Death after High-Dose rAAV9 Gene Therapy in a Patient with Duchenne's Muscular Dystrophy.

We treated a 27-year-old patient with Duchenne's muscular dystrophy (DMD) with recombinant adeno-associated virus (rAAV) serotype 9 containing dSaCas9 (i.e., "dead" Staphylococcus aureus Cas9, in which the Cas9 nuclease activity has been inactivated) fused to VP64; this transgene was designed to up-regulate cortical dystrophin as a custom CRISPR-transactivator therapy. The dose of rAAV used was 1×1014 vector genomes per kilogram of body weight. Mild cardiac dysfunction and pericardial effusion developed, followed by acute respiratory distress syndrome (ARDS) and cardiac arrest 6 days after transgene treatment; the patient died 2 days later. A postmortem examination showed severe diffuse alveolar damage. Expression of transgene in the liver was minimal, and there was no evidence of AAV serotype 9 antibodies or effector T-cell reactivity in the organs. These findings indicate that an innate immune reaction caused ARDS in a patient with advanced DMD treated with high-dose rAAV gene therapy. (Funded by Cure Rare Disease.).

Integrative Multiomics in the Lung Reveals a Protective Role of Asporin in Pulmonary Arterial Hypertension.

BACKGROUND: Integrative multiomics can elucidate pulmonary arterial hypertension (PAH) pathobiology, but procuring human PAH lung samples is rare. METHODS: We leveraged transcriptomic profiling and deep phenotyping of the largest multicenter PAH lung biobank to date (96 disease and 52 control) by integration with clinicopathologic data, genome-wide association studies, Bayesian regulatory networks, single-cell transcriptomics, and pharmacotranscriptomics. RESULTS: We identified 2 potentially protective gene network modules associated with vascular cells, and we validated ASPN, coding for asporin, as a key hub gene that is upregulated as a compensatory response to counteract PAH. We found that asporin is upregulated in lungs and plasma of multiple independent PAH cohorts and correlates with reduced PAH severity. We show that asporin inhibits proliferation and transforming growth factor-ß/phosphorylated SMAD2/3 signaling in pulmonary artery smooth muscle cells from PAH lungs. We demonstrate in Sugen-hypoxia rats that ASPN knockdown exacerbated PAH and recombinant asporin attenuated PAH. CONCLUSIONS: Our integrative systems biology approach to dissect the PAH lung transcriptome uncovered asporin as a novel protective target with therapeutic potential in PAH.

Appendicular lean mass index and motor function in ambulatory patients with Duchenne muscular dystrophy.

INTRODUCTION/AIMS: Appendicular lean mass index (ALMI) has been linked to motor function in patients with Duchenne muscular dystrophy (DMD). However, quantification of the relationship between ALMI and disease-specific clinical outcome assessment trajectories is needed. The purpose of this study was to determine associations between dual-energy x-ray absorptiometry (DXA) derived estimates of ALMI and motor function in ambulatory patients with DMD. METHODS: A retrospective analysis of longitudinal clinical visit data from 137 glucocorticoid-treated patients with DMD collected via structured motor assessment protocol evaluated associations between ALMI and motor function indexed by the North Star Ambulatory Assessment (NSAA) and 10 Meter Walk/run Test (10MWT). Body composition was assessed using DXA. ALMI was calculated by dividing arm and leg lean mass by height in m2; fat mass index (FMI) was calculated by dividing whole body fat mass by height in m2. Linear mixed-effects models were used to estimate associations between ALMI and motor function, controlling for age and FMI. RESULTS: The full prediction model (age, age,2 ALMI, and FMI) explained 57% of the variance in NSAA scores and 63% of the variance in 10MWT speed. A 1 kg/m2 higher ALMI value predicted a 5.4-point higher NSAA score (p < .001) and 0.45 m/s faster 10MWT speed (p < .001). A 1 kg/m2 higher FMI value predicted a 1.5-point lower NSAA score (p < .001) and 0.14 meters/second slower 10MWT speed (p < .001). DISCUSSION: DXA-derived estimates of ALMI and FMI are associated with motor function in DMD and may explain variation in DMD disease progression.

The impact of genotype on age at loss of ambulation in individuals with Duchenne muscular dystrophy treated with corticosteroids: A single-center study of 555 patients.

