Management of Select Adverse Events Following Delandistrogene Moxeparvovec Gene Therapy for Patients With Duchenne Muscular Dystrophy.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a rare, degenerative, recessive X-linked neuromuscular disease. Mutations in the gene encoding dystrophin lead to the absence of functional dystrophin protein. Individuals living with DMD exhibit progressive muscle weakness resulting in loss of ambulation and limb function, respiratory insufficiency, and cardiomyopathy, with multiorgan involvement. Adeno-associated virus vector-mediated gene therapy designed to enable production of functional dystrophin protein is a new therapeutic strategy. Delandistrogene moxeparvovec (Sarepta Therapeutics, Cambridge, MA) is indicated for treatment of ambulatory pediatric patients aged 4 through 5 years with DMD who have an indicated mutation in the DMD gene. OBJECTIVE: Evidence-based considerations for management of potential adverse events following gene therapy treatment for DMD are lacking in clinical literature. Our goal was to provide interdisciplinary consensus considerations for selected treatment-related adverse events (TRAEs) (vomiting, acute liver injury, myocarditis, and immune-mediated myositis) that may arise following gene therapy dosing with delandistrogene moxeparvovec. METHODS: An interdisciplinary panel of 12 specialists utilized a modified Delphi process to develop consensus considerations for the evaluation and management of TRAEs reported in delandistrogene moxeparvovec clinical studies. Panelists completed 2 Questionnaires prior to gathering for an in-person discussion. Consensus was defined as a majority (≥58% ; 7/12) of panelists either agreeing or disagreeing. RESULTS: Panelists agreed that the choice of baseline assessments should be informed by individual clinical indications, the treating provider's judgment, and prescribing information. Corticosteroid dosing for treatment of TRAEs should be optimized by considering individual risk versus benefit for each indication. In all cases involving patients with a confirmed TRAE, consultations with appropriate specialists were suggested. CONCLUSIONS: The Delphi Panel established consensus considerations for the evaluation and management of potential TRAEs for patients receiving delandistrogene moxeparvovec, including vomiting, acute liver injury, myocarditis, and immune-mediated myositis.

The Association Between Physical Activity/Heart Rate Variability Data Obtained Using a Wearable Device and Timed Motor Functional Tests in Patients with Duchenne Muscular Dystrophy: A Pilot Study.

Background: Duchenne muscular dystrophy (DMD) is a devastating X-linked muscle disease. Clinical evaluation of DMD uses patient-intensive motor function tests, and the recent development of wearable devices allows the collection of a variety of biometric information, including physical activity. Objective: In this study, we examined differences in physical activity and heart rate variability (HRV) between patients with DMD and healthy subjects using a wearable device, and investigated any association between these parameters and motor function in patients with DMD. Methods: Participants were 7 patients with DMD and 8 healthy males, whose physical activity and HRV were provided by a wearable device. These data were used to investigate the relationship between both physical activity and HRV parameters and timed motor functional tests [Time to stand from supine, 10-meter walking time (10MWT), North Star Ambulatory Assessment (NSAA), and 6-minute walking test (6MWT)] in patients with DMD. Results: Results of 24-hours physical activity, fat burning, total number of steps and active distance, average step rate, average exercise intensity during walking, exercise, degree of forward lean during walking, maximum heart rate, normalized low frequency power (LF norm), and maximum exercise intensity in patients with DMD were lower than those in control subjects. Physical activity and HRV parameters did not correlate with the time to stand from supine. The 10MWT positively correlated with average heart rate, while NSAA negatively correlated with average heart rate, total frequency power (TF), and very low frequency power (VLF) during arousal. The 6MWT negatively correlated with ratio LF/high frequency power (HF). CONCLUSIONS: Physical activity and HRV indices that differ from those of normal children and that correlate with motor function assessment may serve as digital biomarkers.

Five multivariate Duchenne muscular dystrophy progression models bridging six-minute walk distance and MRI relaxometry of leg muscles.

