in Motor Function or Insight.
Hamilton MJ, McLean J, Cumming S, Ballantyne B, McGhie J, Jampana R, Longman C, Evans JJ, Monckton DG, Farrugia ME.
Front Neurol. 2018 Oct 2;9:780. doi: 10.3389/fneur.2018.00780. eCollection 2018.

What We Do (and Don’t) Know About Cognitive Function in DM1

Published on Thu, 11/01/2018

The Gap in Natural History Data

Cognitive impairment is a substantial unmet need in DM1. Increasingly, drug companies are aware that targeting therapies to the brain will be essential to addressing the overall burden of disease. Yet, therapy development efforts in other types of muscular dystrophy tell us that it is critical to understand disease natural history in order to facilitate efficient and effective clinical trials. Many of the studies to date that have characterized neuropsychological function in DM1 are both limited in scope and underpowered. As a consequence, it currently is unclear whether DM1 is characterized by a global pattern of cognitive deficits or whether specific functions are affected. The key question is—how do we best utilize available resources to construct a natural history of cognitive dysfunction in DM1 that is sufficient to support interventional trial outcome measure selection and to improve patient care?

A Path Forward Through Meta-Analysis

Kees Okkersen and colleagues at Radboud University Medical Center and the University of Amsterdam recently characterized the cognitive profile of DM1 patients through a meta-analysis of psychological data from 40 eligible studies identified in Embase, Medline, and PsychInfo (totaling 1122 patients and 952 controls). Eligible studies employed a large battery of neuropsychological tests. The analytic approach was to characterize the individual cognitive tests as informative of specific cognitive domains and then determine the level of effect from meta-data across each of 12 cognitive domains.

Although effect size varied, performance of DM1 subjects versus controls was impaired across all cognitive domains. Domains most heavily impacted by DM1 included global cognition, intelligence, visual memory, visuospatial perception, visuoconstruction, psychomotor speed, and social cognition. Analyses suggested that conclusions from the pooled data were not influenced by either publication bias or any inordinate impact of single studies.

Current Status of Understanding DM1 Cognitive Profiles

While the research team concluded, based on meta-analysis of a large cohort and the preponderance of evidence, that DM1 is characterized by significant deficits across all cognitive domains, they noted that heterogeneity is the hallmark of this patient group. Detection of a large effect size in any specific cognitive domain could either be due to consistent deficits across DM1 patients, substantial involvement of the specific domain among a subset of patients, or acute sensitivity of the neuropsychological tests that inform that domain. A recent meta-analysis of neuroimaging studies in DM1 validated a similar pattern of widespread and heterogeneous involvement in CNS.

While some of the neuropsychological tests assessed by the research team showed substantial levels of effect and consistency (e.g., Rey-Osterrieth Complex Figure, Wechsler Digit Symbol Coding, and Raven Progressive Matrices), these tests readout on multiple cognitive functions. The research team argued that future studies should include specific, rather than broad, cognitive assessments, and concluded that meta-analyses of the often small cohorts in individual DM1 studies can better elucidate CNS mechanisms as well as inform best practices for future patient assessment.


The cognitive profile of myotonic dystrophy type 1: A systematic review and meta-analysis.
Okkersen K, Buskes M, Groenewoud J, Kessels RPC, Knoop H, van Engelen B, Raaphorst J.
Cortex. 2017 Aug 16;95:143-155. doi: 10.1016/j.cortex.2017.08.008. [Epub ahead of print] Review.

Non-Invasive Biomarkers for DM1

Published on Tue, 10/16/2018

Pharmacodynamic Biomarkers and DM

There is now strong support for the concept that a panel of splicing events may serve as a pharmacodynamic biomarker for go/no go decisions in drug development for DM1. Data establishing splicing event sensitivity to free MBNL levels has converged with the natural history of alternative splicing patterns in DM patients to yield a subset of splicing events with the sensitivity and reproducibility to evaluate candidate therapeutics in early stage clinical trials. Quantitative pharmacodynamic biomarkers are invaluable in de-risking industry drug discovery and development, as they facilitate early stage assessment of molecular target engagement and modulation and may inform dose ranging studies. The only caveat is the dependence of these measures upon repeated muscle biopsies (a risk reduced, but not eliminated, by more tolerable needle biopsies). The identification and validation of a non-invasive assay of patient splicing status would be a valuable step forward for clinical trials in DM.