INTRODUCTION/AIMS: Studies have demonstrated that certain genotypes in Duchenne muscular dystrophy (DMD) have milder or more severe phenotypes. These studies included individuals treated and not treated with corticosteroids and multiple sites with potentially varying standards of care. We aimed to assess genotype-phenotype correlations for age at loss of ambulation (LoA) in a large cohort of individuals with DMD treated with corticosteroids at one center. METHODS: In this retrospective review of medical records, encounters were included for individuals diagnosed with DMD if prescribed corticosteroids, defined as daily deflazacort or prednisone or high-dose weekend prednisone, for 12 consecutive months. Encounters were excluded if the participants were taking disease-modifying therapy. Data were analyzed using survival analysis for LoA and Fisher's exact tests to assess the percentage of late ambulatory (>14 years old) individuals for selected genotypes. RESULTS: Overall, 3948 encounters from 555 individuals were included. Survival analysis showed later age at LoA for exon 44 skip amenable (p = .004), deletion exons 3-7 (p < .001) and duplication exon 2 (p = .043) cohorts and earlier age at LoA for the exon 51 skip amenable cohort (p < .001) when compared with the rest of the cohort. Individuals with deletions of exons 3-7 had significantly more late ambulatory individuals than other cohorts (75%), while those with exon 51 skip amenable deletions had significantly fewer (11.9%) compared with other cohorts. DISCUSSION: This confirms previous observations of genotype-phenotype correlations in DMD and enhances information for trial design and clinical management.

Tm4sf1-marked Endothelial Subpopulation Is Dysregulated in Pulmonary Arterial Hypertension.

The identification and role of endothelial progenitor cells in pulmonary arterial hypertension (PAH) remain controversial. Single-cell omics analysis can shed light on endothelial progenitor cells and their potential contribution to PAH pathobiology. We aim to identify endothelial cells that may have stem/progenitor potential in rat lungs and assess their relevance to PAH. Differential expression, gene set enrichment, cell-cell communication, and trajectory reconstruction analyses were performed on lung endothelial cells from single-cell RNA sequencing of Sugen-hypoxia, monocrotaline, and control rats. Relevance to human PAH was assessed in multiple independent blood and lung transcriptomic data sets. Rat lung endothelial cells were visualized by immunofluorescence in situ, analyzed by flow cytometry, and assessed for tubulogenesis in vitro. A subpopulation of endothelial cells (endothelial arterial type 2 [EA2]) marked by Tm4sf1 (transmembrane 4 L six family member 1), a gene strongly implicated in cancer, harbored a distinct transcriptomic signature enriched for angiogenesis and CXCL12 signaling. Trajectory analysis predicted that EA2 has a less differentiated state compared with other endothelial subpopulations. Analysis of independent data sets revealed that TM4SF1 is downregulated in lungs and endothelial cells from patients and PAH models, is a marker for hematopoietic stem cells, and is upregulated in PAH circulation. TM4SF1+CD31+ rat lung endothelial cells were visualized in distal pulmonary arteries, expressed hematopoietic marker CD45, and formed tubules in coculture with lung fibroblasts. Our study uncovered a novel Tm4sf1-marked subpopulation of rat lung endothelial cells that may have stem/progenitor potential and demonstrated its relevance to PAH. Future studies are warranted to further elucidate the role of EA2 and Tm4sf1 in PAH.

A longitudinal study of creatine kinase and creatinine levels in Duchenne muscular dystrophy.

INTRODUCTION/AIMS: Management of Duchenne muscular dystrophy (DMD) has entered an era featuring novel treatments. Trackable noninvasive biomarkers could improve disease progression monitoring and drug effect detection. Our aim in this study was to measure changes in selected noninvasive biomarkers and assess their relationship to age and motor function. METHODS: We retrospectively studied 555 patients with DMD who had at least 12 months of treatment of glucocorticoids and were not enrolled in trials of potential disease-modifying therapies. We extracted biomarker data of serum creatine kinase (CK), serum creatinine (Cr), urine Cr, and urine Cr/urine osmolality (osm), as well as functional data for age at loss of ambulation and Functional Motor Scale (FMS) values from patients' clinical records. Data were analyzed using linear mixed-model analyses. RESULTS: CK, serum Cr, urine Cr, and urine Cr/urine osm all decreased with declining motor function. CK consistently decreased and FMS score consistently worsened with age without clear inflection points. There was an increased odds ratio for LOA with lower values of CK, serum Cr, urine Cr, and urine Cr/urine osm, most notably for urine Cr. DISCUSSION: Although individual biomarker values are challenging to directly apply clinically, our study has demonstrated that trends over time may complement functional measures in the assessment of individuals with DMD. Future studies could elucidate predictive utility of these biomarkers in assessing motor function changes in DMD.