The study aimed to provide quantitative information on the utilization of MRI transverse relaxation time constant (MRI-T2) of leg muscles in DMD clinical trials by developing multivariate disease progression models of Duchenne muscular dystrophy (DMD) using 6-min walk distance (6MWD) and MRI-T2. Clinical data were collected from the prospective and longitudinal ImagingNMD study. Disease progression models were developed by a nonlinear mixed-effect modeling approach. Univariate models of 6MWD and MRI-T2 of five muscles were developed separately. Age at assessment was the time metric. Multivariate models were developed by estimating the correlation of 6MWD and MRI-T2 model variables. Full model estimation approach for covariate analysis and five-fold cross validation were conducted. Simulations were performed to compare the models and predict the covariate effects on the trajectories of 6MWD and MRI-T2. Sigmoid Imax and Emax models best captured the profiles of 6MWD and MRI-T2 over age. Steroid use, baseline 6MWD, and baseline MRI-T2 were significant covariates. The median age at which 6MWD is half of its maximum decrease in the five models was similar, while the median age at which MRI-T2 is half of its maximum increase varied depending on the type of muscle. The models connecting 6MWD and MRI-T2 successfully quantified how individual characteristics alter disease trajectories. The models demonstrate a plausible correlation between 6MWD and MRI-T2, supporting the use of MRI-T2. The developed models will guide drug developers in using the MRI-T2 to most efficient use in DMD clinical trials.

Respiratory comorbidities and treatments in Duchenne muscular dystrophy: impact on life expectancy and causes of death.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a neuromuscular disorder with progressive decline of pulmonary function increasing the risk of early mortality. The aim of this study was to explore the respiratory-related comorbidities, and the effect of these comorbidities and treatments on life expectancy and causes of death. METHODS: All male patients living in Sweden with DMD, born and deceased 1970-2019, were included. Data regarding causes of death were collected from the Cause of Death Registry and cross-checked with the medical records along with diagnostics and relevant clinical features. RESULTS: Hundred and twenty nine patients were included with a median lifespan of 24.3 years. Acute respiratory failure accounted for 63.3% of respiratory-related causes of death. 70.1% suffered at least one pneumonia, with first episode at a median age of 17.8 years. Hypoventilation was found in 73.0% with onset at 18.1 years. 60.5% had their first pneumonia before established hypoventilation. Age at onset of hypoventilation showed a strong correlation with age at first pneumonia. First pneumonia and scoliosis non-treated with scoliosis surgery increased the risk of dying of respiratory-related causes. In 10% of the patients, first pneumonia resulted in acute tracheostomy or early death. Patients treated with assisted ventilation had higher life expectancy compared to untreated patients. CONCLUSIONS: Our results highlight the importance of identifying subclinical hypoventilation in a timely manner and the importance of an active treatment regime upon clinical signs of pneumonia.

Mitochondria and Reactive Oxygen Species: The Therapeutic Balance of Powers for Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a genetic progressive muscle-wasting disorder that leads to rapid loss of mobility and premature death. The absence of functional dystrophin in DMD patients reduces sarcolemma stiffness and increases contraction damage, triggering a cascade of events leading to muscle cell degeneration, chronic inflammation, and deposition of fibrotic and adipose tissue. Efforts in the last decade have led to the clinical approval of novel drugs for DMD that aim to restore dystrophin function. However, combination therapies able to restore dystrophin expression and target the myriad of cellular events found impaired in dystrophic muscle are desirable. Muscles are higher energy consumers susceptible to mitochondrial defects. Mitochondria generate a significant source of reactive oxygen species (ROS), and they are, in turn, sensitive to proper redox balance. In both DMD patients and animal models there is compelling evidence that mitochondrial impairments have a key role in the failure of energy homeostasis. Here, we highlighted the main aspects of mitochondrial dysfunction and oxidative stress in DMD and discussed the recent findings linked to mitochondria/ROS-targeted molecules as a therapeutic approach. In this respect, dual targeting of both mitochondria and redox homeostasis emerges as a potential clinical option in DMD.

