Introduction Care Considerations supported by the Centers for Disease Control and Prevention for the management of Duchenne muscular dystrophy were published in 2010, but there has been limited study of implementation in the United States. Methods A questionnaire collecting information about standard care practices and perceived barriers was piloted by 9 clinic directors of facilities within the Muscular Dystrophy Surveillance, Tracking and Research network. Results Six clinic directors completed the questionnaire; 1 adult-only clinic was excluded. Over 80% adherence was found for 30 of 55 recommendations examined. Greatest variability was for initiation of corticosteroids, bone health monitoring, type of pulmonary function testing, and psychosocial management. Barriers included unclear guidelines, inadequate time and funding, family-specific barriers and lack of empirical support for some recommendations. Discussion This pilot study showed implementation of the 2010 Care Considerations, except for recommendations based largely on expert consensus. Complete adherence requires more studies and active promotion.
The dystrophinopathies (Duchenne [DMD] and Becker muscular dystrophy) are progressive diseases that until recently had no specific treatments. New FDA pathways to drug approval in rare diseases have resulted in a dramatic increase in the number of treatment trials for DMD and recently, two approved drugs. Health insurance policies for DMD products have been constructed with limited input from neuromuscular specialists directly involved in patient care and without patient input. These policies often reflect a lack of understanding of the disease, clinical population or the treatment. To ensure that policy determinations reflect best clinical practice, we recommend insurers work with neuromuscular specialists with expertise in care for patients with dystrophinopathy, as well as patients and families, and prominent advocacy organizations, such as Parent Project Muscular Dystrophy, in developing policies.
Introduction: The Duchenne Regulatory Science Consortium (D-RSC) was established to develop tools to accelerate drug development for DMD. The resulting tools are anticipated to meet validity requirements outlined by qualification/endorsement pathways at both the U.S. Food and Drug Administration (FDA) and European Medicines Administration (EMA), and will be made available to the drug development community. The initial goals of the consortium include the development of a disease progression model, with the goal of creating a model that would be used to forecast changes in clinically meaningful endpoints, which would inform clinical trial protocol development and data analysis.
Methods: In April of 2016 the consortium and other experts met to formulate plans for the development of the model.
Conclusions: Here we report the results of the meeting, and discussion as to the form of the model that we plan to move forward to develop, after input from the regulatory authorities.
The new ‘Recommendation of the Committee of Ministers to member States on research on biological materials of human origin’, adopted in Europe in May 2016 is confusing and lacks specificity on the research use of biomaterials taken from persons not able to consent. It is possible to interpret the relevant clauses in a restrictive manner and doing so would hamper biobank research, by requiring researchers or biobank curators to examine individual records in detail, to check they are adhering to the Recommendation. This would be particularly problematic for muscular dystrophy and other rare disease research, the progress of which relies increasingly on the sharing of biomaterials and data internationally, as it will add complexity to the logistics of biomaterials and data sharing and introduce barriers for researchers preparing biomaterials for sharing. Such barriers are contradictory to EC policies on promoting and funding rare disease research and removing barriers to better care and treatment. Such policies work in concert with international progress in rare disease research, in particular the NIH’s Rare Diseases Clinical Research Network and Genetic and Rare Diseases Information Centre. The rare disease community has in recent years worked to create a common framework of harmonised approaches to enable the responsible, voluntary, and secure sharing of biomaterials and data. These efforts are supported by the European Commission in such moves as FP7 funding to advance rare disease research and the introduction of National Plans for rare disease; and are bolstered by similar efforts in the USA via the Clinical and Translational Science Awards Program and the NIH/NCATS Patient Registry developments. Introducing Recommendations from the Committee of Ministers, containing clauses which are incompatible to the efforts to advance rare disease research, seems counter-productive.