Predicting Shunt Dependency from the Effect of Cerebrospinal Fluid Drainage on Ventricular Size.

BACKGROUND: Prolonged external ventricular drainage (EVD) in patients with subarachnoid hemorrhage (SAH) leads to morbidity, whereas early removal can have untoward effects related to recurrent hydrocephalus. A metric to help determine the optimal time for EVD removal or ventriculoperitoneal shunt (VPS) placement would be beneficial in preventing the prolonged, unnecessary use of EVD. This study aimed to identify whether dynamics of cerebrospinal fluid (CSF) biometrics can temporally predict VPS dependency after SAH. METHODS: This was a retrospective analysis of a prospective, single-center, observational study of patients with aneurysmal SAH who required EVD placement for hydrocephalus. Patients were divided into VPS-dependent (VPS+) and non-VPS dependent groups. We measured the bicaudate index (BCI) on all available computed tomography scans and calculated the change over time (ΔBCI). We analyzed the relationship of ΔBCI with CSF output by using Pearson's correlation. A k-nearest neighbor model of the relationship between ΔBCI and CSF output was computed to classify VPS. RESULTS: Fifty-eight patients met inclusion criteria. CSF output was significantly higher in the VPS+ group in the 7 days post EVD placement. There was a negative correlation between delta BCI and CSF output in the VPS+ group (negative delta BCI means ventricles become smaller) and a positive correlation in the VPS- group starting from days four to six after EVD placement (p < 0.05). A weighted k-nearest neighbor model for classification had a sensitivity of 0.75, a specificity of 0.70, and an area under the receiver operating characteristic curve of 0.80. CONCLUSIONS: The correlation of ΔBCI and CSF output is a reliable intraindividual biometric for VPS dependency after SAH as early as days four to six after EVD placement. Our machine learning model leverages this relationship between ΔBCI and cumulative CSF output to predict VPS dependency. Early knowledge of VPS dependency could be studied to reduce EVD duration in many centers (intensive care unit length of stay).

The effect of oral bisphosphonate therapy on vertebral morphometry and fractures in patients with Duchenne muscular dystrophy and glucocorticoid-induced osteoporosis.

INTRODUCTION/AIMS: Glucocorticoid-induced osteoporosis with vertebral fractures is frequent in patients with Duchenne muscular dystrophy (DMD). In this study, we evaluated the effects of oral bisphosphonate (BP) therapy on the prevalence and severity of vertebral fractures by vertebral morphometry assessment. METHODS: We reviewed the records and radiographs of patients with DMD who had been treated with oral BP (weekly alendronate) and had undergone routine spine radiographic monitoring for glucocorticoid-induced osteoporosis at Cincinnati Children's Hospital Medical Center between 2010 and 2017. Study outcomes were thoracic and lumbar vertebral fracture prevalence and severity, assessed by Genant semiquantitative grading of vertebral morphometry, for up to 5 years of treatment. RESULTS: Fifty-two patients (median age, 11.8 years; 88% prepubertal; 31% nonambulatory) had been treated with long-term glucocorticoids (median duration, 4.7 years at BP start). Most patients (75%) had mild vertebral height loss or fractures (Genant grade = 0 or 1) at baseline. The prevalence of vertebral fractures at each year of treatment was not statistically different from that at baseline (P = .08-1.00). Serial radiographs showed no longitudinal change in severity by Genant grade in most vertebrae (64%-80%). Improvement in vertebral fracture grade was observed in some patients. DISCUSSION: We observed stable prevalence of vertebral fractures and no change in severity by Genant grade in most vertebrae for up to 5 years of treatment. Oral BP may mitigate development or progression of vertebral fractures and be beneficial for secondary prevention of glucocorticoid-induced osteoporosis in this population.

Age-related changes in appendicular lean mass in males with Duchenne muscular dystrophy: A retrospective review.