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OBJECTIVES: To evaluate the incidence rate of Duchenne muscular dystrophy (DMD) in the male newborns in the Ningxia region and establish a critical threshold for screening DMD in newborns to distinguish between the normal population and affected individuals. METHODS: A total of 10 000 male newborns were screened using immunofluorescence analysis of creatine kinase isoenzyme concentrations in heel spot dried blood specimens. Newborns with the concentrations higher than the critical threshold were recalled for serum creatine kinase measurements. Genetic testing was performed to confirm diagnosis in cases showing abnormalities. RESULTS: Among the screened 10 000 male newborns, two were confirmed to have DMD through genetic testing, resulting in a preliminary estimated incidence rate of 1/5 000 for male newborns in the Ningxia region. The critical threshold for creatine kinase isoenzyme concentration in newborns in this region was determined to be 468.57 ng/mL. CONCLUSIONS: Screening for DMD in newborns is feasible in the Ningxia region. Early screening, diagnosis, and treatment of DMD can improve the quality of life for affected individuals and help families make informed decisions regarding further pregnancies.

Treatment with ataluren in four symptomatic Duchenne carriers. A pilot study.

Duchenne muscular dystrophy (DMD) is a devastating X-linked neuromuscular disorder caused by dystrophin gene deletions (75%), duplications (15-20%) and point mutations (5-10%), a small portion of which are nonsense mutations. Women carrying dystrophin gene mutations are commonly unaffected because the wild X allele may produce a sufficient amount of the dystrophin protein. However, approximately 8-10% of them may experience muscle symptoms and 50% of those over 40 years develop cardiomyopathy. The presence of symptoms defines the individual as an affected "symptomatic or manifesting carrier". Though there is no effective cure for DMD, therapies are available to slow the decline of muscle strength and delay the onset and progression of cardiac and respiratory impairment. These include ataluren for patients with nonsense mutations, and antisense oligonucleotides therapies, for patients with specific deletions. Symptomatic DMD female carriers are not included in these indications and little data documenting their management, often entrusted to the discretion of individual doctors, is present in the literature. In this article, we report the clinical and instrumental outcomes of four symptomatic DMD carriers, aged between 26 and 45 years, who were treated with ataluren for 21 to 73 months (average 47.3), and annually evaluated for muscle strength, respiratory and cardiological function. Two patients retain independent ambulation at ages 33 and 45, respectively. None of them developed respiratory involvement or cardiomyopathy. No clinical adverse effects or relevant abnormalities in routine laboratory values, were observed.

Duchenne muscular dystrophy caused by a deletion (c.5021del) in exon 35 of the DMD gene: A case report and review of the literature.

Duchenne muscular dystrophy (DMD MIM#310200) is a degenerative muscle disease caused by mutations in the dystrophin gene located on Xp21.2. The clinical features encompass muscle weakness and markedly elevated serum creatine kinase levels. An 8-year-old Chinese boy was diagnosed with Duchenne muscular dystrophy (DMD). Whole exome gene sequencing was conducted and the Sanger method was used to validate sequencing. A deletion (c.5021del) in exon 35 of the dystrophin gene was identified, which was predicted to generate a frameshift mutation and create an early termination codon (p.Leu1674CysfsTer47). It has a pathogenic effect against dystrophin in the muscle cell membrane of the patient. As such, prednisone treatment at a dose of 0.75 mg/kg.d was administered. After one month, a notable reduction in fall frequency was observed. Our new finding will expand the pathogenic mutation spectrum causing DMD.

The complex landscape of DMD mutations: moving towards personalized medicine.