Early Support for a Non-Invasive Biomarker for DM1

Dr. Thurman Wheeler and colleagues at Massachusetts General, Harvard Medical, and Boston Children’s have explored the concept that a subset of extracellular RNAs (exRNAs) released into blood or urine may: (a) reflect alternative splicing status in DM-affected tissues and (b) thereby serve as an easily accessible pharmacodynamic biomarker platform for DM1 (Antoury et al., 2018). These studies were supported in part by a grant to facilitate “Development of Biomarkers for MDF Studies” from MDF.

The research team initially found that > 30 transcripts that are alternatively spliced in DM1 muscle biopsies were detectable in human blood and urine samples; follow-up studies confirmed the presence of RNAs in extracellular fluids/exosomal particles. Normalized DMPK expression levels in urine from DM1 patients, by droplet digital PCR, were ~50% of unaffected controls. Assessments of DM1-established alternative splicing events showed that a subset (10/33) also occurred in urine exRNA, including being conserved in longitudinal (6-26 month) studies of the same patients. Assessments of alternative splicing events in blood exRNA did not yield the same value.

Using principal component analysis of 10 alternative splicing events observed in urine exRNA, the research team then generated a putative composite biomarker panel for DM1. The ensuing predictive model of alternative splicing in DM1 proved to be 100% accurate in comparisons of training and independent validation data sets to distinguish DM1 from unaffected controls and in distinguishing disease status of subsequently enrolled subjects. The research team also linked alternative splicing patterns in urine exRNA to variation in DM1 clinical phenotypes, suggesting that modeling of urine exRNA alternative splicing may allow both the tracking of disease progression and the impact of candidate therapeutics.

Finally, to address questions as to the source of urine exRNA, the team assessed alternative splicing in urinary tract cells of DM1 mouse models (the ubiquitous Mbnl1 ko and the tissue-specific HSALR). While kidney and bladder cells of the Mbnl1 ko reflected patterns in skeletal muscle, assessments of the same tissues in the HSALR showed no differences from control mice. These data strongly suggested that the exRNAs assessed in urine reflect exosomes released from urinary tract cells. Some of the alternatively spliced transcripts in urine exRNA also were shown to be altered by antisense oligonucleotide drugs previously shown to correct splicing patterns in DM1 mouse models. The research team’s parallel studies of Duchenne muscular dystrophy also supported the concept that urine exRNA has utility as a pharmacodynamic biomarker in drug intervention studies.

Towards a Non-Invasive Biomarker for DM1

Taken together, these data provide compelling proof of concept that a panel of alternative splicing events assessed in urine may serve as a robust composite biomarker of DM1 progression and as a tool for assessment of candidate therapeutics. A non-invasive biomarker such as this would greatly extend the ability to perform repeated measurements in longitudinal natural history studies (as a disease progression biomarker) and in interventional clinical trials (as patient stratification and pharmacodynamic biomarkers), including making assessment of pediatric DM1 patient cohorts feasible. Although it is not essential to formally qualify a biomarker, existing regulatory agency guidance documents (see References below) provide a valuable evidentiary framework for moving non-invasive biomarker work towards an accepted clinical tool for DM1.


Analysis of extracellular mRNA in human urine reveals splice variant biomarkers of muscular dystrophies.
Antoury L, Hu N, Balaj L, Das S, Georghiou S, Darras B, Clark T, Breakefield XO, Wheeler TM.
Nat Commun. 2018 Sep 25;9(1):3906. doi: 10.1038/s41467-018-06206-0.

Framework for Defining Evidentiary Criteria for Biomarker Qualification. Evidentiary Criteria Writing Group.

Guidance for Industry and FDA Staff: Qualification Process for Drug Development Tools.

Review: What Have We Learned About RAN Translation?

Published on Tue, 10/16/2018

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.


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]

MDF Releases DM1 Care Recommendations

Published on Tue, 09/25/2018

SAN FRANCISCO, CA (September 25, 2018): MDF is pleased to announce the publication of the first-ever Consensus-based Care Recommendations for Adults with Myotonic Dystrophy Type 1. The Quick Reference Guide to the full Consensus-based Care Recommendations was published in Neurology Clinical Practice online September 13. The article will be published in the NCP print version in October. MDF is working internationally to help ensure that the care recommendations are disseminated and adopted broadly.