BACKGROUND: Appendicular lean mass (ALM) trajectory in males with Duchenne muscular dystrophy (DMD) has potential applicability for treatment and research and has not been characterized. METHODS: This chart review included longitudinal data on 499 males with DMD receiving glucocorticoids and 693 controls, ages 5 to 22.9 y. ALM (kg) was measured by dual energy x-ray absorptiometry (DXA). Appendicular lean mass index (ALMI, kg/m2 ) was calculated for height adjustment. Reference centiles were generated using data from healthy controls, and ALM and ALMI Z-scores were calculated for patients with DMD. Generalized linear models were used to estimate median Z-scores by age and functional mobility status (FMS) score. ALM velocity by age was modeled using superimposition, translation and rotation (SITAR). RESULTS: Compared to controls, males with DMD had lower ALM from an early age. ALMI Z-scores dropped below 0 at age 8 y or FMS of 2, and below -2.0 at age 13 y or FMS of 3 (P < .05). Age at peak ALM velocity was similar in both groups, but the magnitude was higher in controls (3.5 vs. 0.7 kg/y, P < .0001). Patients with DMD had a transient loss of ALM around age 12 y, an increase at age 14 y, then a further decline at age 16 y, remaining low thereafter. CONCLUSIONS: Males with DMD have progressive decline in lean mass with age and worsening functional mobility. DXA measurement of ALM may be useful for monitoring lean mass status in patients with DMD, providing valuable information for individual treatment plans and research endeavors.

Global versus individual muscle segmentation to assess quantitative MRI-based fat fraction changes in neuromuscular diseases.

OBJECTIVES: Magnetic resonance imaging (MRI) constitutes a powerful outcome measure in neuromuscular disorders, yet there is a broad diversity of approaches in data acquisition and analysis. Since each neuromuscular disease presents a specific pattern of muscle involvement, the recommended analysis is assumed to be the muscle-by-muscle approach. We, therefore, performed a comparative analysis of different segmentation approaches, including global muscle segmentation, to determine the best strategy for evaluating disease progression. METHODS: In 102 patients (21 immune-mediated necrotizing myopathy/IMNM, 21 inclusion body myositis/IBM, 10 GNE myopathy/GNEM, 19 Duchenne muscular dystrophy/DMD, 12 dysferlinopathy/DYSF, 7 limb-girdle muscular dystrophy/LGMD2I, 7 Pompe disease, 5 spinal muscular atrophy/SMA), two MRI scans were obtained at a 1-year interval in thighs and lower legs. Regions of interest (ROIs) were drawn in individual muscles, muscle groups, and the global muscle segment. Standardized response means (SRMs) were determined to assess sensitivity to change in fat fraction (ΔFat%) in individual muscles, muscle groups, weighted combinations of muscles and muscle groups, and in the global muscle segment. RESULTS: Global muscle segmentation gave high SRMs for ΔFat% in thigh and lower leg for IMNM, DYSF, LGMD2I, DMD, SMA, and Pompe disease, and only in lower leg for GNEM and thigh for IBM. CONCLUSIONS: Global muscle segment Fat% showed to be sensitive to change in most investigated neuromuscular disorders. As compared to individual muscle drawing, it is a faster and an easier approach to assess disease progression. The use of individual muscle ROIs, however, is still of interest for exploring selective muscle involvement. KEY POINTS: • MRI-based evaluation of fatty replacement in muscles is used as an outcome measure in the assessment of 1-year disease progression in 8 different neuromuscular diseases. • Different segmentation approaches, including global muscle segmentation, were evaluated for determining 1-year fat fraction changes in lower limb skeletal muscles. • Global muscle segment fat fraction has shown to be sensitive to change in lower leg and thigh in most of the investigated neuromuscular diseases.

The age-related associative deficit simulated by relational divided attention: encoding strategy and recollection.

According to the associative deficit hypothesis, older adults experience greater difficulty in remembering associations between pieces of information than young adults, despite their relatively intact memory for individual items. It has been demonstrated that this deficit could be simulated by depleting resources for relational processing. The current study examines the possible mechanisms underlying this simulation. Item and associative memory were assessed using a process dissociation paradigm in which word pairs were encoded under full attention (FA) or relational divided attention (DA) conditions across three groups: FA older adults (n = 24), FA young adults (n = 24), and DA young adults (n = 24). Recollection and familiarity were estimated for the associative memory performance. Relative to FA young adults, both older adults and DA young adults showed an associative deficit, and reduced use of recollection and high-level relational encoding strategies. Regression analyses suggested that the effects of age and DA on associative memory were largely driven by the variance in recollection and encoding strategy use. The results suggest that depletion of attentional resources for relational processing impairs associative memory through disrupting the use of effective encoding strategies and recollection, which largely simulates age-related associative deficit.