The aim of this study was to determine whether prednisone and deflazacort play a different role in child behavior and perceived health related psychosocial quality of life in ambulant boys with Duchenne Muscular Dystrophy. As part of a prospective natural-history study, parents of sixty-seven ambulant boys with DMD (27 taking prednisone, 15 taking deflazacort, 25 were steroid naïve) completed the Child Behavior Checklist (CBCL) for assessment of behavioral, emotional and social problems and both parents and boys with DMD completed the PedsQL™4.0 generic core scale short form. Boys with DMD had higher rates of general behavioral problems than age-matched peers. No significant differences were found among the groups for any of the CBCL syndrome scales raw scores, including internalizing and externalizing behaviors; however, on average boys taking deflazacort demonstrated more withdrawn behaviors than those taking prednisone, while on average the boys taking prednisone demonstrated more aggressive behaviors than boys taking deflazacort. Age, internalizing and externalizing behaviors accounted for 39 and 48% of the variance in psychosocial quality of life for both parents and boys with DMD, respectively. Overall, the use of steroids was not associated with more behavioral problems in boys with DMD. As behavior played a significant role in psychosocial quality of life, comprehensive assessment and treatment of behavioral problems is crucial in this population.
Exon-skipping via synthetic antisense oligonucleotides represents one of the most promising potential therapies for Duchenne muscular dystrophy (DMD), yet this approach is highly sequence-specific and thus each oligonucleotide is of benefit to only a subset of patients. The discovery that dystrophin mRNA is subject to translational suppression by the microRNA miR31, and that miR31 is elevated in the muscle of DMD patients, raises the possibility that the same oligonucleotide chemistries employed for exon skipping could be directed toward relieving this translational block. This approach would act synergistically with exon skipping where possible, but by targeting the 3’UTR it would further be of benefit to the many DMD patients who express low levels of in-frame transcript. We here present investigations into the feasibility of combining exon skipping with several different strategies for miR31-modulation, using both in vitro models and the mdx mouse (the classical animal model of DMD), and monitoring effects on dystrophin at the transcriptional and translational level. We show that despite promising results from our cell culture model, our in vivo data failed to demonstrate similarly reproducible enhancement of dystrophin translation, suggesting that miR31-modulation may not be practical under current oligonucleotide approaches. Possible explanations for this disappointing outcome are discussed, along with suggestions for future investigations.
Background: The mdx mouse model for the fatal muscle wasting disease Duchenne Muscular Dystrophy (DMD) shows a very mild pathology once growth has ceased, with low levels of myofibre necrosis in adults. However, from about 3 weeks of post-natal age, muscles of juvenile mdx mice undergo an acute bout of severe necrosis and inflammation: this subsequently decreases and stabilises to lower adult levels by about 6 weeks of age. Prior to the onset of this severe dystropathology, we have shown that mdx mice are deficient in the amino acid taurine (potentially due to weaning), and we propose that this exacerbates myofibre necrosis and inflammation in juvenile mdx mice. Objectives: The purpose of this study was to increase taurine availability to pre-weaned juvenile mdx mice (from 14 days of age), to evaluate the impact on levels of myofibre necrosis and inflammation (at 22 days) during the acute period of severe dystropathology. Results: Untreated 22 day old mdx muscle was not deficient in taurine, with similar levels to normal C57 control muscle. However taurine treatment, which increased the taurine content of young dystrophic muscle (by 40%), greatly reduced myofibre necrosis (by 75%) and prevented significant increases in 3 markers of inflammation. Conclusion: Taurine was very effective at preventing the acute phase of muscle damage that normally results in myofibre necrosis and inflammation in juvenile mdx mice, supporting continued research into the use of taurine as a therapeutic intervention for protecting growing muscles of young DMD boys
The generation of disease-specific induced pluripotent stem cells (iPSCs) holds a great promise for understanding disease mechanisms and for drug screening. Recently, patient-derived iPSCs, containing identical genetic anomalies of the patient, have offered a breakthrough approach to studying Duchenne muscular dystrophy (DMD), a fatal disease caused by the mutation in the dystrophin gene. However, development of scalable and high fidelity DMD-iPSCs is hampered by low reprogramming efficiency, the addition of expensive growth factors and slow kinetics of disease-specific fibroblasts. Here, we show an efficient generation of DMD-iPSCs on bFGF secreting human foreskin fibroblast feeders (I-HFF) by employing single polycistronic lentiviral vector for delivering of transcription factors to DMD patient-specific fibroblast cells. Using this method, DMD-iPSCs generated on I-HFF feeders displayed pluripotent characteristics and disease genotype with improved reprogramming efficiency and kinetics over to mouse feeders. Moreover, we were able to maintain disease-specific iPSCs without additional supplementation of bFGF on I-HFF feeders. Our findings offer improvements in the generation of DMD-iPSCs and will facilitate in understanding of pathological mechanisms and screening of safer drugs for clinical intervention. Key Words: Duchenne Muscular Dystrophy, Reprogramming, Induced pluripotent Stem Cells, Immortalized Human Feeder, Basic Fibroblast Growth Factor, Stem Cell Cassette