Currently no evidence-based guideline exists to establish a standard of care for myotonic dystrophy, and a comprehensive care guideline will not be available until a number of studies are conducted to establish the rigorous evidence needed to create one. As a result, patients report difficulty accessing quality care and informed clinicians. Sixty-six clinicians highly experienced in the care of people living with myotonic dystrophy type 1 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.

Consensus-based Care Recommendations for Adults with Myotonic Dystrophy Type 1 Resources:

Update: DM1 Care Recommendations are now available in German, Italian, French, French-Canadian, Spanish, Swedish & Georgian! Download the recommendations 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, DM may affect as many as 1:2,550 people worldwide, 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.

Furamidine Mechanism of Action in DM1

Published on Tue, 09/25/2018

Small Molecule Approaches to DM1

A variety of small molecules have been evaluated in models of DM1 as putative therapeutics. Small molecules have the advantage of chemical optimization of drug-like traits, including blood-brain barrier permeability, and thus are attractive for multisystemic disorders like DM1.

Prior studies of the small molecule, pentamidine, and its analogs showed efficacy in restoring splicing defects in DM1 cells and animal models and suggested that the mechanism of action was binding to and inhibition of transcription of the expanded repeat transcript (Coonrod et al., 2013). Chemical modification/analysis of structure-activity relationships of the pentamidine backbone led to identification of the more efficacious and less toxic molecule, furamidine (Siboni et al., 2015).

In evaluation of compounds for marketing approval, FDA and other regulatory agencies regard understanding of the molecular target and mechanism of action as important factors in establishing confidence in the efficacy and safety of candidate therapeutics. Thus, mechanistic studies, using cell and animal models in preclinical studies and molecular markers in clinical trials, represent important steps in evaluation of candidate therapeutics for DM.

Mechanism of Action of Furamidine

Dr. Andy Berglund (University of Florida) and colleagues have built upon their prior work with pentamidine analogs to examine the mechanisms of action (MOA) of furamidine in DM1 models (Jenquin et al., 2018). Dr. Leslie Coonrod, a former MDF Postdoctoral Fellow, was a coauthor on the publication. Information on the structure, properties, vendors, publications, and patents around furamidine is available in the public chemical database, PubChem. Overall the research team reported promiscuous activity for furamidine, potentially impacting multiple pathways in restoring the splicopathy that characterizes DM1.

Furamidine was evaluated in HSALR mice for safety and impact upon gene expression and splicing and in DM1 myotubes for safety and impact on splicing. Head to head comparisons were made with another pentamidine analog, heptamidine.

In the HSALR model, furamidine (daily, over 7 days) reduced HSA transgene levels and rescued multiple splicing events, suggesting binding of CTG•CAG expanded repeats and transcription inhibition as an important MOA for the drug. In comparison to heptamidine, furamidine rescued more splicing events in the mouse model. Evaluation of furamidine in a patient myoblast line (~2900 repeats) also showed partial rescue of the characteristic mis-splicing pattern. Although dose-limiting toxicity was seen in the cell line studies, efficacy on splicing was obtain at 10x and greater multiples below toxic dose—this was confirmed in follow-up cell toxicity assays. However, in the cell-based assays and in contrast to the HSALR data, the impact of the drug on CUG RNA levels was modest.

In additional studies with the human DM1 cell lines, data suggest that furamidine reduces nuclear foci and disrupts the binding of MBNL1 to expanded CUG repeats. Yet, at higher concentrations, furamidine exacerbated mis-splicing while producing a significant reduction in nuclear foci—a finding that the research team first interpreted as drug-induced reduction of MBNL levels; this hypothesis was not confirmed as transcript and protein levels were increased by furamidine treatment.

Assessing a Complex MOA

Taken together, furamidine exhibited a complex MOA, with both similar and discordant findings in cell vs. animal models and across a 100-fold dosing range studied by the research team. They conclude that its primary MOA in the HSALR mouse appears to be inhibition of transcription of the expanded repeat, but cannot exclude disruption of MBNL from expanded CUG repeat binding. By contrast, the team posits that increased levels of MBNL proteins and furamidine-induced disruption of the MBNL–CUG complex represent the primary MOA for splicing rescue in patient cell lines. Differences in the pathways engaged by the effective drug concentrations at the target tissues (i.e., tissue bioavailability/exposure) may, at least in part, explain differences in MOA findings in the two models.


