Research

New Perspectives on Respiratory Involvement in DM1

Published on Tue, 03/19/2019

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.

Decline in Daily and Social Activities in DM1

Published on Tue, 03/19/2019

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]

 

New Research Study on Cognitive Function and Neuroimaging CDM

Published on Thu, 03/07/2019

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.

Characterizing Pediatric DM1

Published on Tue, 02/12/2019

The Optimal Cohort for Clinical Trials in DM1

Choice of a cohort for interventional clinical trials of a candidate therapy can be challenging for any neuromuscular disease. For diseases with onset at a variety of life stages, comprehensive understanding of natural history of each patient subgroup is critical in being able to define biomarkers and endpoint measures capable of assessing safety and efficacy within the normal duration of a clinical trial. Such information, in turn, informs the choice of an appropriate trial cohort that offers the best opportunity to assess the candidate drug or biologic.

For diseases like SMA and Pompe disease, the rapid progression and clear endpoints seen for the youngest patient subgroups can lend clarity to clinical trials and, indeed, choosing these subgroups may accelerate drug discovery, development, and regulatory approval. Alternatively, disease properties, current level of understanding, and/or regulatory considerations (see FDA guidances for pediatric studies) may mandate choice of an adult cohort for the initial clinical trials.

Experience to date in DM1/CDM suggests that choice of study cohort for interventional clinical trials remains an unresolved issue—sufficiently thorough and well-powered natural history studies can clarify this decision. An adequate understanding of natural history also has value as a fundamental baseline for the DM field to move from current experienced-based to potentially more effective evidence-based patient management.

Better Resolution on the Natural History of Pediatric DM1

Data in the French DM-Scope registry (currently including 2,697 patients with genetically confirmed DM1) has already been used to achieve important advancements in understanding of DM1 (De Antonio et al., 2016; Dougan et al., 2016), particularly in the refinement of DM1 subgroups and gender differences. Such a registry of well-characterized study subjects offers a multitude of opportunities to understand the disease; mechanisms have been established for access to registry data by qualified individuals.

In a new examination of data in DM-Scope, Dr. Emmanuelle Lagrue (CHRU Tours and INSERM) and colleagues report out in Neurology on the natural history of 314 children with pediatric-onset DM1 (Lagrue et al., 2019). The cohort was 52% female and included children with congenital- (55%), infantile- (31%), and juvenile-onset (14%) forms. Although phenotypic assessments were broad spectrum, neurodevelopmental consequences received particularly detailed attention from the study team.

CTG repeat size ranged from 74 to 3,000 and generally correlated with severity. Hypotheses have been offered regarding the primarily maternal transmission of CDM (Barbé et al., 2017); in the current study, paternal transmission in CDM was higher than anticipated (13%), but increased in the other pediatric DM1 subtypes. As previously reported for adult DM1 subtypes (De Antonio et al., 2016), the pediatric cohort exhibited a phenotypic continuum, but with highly prevalent neurodevelopmental symptoms. Most common among these were cognitive slowing (83%), attention deficit (64%), written (64%) and spoken (63%) language disorders, difficulties in fine motor skills (60%), and dyspraxia (47%). 5% were on the autism spectrum.

Musculoskeletal impairment was considered to be mild (proximal weakness in ~12%, primarily in CDM; inability to walk seen only in CDM (but <4%)), and clinical myotonia observed in 66% of children. Cardiorespiratory impairment was also not highly prevalent (15% exhibited cardiac abnormalities and 27% altered pulmonary function), but when present could be life-threatening. The research team also described a constellation of other organ system involvement, from cataracts (7%, mainly in CDM) to GI disorders.

Moving Toward Evidence Based Medicine for DM1

In a process facilitated by MDF, consensus-based care recommendations have been published for adult DM1 (Ashizawa et al., 2018). None have yet been published for pediatric DM1. As yet, the care recommendations are based upon experiences of professionals who most frequently see DM1 patients, and there is not yet a body of work on which to generate evidence-based standards of care. Natural history studies, such as that provided by the DM-Scope team here, provide important data to guide the type and timing of medical specialty engagement/clinical examinations that patients should receive. The pedDM-Scope study is cross-sectional and longitudinal studies of this patient population are likely to improve both clinical trial readiness and clinical management of patients living with pediatric DM1.