Duchenne muscular dystrophy (DMD) is a progressive, life-limiting muscle-wasting disease. Although no curative treatment is yet available, comprehensive multidisciplinary care has increased life expectancy significantly in recent decades. An international consensus care publication in 2010 outlined best-practice care, which includes corticosteroid treatment, respiratory, cardiac, orthopedic and rehabilitative interventions to address disease manifestations. While disease specialists are largely aware of these care standards, local physicians responsible for the day-to-day care of patients and families may be less familiar. To facilitate optimal care, a one-page document has been generated from published care recommendations, summarizing the key elements of comprehensive care for people living with DMD (“Imperatives for Duchenne muscular dystrophy). This document was developed through an international collaboration between Parent Project Muscular Dystrophy (PPMD), United Parent Projects Muscular Dystrophy (UPPMD) and TREAT-NMD.
The Performance of Upper Limb (PUL) test was specifically developed for the assessment of upper limbs in Duchenne muscular dystrophy (DMD). The first published data have shown that early signs of involvement can also be found in ambulant DMD boys. The aim of this longitudinal Italian multicentric study was to evaluate the correlation between the 6 Minute Walk Test (6MWT) and the PUL in ambulant DMD boys. Both 6MWT and PUL were administered to 164 ambulant DMD boys of age between 5.0 and 16.17 years (mean 8.82).
The 6 minute walk distance (6MWD) ranged between 118 and 557 (mean: 376.38, SD: 90.59). The PUL total scores ranged between 52 and 74 (mean: 70.74, SD: 4.66). The correlation between the two measures was 0.499.
The scores on the PUL largely reflect the overall impairment observed on the 6MWT but the correlation was not linear. The use of the PUL appeared to be less relevant in the very strong patients with 6MWD above 400 meters, who, with few exceptions had near full scores. In patients with lower 6MWD the severity of upper limb involvement was more variable and could not always be predicted by the 6MWD value or by the use of steroids.
Our results confirm that upper limb involvement can already be found in DMD boys even in the ambulant phase.
Introduction: One of the major challenges in the neuromuscular field has been lack of upper extremity outcome measures that can be useful for clinical therapeutic efficacy studies. Using vision-based sensor system and customized software, 3-dimensional (3D) upper extremity motion analysis can reconstruct a reachable workspace as a valid, reliable and sensitive outcome measure in various neuromuscular conditions where proximal upper extremity range of motion and function is impaired.
Methods: Using a stereo-camera sensor system, 3D reachable workspace envelope surface area normalized to an individual’s arm length (relative surface area: RSA) to allow comparison between subjects was determined for 20 healthy controls and 9 individuals with varying degrees of upper extremity dysfunction due to neuromuscular conditions. All study subjects were classified based on Brooke upper extremity function scale. Right and left upper extremity reachable workspaces were determined based on three repeated measures. The RSAs for each frontal hemi-sphere quadrant and total reachable workspaces were determined with and without loading condition (500 gram wrist weight). Data were analyzed for assessment of the developed system and validity, reliability, and sensitivity to change of the reachable workspace outcome.
Results: The mean total RSAs of the reachable workspace for the healthy controls and individuals with NMD were significantly different (0.586 ± 0.085 and 0.299 ± 0.198 respectively; p<0.001). All quadrant RSAs were reduced for individuals with NMDs compared to the healthy controls and these reductions correlated with reduced upper limb function as measured by Brooke grade. The upper quadrants of reachable workspace (above the shoulder level) demonstrated greatest reductions in RSA among subjects with progressive severity in upper extremity impairment. Evaluation of the developed outcomes system with the Bland-Altman method demonstrated narrow 95% limits of agreement (LOA) around zero indicating high reliability. In addition, the intraclass correlation coefficient (ICC) was 0.97. Comparison of the reachable workspace with and without loading condition (wrist weight) showed significantly greater RSA reduction in the NMD group than the control group (p<0.012), with most of the workspace reduction occurring in the ipsilateral upper quadrant relative to the tested arm (p<0.001). Reduction in reachable workspace due to wrist weight was most notable in those subjects with NMD with marginal strength reserve and moderate degree of impairment (Brooke = 2) rather than individuals with mild upper extremity impairment (Brooke = 1) or individuals who were more severely impaired (Brooke =3).