Reducing levels of toxic RNA with small molecules.
Coonrod LA, Nakamori M, Wang W, Carrell S, Hilton CL, Bodner MJ, Siboni RB, Docter AG, Haley MM, Thornton CA, Berglund JA.
ACS Chem Biol. 2013 Nov 15;8(11):2528-37. doi: 10.1021/cb400431f. Epub 2013 Sep 27.

Biological Efficacy and Toxicity of Diamidines in Myotonic Dystrophy Type 1 Models.
Siboni RB, Bodner MJ, Khalifa MM, Docter AG, Choi JY, Nakamori M, Haley MM, Berglund JA.
J Med Chem. 2015 Aug 13;58(15):5770-80. doi: 10.1021/acs.jmedchem.5b00356. Epub 2015 Jul 21.

Furamidine rescues myotonic dystrophy type I associated mis-splicing through multiple mechanisms.
Jenquin JR, Coonrod LA, Silverglate QA, Pellitier NA, Hale MA, Xia G, Nakamori M, Berglund JA.
ACS Chem Biol. 2018 Aug 17. doi: 10.1021/acschembio.8b00646. [Epub ahead of print]

Determinants of Respiratory Function in DM1

Published on Thu, 09/06/2018

Respiratory dysfunction is a major contributor to morbidity and mortality in DM. An evidence-based approach is essential to understanding the underlying risk factors and appropriate actions in management of respiratory status in DM patients. Such an understanding of the natural history and relative value of interventions for respiratory dysfunction is also essential in the design of interventional clinical trials. Careful natural history studies are the path forward to improved clinical care and informed clinical trials.

Understanding the Risk Factors Behind Respiratory Function in DM1

Dr. Ghilas Boussaïd (Hôpital Raymond Poincaré, Garches, France) and colleagues have evaluated the relationship of DM1 genotype and other respiratory function determinants in the progression of respiratory dysfunction. Their prospective observational study provided data on 283 subjects, followed for five years or until loss to follow-up, for regression modeling of functional changes over time.

Respiratory function parameters associated with CTG repeat length were determined via a multivariate linear regression analysis. Higher peak cough impairment and lower vital capacity and maximum inspiratory pressure were associated with longer CTG repeats. Observed decline over time in vital capacity was associated with longer CTG repeats, older baseline age, and higher baseline BMI values. Longer CTG repeats also correlated with larger decreases in maximum inspiratory pressure, maximum expiratory pressure, and increased risk of death. Very long repeats (>1000) were associated with annual vital capacity declines as high as 36%--these rapid declines flag adult CDM patients for very close respiratory monitoring.

Impact of Respiratory Care

Non-invasive ventilation was in use for 13% of study subjects at baseline and was initiated in 41% of the remaining subjects during follow-up. Decision to initiate non-invasive ventilation was associated with lower peak cough flow after accounting for age and arterial CO2 tension. Non-invasive ventilation improved vital capacity. The authors posit that closer respiratory follow-up is warranted for patients with long CTG repeats and/or high BMI. They also noted the compliance issues with non-invasive ventilation in DM1 patients and highlighted the importance of considering sociological and psychological variables in future studies of respiratory function and non-invasive ventilation.

Taken together, the authors established that long CTG repeats are associated with a more severe respiratory phenotype and faster functional decline. Obesity was also identified as an important risk factor for respiratory status. They did not identify an association between non-invasive ventilation and many measure of improvements in respiratory status, but concede limitations in this study. Overall, starting early with regular peak cough flow assessments and following patients closely, particularly in adults with CDM, were seen as an effective means of reducing risks of respiratory dysfunction.


Genotype and other determinants of respiratory function in myotonic dystrophy type 1.
Boussaïd G, Wahbi K, Laforet P, Eymard B, Stojkovic T, Behin A, Djillali A, Orlikowski D, Prigent H, Lofaso F.
Neuromuscul Disord. 2017 Dec 26. pii: S0960-8966(17)30524-2. doi: 10.1016/j.nmd.2017.12.011. [Epub ahead of print]