References:

Unravelling the myotonic dystrophy type 1 clinical spectrum: A systematic registry-based study with implications for disease classification.
De Antonio M, Dogan C, Hamroun D, Mati M, Zerrouki S, Eymard B, Katsahian S, Bassez G; French Myotonic Dystrophy Clinical Network.
Rev Neurol (Paris). 2016 Oct;172(10):572-580. doi: 10.1016/j.neurol.2016.08.003. Epub 2016 Sep 21.

Gender as a Modifying Factor Influencing Myotonic Dystrophy Type 1 Phenotype Severity and Mortality: A Nationwide Multiple Databases Cross-Sectional Observational Study.
Dogan C, De Antonio M, Hamroun D, Varet H, Fabbro M, Rougier F, Amarof K, Arne Bes MC, Bedat-Millet AL, Behin A, Bellance R, Bouhour F, Boutte C, Boyer F, Campana-Salort E, Chapon F, Cintas P, Desnuelle C, Deschamps R, Drouin-Garraud V, Ferrer X, Gervais-Bernard H, Ghorab K, Laforet P, Magot A, Magy L, Menard D, Minot MC, Nadaj-Pakleza A, Pellieux S, Pereon Y, Preudhomme M, Pouget J, Sacconi S, Sole G, Stojkovich T, Tiffreau V, Urtizberea A, Vial C, Zagnoli F, Caranhac G, Bourlier C, Riviere G, Geille A, Gherardi RK, Eymard B, Puymirat J, Katsahian S, Bassez G.
PLoS One. 2016 Feb 5;11(2):e0148264. doi: 10.1371/journal.pone.0148264. eCollection 2016.

A large multicenter study of pediatric myotonic dystrophy type 1 for evidence-based management.
Lagrue E, Dogan C, De Antonio M, Audic F, Bach N, Barnerias C, Bellance R, Cances C, Chabrol B, Cuisset JM, Desguerre I, Durigneux J, Espil C, Fradin M, Héron D, Isapof A, Jacquin-Piques A, Journel H, Laroche-Raynaud C, Laugel V, Magot A, Manel V, Mayer M, Péréon Y, Perrier-Boeswillald J, Peudenier S, Quijano-Roy S, Ragot-Mandry S, Richelme C, Rivier F, Sabouraud P, Sarret C, Testard H, Vanhulle C, Walther-Louvier U, Gherardi R, Hamroun D, Bassez G.
Neurology. 2019 Jan 18. pii: 10.1212/WNL.0000000000006948. doi: 10.1212/WNL.0000000000006948. [Epub ahead of print]

CpG Methylation, a Parent-of-Origin Effect for Maternal-Biased Transmission of Congenital Myotonic Dystrophy.
Barbé L, Lanni S, López-Castel A, Franck S, Spits C, Keymolen K, Seneca S, Tomé S, Miron I, Letourneau J, Liang M, Choufani S, Weksberg R, Wilson MD, Sedlacek Z, Gagnon C, Musova Z, Chitayat D, Shannon P, Mathieu J, Sermon K, Pearson CE.
Am J Hum Genet. 2017 Mar 2;100(3):488-505. doi: 10.1016/j.ajhg.2017.01.033.

Consensus-based care recommendations for adults with myotonic dystrophy type 1.
Ashizawa T, Gagnon C, Groh WJ, Gutmann L, Johnson NE, Meola G, Moxley R 3rd, Pandya S, Rogers MT, Simpson E, Angeard N, Bassez G, Berggren KN, Bhakta D, Bozzali M, Broderick A, Byrne JLB, Campbell C, Cup E, Day JW, De Mattia E, Duboc D, Duong T, Eichinger K, Ekstrom AB, van Engelen B, Esparis B, Eymard B, Ferschl M, Gadalla SM, Gallais B, Goodglick T, Heatwole C, Hilbert J, Holland V, Kierkegaard M, Koopman WJ, Lane K, Maas D, Mankodi A, Mathews KD, Monckton DG, Moser D, Nazarian S, Nguyen L, Nopoulos P, Petty R, Phetteplace J, Puymirat J, Raman S, Richer L, Roma E, Sampson J, Sansone V, Schoser B, Sterling L, Statland J, Subramony SH, Tian C, Trujillo C, Tomaselli G, Turner C, Venance S, Verma A, White M, Winblad S.
Neurol Clin Pract. 2018 Dec;8(6):507-520. doi: 10.1212/CPJ.0000000000000531.