Neurodevelopmental, behavioral, and emotional symptoms in Becker muscular dystrophy.

INTRODUCTION: Becker muscular dystrophy (BMD) results in decreased dystrophin with implications for mental health. METHODS: This is a retrospective case series of neurodevelopmental, behavioral, and emotional symptoms and respective pharmacotherapies of 70 patients with BMD. RESULTS: Fifty-four (77.1%) patients exhibited at least one symptom, and 19 (27.1%) patients exhibited four or more symptoms. The most prevalent symptoms were specific learning disabilities or special education needs (31.4%), inattention/hyperactivity (35.7%), language/speech delays (35.7%), and emotional or behavioral dysregulation (38.6%). Fisher's exact tests indicated that anxiety was more prevalent with mutations upstream of exon 30 (P = .049), but the prevalence of other symptoms did not differ with respect to mutation sites. Similarly, the number of symptoms individual patients with BMD exhibited did not differ with respect to mutation sites. Seventeen (24.3%) patients required pharmacotherapy to manage symptoms. DISCUSSION: Neurodevelopmental, behavioral, and emotional symptoms are prevalent in patients with BMD regardless of dystrophin gene mutation site.

Recombinant human insulin-like growth factor-1 therapy for 6 months improves growth but not motor function in boys with Duchenne muscular dystrophy.

INTRODUCTION: Recombinant human insulin-like growth factor-1 (rhIGF-1) is a growth factor and has anabolic effects on muscle. We investigated whether rhIGF-1 therapy: 1) improves or preserves muscle function; and 2) improves growth in boys with Duchenne muscular dystrophy (DMD). METHODS: In this study we compared prepubescent, ambulatory, glucocorticoid-treated boys with DMD (n = 17) vs controls (glucocorticoid therapy only, n = 21) in a 6-month-long, prospective, randomized, controlled trial of subcutaneous rhIGF-1 therapy. The primary outcome was 6-minute walk distance (6MWD). Secondary outcomes included height velocity (HV), change in height standard deviation score (ΔHtSDS), motor function, cardiopulmonary function, body composition, insulin sensitivity, quality of life, and safety. RESULTS: Change in 6MWD was similar between groups (rhIGF-1 vs controls [mean ± SD]: 3.4 ± 32.4 vs -5.1 ± 50.2 meters, P = .53). Treated subjects grew more than controls (HV: 6.5 ± 1.7 vs 3.3 ± 1.3 cm/year, P < .0001; 6-month ΔHtSDS: 0.25, P < .0001). Lean mass and insulin sensitivity increased in treated subjects. DISCUSSION: In boys with DMD, 6 months of rhIGF-1 therapy did not change motor function, but it improved linear growth.

Neurodevelopmental, behavioral, and emotional symptoms common in Duchenne muscular dystrophy.

INTRODUCTION: We studied neurodevelopmental and behavioral/emotional symptoms in patients with Duchenne muscular dystrophy (DMD). METHODS: Retrospective case series of neurodevelopmental and behavioral/emotional symptoms obtained through review of systems of 700 DMD patients in relation to dystrophin gene mutations. RESULTS: The most common symptoms encountered were emotional/behavioral dysregulation (38.7%), inattention/hyperactive features (31.4%), obsessive and compulsive features (25.0%), and language/speech delays (24.4%). Most patients (72.7%) had at least one symptom. Patients with mutations near the 3' end of the dystrophin gene were at higher risk for developing inattention/hyperactive features, language/speech delays, and global intellectual delays. Those with mutations between exon 31 and 79 had higher risk of clustering of symptoms when compared with those upstream of exon 30. DISCUSSION: Neurodevelopmental, emotional, and behavioral symptoms are common comorbidities in DMD. There is higher prevalence of inattention/hyperactive features, language/speech delays, and global intellectual delays in genotypes affecting the 3' end of the dystrophin gene.

The care of patients with Duchenne, Becker, and other muscular dystrophies in the COVID-19 pandemic.