Discussion: The developed reachable workspace evaluation method using scalable 3D vision technology appears promising as an outcome measure system for clinical studies. A rationally-designed combination of upper extremity outcome measures including a region-specific global upper extremity outcome measure, such as the reachable workspace, complemented by targeted disease- or function-specific endpoints, may be optimal for future clinical efficacy trials.
Duchenne muscular dystrophy is a lethal, progressive, muscle-wasting disease caused by mutations in the DMD gene. Structural remodelling processes are responsible for muscle atrophy and replacement of myofibers by fibrotic and adipose tissues. Molecular interventions modulating catabolic pathways, such as the ubiquitin-proteasome and the autophagy-lysosome systems, are under development for Duchenne and other muscular dystrophies. The Akt signaling cascade is one of the main pathways involved in protein synthesis and autophagy repression and is known to be up-regulated in dystrophin null mdx mice.
We report that autophagy is triggered by fasting in the tibialis anterior muscle of control mice but not in mdx mice. Mdx mice show persistent Akt activation upon fasting and failure to increase the expression of FoxO3 regulated autophagy and atrophy genes, such as Bnip3 and Atrogin1. We also provide evidence that autophagy is differentially regulated in mdx tibialis anterior and diaphragm muscles.
Our data support the concept that autophagy is impaired in the tibialis anterior muscle of mdx mice and that the regulation of autophagy is muscle type dependent. Differences between muscle groups should be considered during the pre-clinical development of therapeutic strategies addressing muscle metabolism.
Drug trials in children engage with many ethical issues, from drug-related safety concerns to communication with patients and parents, and recruitment and informed consent procedures. This paper addresses the field of neuromuscular disorders where the possibility of genetic, mutation-specific treatments, has added new complexity. Not only must trial design address issues of equity of access, but researchers must also think through the implications of adopting a personalised medicine approach, which requires a precise molecular diagnosis, in addition to other implications of developing orphan drugs.
It is against this background of change and complexity that the Project Ethics Council (PEC) was established within the TREAT-NMD EU Network of Excellence. The PEC is a high level advisory group that draws upon the expertise of its interdisciplinary membership which includes clinicians, lawyers, scientists, parents, representatives of patient organisations, social scientists and ethicists. In this paper we describe the establishment and terms of reference of the PEC, give an indication of the range and depth of its work and provide some analysis of the kinds of complex questions encountered. The paper describes how the PEC has responded to substantive ethical issues raised within the TREAT-NMD consortium and how it has provided a wider resource for any concerned parent, patient, or clinician to ask a question of ethical concern. Issues raised range from science related ethical issues, issues related to hereditary neuromuscular diseases and the new therapeutic approaches and questions concerning patients rights in the context of patient registries and bio-banks. We conclude by recommending the PEC as a model for similar research contexts in rare diseases.
Duchenne muscular dystrophy (DMD) is characterized by the absence of dystrophin in muscles. A therapeutic approach to restore dystrophin expression in DMD patient’s muscles is the transplantation of muscle precursor cells (MPCs). However, this transplantation is limited by the low MPC capacity to migrate beyond the injection trajectory. Matrix metalloproteases (MMPs) are key regulatory molecules in the remodeling of extracellular matrix (ECM) components. MPCs over-expressing MMP-9 were tested by zymography, migration and invasion assays in vitro and by transplantation in mouse muscle. In vitro, MPCs over-expressing MMP-9 have a better invasion capacity than control MPCs. When these cells are transplanted in mouse muscles, the transplantation success is increased by more than 50% and their dispersion is higher than normal cells. MMP-9 over-expression could thus be an approach to improve cell transplantation in DMD patients by increasing the dispersion capacity of transplanted cells.