Health-Related Quality of Life in DM1

Published on Tue, 02/12/2019

The U.S. Center for Disease Control and Prevention (CDC) defines health-related quality of life (HRQoL) as “an individual’s or a group’s perceived physical and mental health over time.” The various tools used to measure HRQoL get at physical, mental, emotional, and social functioning. HRQoL assessments can, in turn, yield important burden of disease information on the quality of relationships, expressed emotions and resilience, realization of potential, and level of overall satisfaction with life. As with any clinical assessment tool, issues of sensitivity, reproducibility, and validity for use in a given population are important to discern.

Health-Related Quality of Life in DM1

A new report in the journal, The Patient—Patient-Centered Outcomes Research, undertook a literature review of HRQoL in adult-onset DM1, focusing on 19 publications meeting selection criteria. The resulting burden of disease conclusions should help inform patient families, researchers, drug developers, public policy experts, and regulatory authorities.

The DM1 HRQoL study was undertaken by Dr. Erik Landfeldt (Karolinska Institutet and ICON plc) and colleagues (Landfeldt et al., 2019). The team sought to determine the geographic focus of and instruments used in studies of adult-onset DM1 HRQoL, and to report a synthesis of findings from a meta-analysis of eligible studies. Study search and selection criteria followed established guidelines for such analyses (PRISMA), starting with all articles found in Embase, Web of Science, and PubMed and filtering based upon publication year (since 2000), language (English), cohort size (excluding reports of ≤ 5 subjects), and publication type (excluding reviews and op/eds). Starting with 266 unique publications from keyword-based literature searches, 19 articles met criteria for inclusion in the meta-analysis.

The geographic focus of the DM1 HRQoL studies included 8 countries in Europe, North America, or South America. The instrument used by most was SF-36 (n = 19), with INQoL (n = 6) and Cantril’s Ladder (n = 1) also used.

The majority of studies reported that all SF-36 subscale scores were lower in adult-onset DM1 than in control populations (2 studies reported lower physical health, but not mental health, scores). Considerable cross-study heterogeneity in mean reported values, subtending much of the 0-100 SF-36 range, was observed for many subscale scores—including physical functioning (scores ranged from 38 to 82), role physical (from 22 to 95), and role emotional (from 28 to 96). Similar heterogeneity in reported scores was seen for studies using the INQoL instrument.

Finally, the Cantril’s Ladder used in one study evaluated here reported a mean HRQoL score that was not different from that of health relatives or unaffected family members, suggesting it was the least useful measure for this purpose.

Conclusions

Although two instruments (SF-36 and INQoL) have been used extensively in adult-onset DM1, a concerning level of heterogeneity in mean scores was seen across the 19 studies used in the analysis reported here. Whether this reflects variability in the cohorts evaluated in the different studies or flaws in the HRQoL assessment instruments is unclear. A deeper analysis of the patient populations assessed in individual studies (e.g., assessing, when possible, the placement of patients on the DM1 spectrum as identified by De Antonio et al., 2016) might yield underlying explanations for the high degree of heterogeneity. The study team also suggests the operation of demographic, cultural, or instrument psychometric properties as explanations for the high degree of variability. Questions about whether these instruments had been sufficiently validated for use in DM1 must be answered if they are to be of value for natural history studies or interventional clinical trials.

References:

Health-Related Quality of Life in Patients with Adult-Onset Myotonic Dystrophy Type 1: A Systematic Review.
Landfeldt E, Edström J, Jimenez-Moreno C, van Engelen BGM, Kirschner J, Lochmüller H.
Patient. 2019 Feb 4. doi: 10.1007/s40271-019-00357-y. [Epub ahead of print] Review.