The coronavirus disease 2019 (COVID-19) pandemic has resulted in the reorganization of health-care settings affecting clinical care delivery to patients with Duchenne and Becker muscular dystrophy (DBMD) as well as other inherited muscular dystrophies. The magnitude of the impact of this public health emergency on the care of patients with DBMD is unclear as they are suspected of having an increased risk for severe manifestations of COVID-19. In this article, the authors discuss their consensus recommendations pertaining to care of these patients during the pandemic. We address issues surrounding corticosteroid and exon-skipping treatments, cardiac medications, hydroxychloroquine use, emergency/respiratory care, rehabilitation management, and the conduct of clinical trials. We highlight the importance of collaborative treatment decisions between the patient, family, and health-care provider, considering any geographic or institution-specific policies and precautions for COVID-19. We advocate for continuing multidisciplinary care for these patients using telehealth.

Duchenne Muscular Dystrophy: the Heart of the Matter.

PURPOSE OF REVIEW: Duchenne muscular dystrophy is one of many neuromuscular disorders, but it frequently causes severe disability early in life and early death. Cardiac involvement is an important cause of morbidity and mortality. RECENT FINDINGS: Heart disease in Duchenne muscular dystrophy can include a cardiomyopathy leading to end-stage heart failure along with associated supraventricular and ventricular arrhythmias. This article reviews the diagnosis and treatment of heart disease in Duchenne muscular dystrophy as well as emerging therapies.

Comparison of Pulmonary Function Decline in Steroid-Treated and Steroid-Naïve Patients with Duchenne Muscular Dystrophy.

OBJECTIVE: To describe and compare the lung function decline in patients with Duchenne muscular dystrophy on glucocorticoid therapy in contrast with glucocorticoid-naïve patients, and to define the deciles of pulmonary decline in glucocorticoid-treated patients. STUDY DESIGN: This retrospective study examined lung function of patients with Duchenne muscular dystrophy over 6 years of age followed between 2001 and 2015 at 2 centers-glucocorticoid-treated patients in Cincinnati, Ohio, and glucocorticoid-naïve patients in Paris, France. Forced vital capacity (FVC, FVC%), forced expiratory volume in 1 second, maximal inspiratory pressure, maximal expiratory pressure, and peak expiratory flow data were analyzed. Only FVC data were available for the French cohort. RESULTS: There were 170 glucocorticoid-treated patients (92%), 5 patients (2.7%) with past glucocorticoid use, and 50 French glucocorticoid-naïve patients. The peak absolute FVC was higher and was achieved at earlier ages in glucocorticoid-treated compared with glucocorticoid-naïve patients (peak FVC, 2.4 ± 0.6 L vs 1.9 ± 0.7 L; P < .0001; ages 13.5 ± 3.0 years vs 14.3 ± 2.8 years; P = .03). The peak FVC% was also higher and was achieved at earlier ages in glucocorticoid-treated patients (peak FVC%, 105.1 ± 25.1% vs 56 ± 20.9%; P < .0001; ages 11.9 ± 2.9 years vs 13.6 ± 3.2 years; P = .002). Rates of decline for both groups varied with age. Maximal rates of decline were 5.0 ± 0.26% per year (12-20 years) for glucocorticoid-treated and 5.1 ± 0.39% per year for glucocorticoid-naïve patients (11-20 years; P = .2). Deciles of FVC% decline in glucocorticoid-treated patients show that patients experience accelerated decline at variable ages. CONCLUSIONS: These data describe nonlinear rates of decline of pulmonary function in patients with Duchenne muscular dystrophy, with improved function in glucocorticoid-treated patients. FVC% deciles may be a useful tool for clinical and research use.

Towards regulatory endorsement of drug development tools to promote the application of model-informed drug development in Duchenne muscular dystrophy.

Drug development for rare diseases is challenged by small populations and limited data. This makes development of clinical trial protocols difficult and contributes to the uncertainty around whether or not a potential therapy is efficacious. The use of data standards to aggregate data from multiple sources, and the use of such integrated databases to develop statistical models can inform protocol development and reduce the risks in developing new therapies. Achieving regulatory endorsement of such models through defined pathways at the US Food and Drug Administration and European Medicines Authority allows such tools to be used by the drug development community for defined contexts of use without further need for discussion of the underlying model(s). The Duchenne Regulatory Science Consortium (D-RSC) has brought together multiple stakeholders to develop a clinical trial simulation tool for Duchenne muscular dystrophy using such an approach. Here we describe the work of D-RSC as an example of how such an approach may be effective at reducing uncertainty in drug development for rare diseases, and thus bringing effective therapies to patients faster.