Duchenne muscular dystrophy (DMD) is a severe genetic disorder characterized by progressive muscle degeneration, with respiratory and cardiac complications, caused by mutations in the DMD gene, encoding the protein dystrophin. Various DMD mutations result in different phenotypes and disease severity. Understanding genotype/phenotype correlations is essential to optimize clinical care, as mutation-specific therapies and innovative therapeutic approaches are becoming available. Disease modifier genes, trans-active variants influencing disease severity and phenotypic expressivity, may modulate the response to therapy, and become new therapeutic targets. Uncovering more disease modifier genes via extensive genomic mapping studies offers the potential to fine-tune prognostic assessments for individuals with DMD. This review provides insights into genotype/phenotype correlations and the influence of modifier genes in DMD.

Implication of Corneal Refractive Surgery in Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is an X-linked disorder due to a dystrophin mutation and is the leading cause of muscular dystrophy. DMD presents with characteristic systemic effects, including severe muscular atrophy, cardiomyopathy, and ocular manifestations. Performing corneal refractive surgeries in patients with DMD raises concerns regarding patient positioning, risk of cataracts, and other comorbid conditions. Published reports of photorefractive keratectomy, laser-assisted in situ keratomileuses, and small incision lenticule extraction are lacking in this population. Here, we discuss a patient being evaluated for a corneal refractive surgery. This article also discusses the current understanding of DMD, known ocular manifestations, and factors to consider when evaluating a patient for potential corrective vision laser surgery.

Computer-Aided Diagnosis of Duchenne Muscular Dystrophy Based on Texture Pattern Recognition on Ultrasound Images Using Unsupervised Clustering Algorithms and Deep Learning.

OBJECTIVE: The feasibility of using deep learning in ultrasound imaging to predict the ambulatory status of patients with Duchenne muscular dystrophy (DMD) was previously explored for the first time. The present study further used clustering algorithms for the texture reconstruction of ultrasound images of DMD data sets and analyzed the difference in echo intensity between disease stages. METHODS: k-means (Kms) and fuzzy c-means (FCM) clustering algorithms were used to reconstruct the DMD data-set textures. Each image was reconstructed using seven texture-feature categories, six of which were used as the primary analysis items. The task of automatically identifying the ambulatory function and DMD severity was performed by establishing a machine-learning model. RESULTS: The experimental results indicated that the Gaussian Naïve Bayes and k-nearest neighbors classification models achieved an accuracy of 86.78% in ambulatory function classification. The decision-tree model achieved an identification accuracy of 83.80% in severity classification. A deep convolutional neural network model was established as the main structure of the deep-learning model while automatic auxiliary interpretation tasks of ambulatory function and severity were performed, and data augmentation was used to improve the recognition performance of the trained model. Both the visual geometry group (VGG)-16 and VGG-19 models achieved 98.53% accuracy in ambulatory-function classification. The VGG-19 model achieved 92.64% accuracy in severity classification. CONCLUSION: Regarding the overall results, the Kms and FCM clustering algorithms were used in this study to reconstruct the characteristic texture of the gastrocnemius muscle group in DMD, which was indeed helpful in quantitatively analyzing the deterioration of the gastrocnemius muscle group in patients with DMD at different stages. Subsequent combination of machine-learning and deep-learning technologies can automatically and accurately assist in identifying DMD symptoms and tracking DMD deterioration for long-term observation.

Heart in Disguise: Unmasking a Novel Gene Deletion in Dilated Cardiomyopathy.

Dilated cardiomyopathy (DCM) is an underrecognized condition with a myriad of etiologies, but it is often labeled idiopathic. However, genetic mutations are emerging as a more common cause of idiopathic DCM than previously believed. Herein, we present a case of a previously healthy 45-year-old woman who presented with three weeks of exertional dyspnea and orthopnea. An echocardiogram showed DCM with severely reduced systolic function and diastolic dysfunction. She was extensively worked up for potential etiologies of her heart failure which included HIV testing, parasite smear, viral serologies, autoimmune testing, cardiac MRI for infiltrative diseases, and coronary catheterization. She was ultimately tested for genetic mutations which revealed a 49-51 exon deletion of the dystrophin (Duchenne muscular dystrophy (DMD)) gene. This case highlights the guideline-based evaluation and management of new-onset heart failure in a healthy 45-year-old female without known predisposing risk factors or family history. It also sheds light on the expansive genetic etiologies that have only recently been identified in those with idiopathic cardiomyopathy. Further research is crucial to improve our understanding of genetic associations of cardiomyopathy.