Unravelling the myotonic dystrophy type 1 clinical spectrum: A systematic registry-based study with implications for disease classification.
De Antonio M, Dogan C, Hamroun D, Mati M, Zerrouki S, Eymard B, Katsahian S, Bassez G; French Myotonic Dystrophy Clinical Network.
Rev Neurol (Paris). 2016 Oct;172(10):572-580. doi: 10.1016/j.neurol.2016.08.003. Epub 2016 Sep 21.

Publication of Christopher Project Report

Published on Tue, 02/12/2019

The Christopher Project is a partnership between patient advocacy organizations, health care providers/academic medical centers, and patients living with myotonic dystrophy, designed to determine North American patient and family member experiences with DM. Results from the cross-sectional, survey-based study have recently been published in Muscle and Nerve (Hagerman et al., 2019). The affected individual survey included 156 questions assessing DM demographics, diagnosis, symptoms, daily activity challenges, healthcare, insurance, treatments and interventions, and access to information and resources. The family member/caretaker survey included 97 questions regarding the symptoms and daily life activities of their family member or person under their care. DM type was self-identified. Results were reported from 1,180 patients and 402 family members/caregivers who responded to the survey.

Taken together, data from the Christopher Project helps to define unmet needs of patients living with DM and their family members or caretakers. These data are vital for development and design of clinical trials, clinical management strategies, and public health care policy.

Reference:

The Myotonic Dystrophy Experience: A North American Cross-Sectional Study.
Hagerman KA, Howe SJ, Heatwole CE; Christopher Project Reference Group.
Muscle Nerve. 2019 Jan 24. doi: 10.1002/mus.26420. [Epub ahead of print]

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.

References:

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]

Lessons Learned: Targeting RNA as a Therapeutic Strategy

Published on Tue, 12/11/2018

RNA Becoming a Mainstream Therapeutic Target?

The term “RNA World” has been attributed to the biochemist and Nobel laureate, Walter Gilbert, circa 1986. At the time, the reference was to a hypothetical stage in the origin of life, where proteins were not the primary implementers of the genetic code and RNA mediated the functions of early life forms. Since then, there has been nearly exponential growth in understanding of a broader RNA World—just some of the Nobel-level recognition for these discoveries include Sidney Altman and Tom Cech (1986) for work on the catalytic properties of RNA and Andrew Fire and Craig Mello (2006) for discovery of RNAi. Understanding the diversity in types and processing of RNA has yielded compelling targets for drug discovery. Perhaps the most noteworthy, recent advance is the development of the antisense oligonucleotide drug, Spinraza, which has produced dramatic improvements in SMA patients by altering splicing of the SMN2 gene. For DM1, much hope has been placed on the strategy of antisense oligo-driven RNase degradation of expanded repeat DMPK transcripts.

Targeting RNA with Small Molecule Drugs

While biologics (e.g., gene therapy, genome editing) and large molecule drugs (e.g., antisense oligos) may indeed prove successful in addressing DM, they ultimately must overcome barriers, such as bioavailability, to gain access to the multiplicity of tissue targets in the disease. Small molecule drugs represent a potentially faster track alternative to exploit RNA primary sequence, as well as secondary structure, in the discovery and development of therapies for DM.

Dr. Matt Disney and colleagues at Scripps Research Institute, Florida have published an overview of strategies to target RNA with small molecules, “Drugging the RNA World” (Disney et al., 2018). Although DM is but one of the indications discussed, the review contains important guidance for drug development in this disease.

Ribosomal RNAs (rRNA) were among the earliest RNA targets for drug development as the mechanism of action of some classes of antibacterials was linked to disruption of rRNA/tRNA interactions.

The authors describe how this early validation of RNA as a target led to designing small molecule compounds based on RNA structure—this section comprises the major thrust of the review. In an effort to target small molecules to the transcriptome, Novartis and Roche/PTC sought to impact diseases by altering splicing (e.g., SMA) or codon signals (e.g., DMD). The authors argue that increased understanding of RNA has led to an appreciation that putative RNA targets now outnumber protein targets and present a potentially more druggable environment. They also note that RNA secondary structure plays a key role both in its functionality and, via altered structure, in disease states (e.g., triplet repeat expansion disorders such as DM where altered secondary structure alters availability of RNA binding proteins).