Progression of Ankle Plantarflexion Contractures and Functional Decline in Duchenne Muscular Dystrophy: Implications for Physical Therapy Management.

PURPOSE: This study characterizes the progressive loss of ankle dorsiflexion range of motion in boys with Duchenne muscular dystrophy (DMD), the relationship to functional decline, and the implications for physical therapy management. METHODS: Longitudinal data for 332 boys with DMD were extracted from medical records and analyzed. Summary statistics for age, number of visits, ankle dorsiflexion measures, and North Star Ambulatory Assessment (NSAA) scores were computed. RESULTS: Ankle dorsiflexion motion ranged from -32.5 to 25 degrees. Progression of ankle contractures is demonstrated by a trend line: slope -1.43 per year. NSAA score was estimated to decline approximately 0.23 points per 1 degree of ankle dorsiflexion lost. CONCLUSIONS: The results of this study describe the progression of ankle contractures and functional decline in DMD. The findings may help inform decisions regarding interventions to support participants with DMD and their families.

Ataluren in patients with nonsense mutation Duchenne muscular dystrophy (ACT DMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a severe, progressive, and rare neuromuscular, X-linked recessive disease. Dystrophin deficiency is the underlying cause of disease; therefore, mutation-specific therapies aimed at restoring dystrophin protein production are being explored. We aimed to assess the efficacy and safety of ataluren in ambulatory boys with nonsense mutation DMD. METHODS: We did this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 54 sites in 18 countries located in North America, Europe, the Asia-Pacific region, and Latin America. Boys aged 7-16 years with nonsense mutation DMD and a baseline 6-minute walk distance (6MWD) of 150 m or more and 80% or less of the predicted normal value for age and height were randomly assigned (1:1), via permuted block randomisation (block size of four) using an interactive voice-response or web-response system, to receive ataluren orally three times daily (40 mg/kg per day) or matching placebo. Randomisation was stratified by age (<9 years vs ≥9 years), duration of previous corticosteroid use (6 months to <12 months vs ≥12 months), and baseline 6MWD (<350 m vs ≥350 m). Patients, parents and caregivers, investigational site personnel, PTC Therapeutics employees, and all other study personnel were masked to group allocation until after database lock. The primary endpoint was change in 6MWD from baseline to week 48. We additionally did a prespecified subgroup analysis of the primary endpoint, based on baseline 6MWD, which is reflective of anticipated rates of disease progression over 1 year. The primary analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01826487. FINDINGS: Between March 26, 2013, and Aug 26, 2014, we randomly assigned 230 patients to receive ataluren (n=115) or placebo (n=115); 228 patients comprised the intention-to-treat population. The least-squares mean change in 6MWD from baseline to week 48 was -47·7 m (SE 9·3) for ataluren-treated patients and -60·7 m (9·3) for placebo-treated patients (difference 13·0 m [SE 10·4], 95% CI -7·4 to 33·4; p=0·213). The least-squares mean change for ataluren versus placebo in the prespecified subgroups was -7·7 m (SE 24·1, 95% CI -54·9 to 39·5; p=0·749) in the group with a 6MWD of less than 300 m, 42·9 m (15·9, 11·8-74·0; p=0·007) in the group with a 6MWD of 300 m or more to less than 400 m, and -9·5 m (17·2, -43·2 to 24·2; p=0·580) in the group with a 6MWD of 400 m or more. Ataluren was generally well tolerated and most treatment-emergent adverse events were mild to moderate in severity. Eight (3%) patients (n=4 per group) reported serious adverse events; all except one event in the placebo group (abnormal hepatic function deemed possibly related to treatment) were deemed unrelated to treatment. INTERPRETATION: Change in 6MWD did not differ significantly between patients in the ataluren group and those in the placebo group, neither in the intention-to-treat population nor in the prespecified subgroups with a baseline 6MWD of less than 300 m or 400 m or more. However, we recorded a significant effect of ataluren in the prespecified subgroup of patients with a baseline 6MWD of 300 m or more to less than 400 m. Baseline 6MWD values within this range were associated with a more predictable rate of decline over 1 year; this finding has implications for the design of future DMD trials with the 6-minute walk test as the endpoint. FUNDING: PTC Therapeutics.