Inhibition of miR-25 ameliorates cardiac and skeletal muscle dysfunction in aged mdx/utrn haploinsufficient (+/-) mice.

Dystrophic cardiomyopathy is a significant feature of Duchenne muscular dystrophy (DMD). Increased cardiomyocyte cytosolic calcium (Ca2+) and interstitial fibrosis are major pathophysiological hallmarks that ultimately result in cardiac dysfunction. MicroRNA-25 (miR-25) has been identified as a suppressor of both sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) and mothers against decapentaplegic homolog-7 (Smad7) proteins. In this study, we created a gene transfer using an miR-25 tough decoy (TuD) RNA inhibitor delivered via recombinant adeno-associated virus serotype 9 (AAV9) to evaluate the effect of miR-25 inhibition on cardiac and skeletal muscle function in aged dystrophin/utrophin haploinsufficient mice mdx/utrn (+/-), a validated transgenic murine model of DMD. We found that the intravenous delivery of AAV9 miR-25 TuD resulted in strong and stable inhibition of cardiac miR-25 levels, together with the restoration of SERCA2a and Smad7 expression. This was associated with the amelioration of cardiomyocyte interstitial fibrosis as well as recovered cardiac function. Furthermore, the direct quadricep intramuscular injection of AAV9 miR-25 TuD significantly restored skeletal muscle Smad7 expression, reduced tissue fibrosis, and enhanced skeletal muscle performance in mdx/utrn (+/-) mice. These results imply that miR-25 TuD gene transfer may be a novel therapeutic approach to restore cardiomyocyte Ca2+ homeostasis and abrogate tissue fibrosis in DMD.

The extracellular matrix differentially directs myoblast motility and differentiation in distinct forms of muscular dystrophy: Dystrophic matrices alter myoblast motility.

Extracellular matrix (ECM) pathologic remodeling underlies many disorders, including muscular dystrophy. Tissue decellularization removes cellular components while leaving behind ECM components. We generated "on-slide" decellularized tissue slices from genetically distinct dystrophic mouse models. The ECM of dystrophin- and sarcoglycan-deficient muscles had marked thrombospondin 4 deposition, while dysferlin-deficient muscle had excess decorin. Annexins A2 and A6 were present on all dystrophic decellularized ECMs, but annexin matrix deposition was excessive in dysferlin-deficient muscular dystrophy. Muscle-directed viral expression of annexin A6 resulted in annexin A6 in the ECM. C2C12 myoblasts seeded onto decellularized matrices displayed differential myoblast mobility and fusion. Dystrophin-deficient decellularized matrices inhibited myoblast mobility, while dysferlin-deficient decellularized matrices enhanced myoblast movement and differentiation. Myoblasts treated with recombinant annexin A6 increased mobility and fusion like that seen on dysferlin-deficient decellularized matrix and demonstrated upregulation of ECM and muscle cell differentiation genes. These findings demonstrate specific fibrotic signatures elicit effects on myoblast activity.

Survival among patients receiving eteplirsen for up to 8 years for the treatment of Duchenne muscular dystrophy and contextualization with natural history controls.