The Disney group goes on to describe what they term as a ‘two-dimensional combinatorial screening strategy (2DCS)’ to identify small molecule compounds that can selectively target RNA. They note that current knowledge and models of RNA secondary structure are sufficient to evaluate how small molecules may interact, but that information is lacking in regard to the chemical space of targetable RNA motifs. The 2DCS strategy utilized by Disney is designed to identify ‘RNA motif-binding landscapes’ for small molecule compounds and has been successful in identifying high affinity compounds (down to low nanomolar) targeting RNA. With the 2DCS screening tool in hand, the task became matching up compounds from the screens with bioinformatics data on the structure of the intended target RNA.

The remainder of the review considers several specific examples of targeting RNA with small molecule compounds, including targeting protein binding sites in miRNAs causally linked to disease, profiling interactions between small molecules and RNA in cell models using Chem-CLIP, targeting protein binding sites in repeat expansion disorders, affecting RNA subcellular localization and function (including developing imaging techniques to assess outcomes of the approach), and targeting protein binding sites in telomerase RNA as a chemotherapeutic or in pre-mRNAs to alter splicing in FTDP or SMA. The reader gains an excellent worldview of the potential for targeting RNA-based diseases. The Disney review is but one of a series of articles on the RNA World in a recent issue of Cold Spring Harbor Perspectives in Biology.

Practical Application

Practical application of the technology discussed in the review has led to the formation of Expansion Therapeutics, seeking to develop a small molecule, RNA-targeting drug for DM1 and DM2. Understanding of RNA biology and the availability of novel strategies and tools described here is helping to optimize the efficacy and safety of drugs with the potential to reach multiple target tissues in DM patients. A plethora of DM-targeting strategies likely lies within this broad RNA World.

Reference:

Drugging the RNA World.
Disney MD, Dwyer BG, Childs-Disney JL.
Cold Spring Harb Perspect Biol. 2018 Nov 1;10(11). pii: a034769. doi: 10.1101/cshperspect.a034769.

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.

References:

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]

Drug Development Informed with TACT

Published on Tue, 12/11/2018

TREAT-NMD Background

The TREAT-NMD network has been responsible for significant infrastructure projects to advance the diagnosis, treatment, and care of patients with neuromuscular diseases. Among its ongoing projects is the TREAT-NMD Advisory Committee for Therapeutics (TACT). TACT provides non-conflicted, thorough, and expert reviews of therapy development projects independent of funding. The goal is to optimize the development of drugs and biologics for neuromuscular disease indications. One need only review the sample TACT application form to see the depth and breadth of the review process.

Availability of TACT Review Process

TACT reviews therapy development projects for academic researchers and biotechnology/pharmaceutical companies. The next TACT review meeting will be held in Glasgow, UK between 12th-13th April 2019 and will review up to four applications.

TACT has received a number of applications so far for this review cycle but would like to encourage additional applications from stakeholders across the neuromuscular community, involved in therapy development whether they be academic-led groups or from industry. TACT's goal is to provide advice on the position of potential therapies along a realistic pathway to clinical trials and registration by evaluating preclinical data as well as drug development considerations that are crucial for the conduct of studies that generate meaningful data. TACT has reviewed more than 50 applications since 2009. Further details about the committee of experts, process and the benefits of a TACT review can be found on the TREAT-NMD website.

Later in 2019, there will be a second review cycle with a meeting on 2-3 November (location to be confirmed) and we welcome applications for this meeting as well.

TACT provided this comment from Fulcrum Therapeutics on the review of their candidate therapeutic for FSHD:

"On behalf of Fulcrum, and patients, thank you for the thoughtful review of Fulcrum's proposal on the development of FTX-1821. We appreciate the time and effort that the TACT invested into considering our proposal and making suggestions that we believe will strengthen our proposition. The review was exceptionally well written with clear recommendations and reflects well on the mission of TACT. Thank you." Robert Gould, President and CEO, Fulcrum Therapeutics, 2018

Connecting with TACT

MDF encourages the DM community to take advantage of the opportunity offered by TACT. If you would like to submit a proposal for this meeting or require further details, please contact Cathy Turner (catherine.turner@newcastle.ac.uk) for more information.