INTRODUCTION/AIMS: Eteplirsen, approved in the US for patients with Duchenne muscular dystrophy (DMD) with exon 51 skip-amenable variants, is associated with attenuated ambulatory/pulmonary decline versus DMD natural history (NH). We report overall survival in a US cohort receiving eteplirsen and contextualize these outcomes versus DMD NH. METHODS: US patients with DMD receiving eteplirsen were followed through a patient support program, with data collected on ages at eteplirsen initiation and death/end of follow-up. Individual DMD NH data were extracted by digitizing Kaplan-Meier (KM) curves from published systematic and targeted literature reviews. Overall survival age was analyzed using KM curves and contextualized with DMD NH survival curves; subanalyses considered age groups and duration of eteplirsen exposure. Overall survival time from treatment initiation was also evaluated. RESULTS: A total of 579 eteplirsen-treated patients were included. During a total follow-up of 2119 person-years, median survival age was 32.8 years. DMD NH survival curves extracted from four publications (follow-up for 1224 DMD NH controls) showed overall pooled median survival age of 27.4 years. Eteplirsen-treated patients had significantly longer survival from treatment initiation versus age-matched controls (age-adjusted hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.44-0.98; p < .05). Longer treatment exposure was associated with improved survival (HR, 0.15; 95% CI, 0.05-0.41; p < .001). Comparisons using different DMD NH cohorts to address common risks of bias yielded consistent findings. DISCUSSION: Data suggest eteplirsen may prolong survival in patients with DMD across a wide age range. As more data become available, the impact of eteplirsen on survival will be further elucidated.

Comparison of energy expenditure of individuals with Duchenne muscular dystrophy in the sitting posture on the ground and in water.

Duchenne Muscular Dystrophy (DMD) is one of the most frequent childhood dystrophies, affecting cardiopulmonary functions and walking ability. One of the main symptoms is fatigue, which is caused by altered muscle metabolism related to energy expenditure (EE). Aquatic physiotherapy is a therapeutic modality that facilitates the maintenance of this posture because of immersion on the body. This cross-sectional observational study aimed to compare the EE on the ground and water of individuals with DMD through oxygen consumption in the maintenance of sitting posture. The individuals were in a sitting position on the ground and in the water for 20 min for the assessments. The variables peripheral oxygen saturation, heart rate, maximum expiratory pressure, maximum inspiratory pressure, forced vital capacity, respiratory quotient (RQ), and oxygen consumption per kilogram of body weight (VO2 /kg) were compared, adopting a significance of 5 %. No difference was found between medians and quartiles of RQ when comparing the two environments. The same was observed for VO2 /Kg values on the ground and in water. The data from this study demonstrate that the EE of individuals with DMD did not change when maintaining a sitting posture on the ground and in water.

Cell-mediated exon skipping normalizes dystrophin expression and muscle function in a new mouse model of Duchenne Muscular Dystrophy.

Cell therapy for muscular dystrophy has met with limited success, mainly due to the poor engraftment of donor cells, especially in fibrotic muscle at an advanced stage of the disease. We developed a cell-mediated exon skipping that exploits the multinucleated nature of myofibers to achieve cross-correction of resident, dystrophic nuclei by the U7 small nuclear RNA engineered to skip exon 51 of the dystrophin gene. We observed that co-culture of genetically corrected human DMD myogenic cells (but not of WT cells) with their dystrophic counterparts at a ratio of either 1:10 or 1:30 leads to dystrophin production at a level several folds higher than what predicted by simple dilution. This is due to diffusion of U7 snRNA to neighbouring dystrophic resident nuclei. When transplanted into NSG-mdx-Δ51mice carrying a mutation of exon 51, genetically corrected human myogenic cells produce dystrophin at much higher level than WT cells, well in the therapeutic range, and lead to force recovery even with an engraftment of only 3-5%. This level of dystrophin production is an important step towards clinical efficacy for cell therapy.

The unconditioned fear response in vertebrates deficient in dystrophin.

Dystrophin loss due to mutations in the Duchenne muscular dystrophy (DMD) gene is associated with a wide spectrum of neurocognitive comorbidities, including an aberrant unconditioned fear response to stressful/threat stimuli. Dystrophin-deficient animal models of DMD demonstrate enhanced stress reactivity that manifests as sustained periods of immobility. When the threat is repetitive or severe in nature, dystrophinopathy phenotypes can be exacerbated and even cause sudden death. Thus, it is apparent that enhanced sensitivity to stressful/threat stimuli in dystrophin-deficient vertebrates is a legitimate cause of concern for patients with DMD that could impact neurocognition and pathophysiology. This review discusses our current understanding of the mechanisms and consequences of the hypersensitive fear response in preclinical models of DMD and the potential challenges facing clinical translatability.

Newborn screening for Duchenne muscular dystrophy: the perspectives of stakeholders.

Background: The rapidly evolving clinical landscape of Duchenne muscular dystrophy (DMD) is driving innovative approaches for early diagnosis through genomic newborn bloodspot screening (NBS). However, the potential impact of these programs on families and healthcare systems remains unexplored. This study assessed the perceived benefits, harms, barriers, and enablers for DMD NBS amongst primary caregivers of children with DMD and healthcare professionals (HCPs). Methods: This Australian multi-centre cross-sectional study used a mixed-methods convergent methodology. Participants completed a codeveloped questionnaire and their perceptions on the utility, model of care, and processes of DMD NBS were thematically analysed. Findings: Participants included 50 caregivers and 26 HCPs (68.5% and 53.1% response rate respectively). Most caregivers (40/50, 80%) perceived net benefits of DMD NBS and highlighted an early diagnosis as actionable knowledge, even with the current paucity of disease modifying therapies. This knowledge was valued to enable access to multidisciplinary supportive care (29/50, 58%), clinical trials (27/50, 54%), psychological support (28/50, 56%), inform reproductive planning (27/50, 54%), and facilitate financial planning based on the future needs of their child (27/50, 54%). Whilst HCPs acknowledged these opportunities, only 16/26 (61.5%) believed there were definite net benefits, with notable concerns over the psychological harms of diagnostic knowledge without a recourse to disease modifying therapeutic intervention early in life. Interpretation: Caregivers and HCPs perceived a range of potential benefits of DMD NBS. Health system readiness will be founded on developing an integrated model of care that not only supports the psychosocial and information needs of families receiving a newborn diagnosis of DMD, but also provides care and clinical surveillance for individuals for whom a diagnosis may remain uncertain. Funding: Medical Research Futures fund (GNT2017165, MRF2015965).

Amelioration of Morphological Pathology in Cardiac, Respiratory, and Skeletal Muscles Following Intraosseous Administration of Human Dystrophin Expressing Chimeric (DEC) Cells in Duchenne Muscular Dystrophy Model.

Duchenne Muscular Dystrophy (DMD) is a lethal disease caused by mutation in the dystrophin gene. Currently there is no cure for DMD. We introduced a novel human Dystrophin Expressing Chimeric (DEC) cell therapy of myoblast origin and confirmed the safety and efficacy of DEC in the mdx mouse models of DMD. In this study, we assessed histological and morphological changes in the cardiac, diaphragm, and gastrocnemius muscles of the mdx/scid mice after the transplantation of human DEC therapy via the systemic-intraosseous route. The efficacy of different DEC doses was evaluated at 90 days (0.5 × 106 and 1 × 106 DEC cells) and 180 days (1 × 106 and 5 × 106 DEC cells) after administration. The evaluation of Hematoxylin & Eosin (H&E)-stained sectional slices of cardiac, diaphragm, and gastrocnemius muscles included assessment of muscle fiber size by minimal Feret's diameter method using ImageJ software. The overall improvement in muscle morphology was observed in DMD-affected target muscles in both studies, as evidenced by a shift in fiber size distribution toward the wild type (WT) phenotype and by an increase in the mean Feret's diameter compared to the vehicle-injected controls. These findings confirm the long-term efficacy of human DEC therapy in the improvement of overall morphological pathology in the muscles affected by DMD and introduce DEC as a novel therapeutic approach for DMD patients.