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INTRODUCTION/AIMS: Although muscle structure measures from magnetic resonance imaging (MRI) have been used to assess disease severity in muscular dystrophies, little is known about how these measures are affected in myotonic dystrophy type 2 (DM2). We aim to characterize lower extremity muscle fat fraction (MFF) as a potential biomarker of disease severity, and evaluate its relationship with motor performance in DM2. METHODS: 3-Tesla MRIs were obtained from nine patients with DM2 and six controls using a T1W-Dixon protocol. To calculate MFF, muscle volumes were segmented from proximal, middle, and distal regions of the thigh and calf. Associations between MFF and motor performance were calculated using Spearman's correlations (ρ). RESULTS: Mean age of DM2 participants was 62 ± 11 y (89% female), and mean symptom duration was 20 ± 12 y. Compared to controls, the DM2 group had significantly higher MFF in the thigh and the calf segments (p-value = .002). The highest MFF at the thigh in DM2 was located in the posterior compartment (39.7 ± 12.9%) and at the calf was the lateral compartment (31.5 ± 8.7%). In the DM2 group, we found a strong correlation between the posterior thigh MFF and the 6-min walk test (ρ = -.90, p-value = .001). The lateral calf MFF was also strongly correlated with the step test (ρ = -0.82, p-value = .006). DISCUSSION: Our pilot data suggest a potential correlation between lower extremity MFF and some motor performance tests in DM2. Longitudinal studies with larger sample sizes are required to validate MFF as a marker of disease severity in DM2.
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Distrofias Musculares , Distrofia Miotónica , Humanos , Femenino , Masculino , Distrofia Miotónica/diagnóstico por imagen , Proyectos Piloto , Músculo Esquelético/diagnóstico por imagen , Extremidad Inferior/diagnóstico por imagen , Imagen por Resonancia Magnética/métodosRESUMEN
Duchenne muscular dystrophy (DMD) is caused by loss of dystrophin in muscle, and while all patients share the primary gene and biochemical defect, there is considerable patient-patient variability in clinical symptoms. We sought to develop multivariate models of serum protein biomarkers that explained observed variation, using functional outcome measures as proxies for severity. Serum samples from 39 steroid-naïve DMD boys 4 to <7 years enrolled into a clinical trial of vamorolone were studied (NCT02760264). Four assessments of gross motor function were carried out for each participant over a 6-week interval, and their mean was used as response for biomarker models. Weighted correlation network analysis was used for unsupervised clustering of 1305 proteins quantified using SOMAscan® aptamer profiling to define highly representative and connected proteins. Multivariate models of biomarkers were obtained for time to stand performance (strength phenotype; 17 proteins) and 6 min walk performance (endurance phenotype; 17 proteins) including some shared proteins. Identified proteins were tested with associations of mRNA expression with histological severity of muscle from dystrophinopathy patients (n = 28) and normal controls (n = 6). Strong associations predictive of both clinical and histological severity were found for ERBB4 (reductions in both blood and muscle with increasing severity), SOD1 (reductions in muscle and increases in blood with increasing severity) and CNTF (decreased levels in blood and muscle with increasing severity). We show that performance of DMD boys was effectively modeled with serum proteins, proximal strength associated with growth and remodeling pathways and muscle endurance centered on TGFß and fibrosis pathways in muscle.
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Biomarcadores/sangre , Distrofina/sangre , Distrofia Muscular de Duchenne/sangre , Niño , Preescolar , Humanos , Masculino , Distrofia Muscular de Duchenne/tratamiento farmacológico , Distrofia Muscular de Duchenne/patología , Oligonucleótidos , Fenotipo , Pregnadienodioles/administración & dosificación , Índice de Severidad de la Enfermedad , Esteroides/metabolismoRESUMEN
Nuclear factor κB (NF-κB) is a transcription factor important for regulating innate and adaptive immunity, cellular proliferation, apoptosis, and senescence. Dysregulation of NF-κB and its upstream regulator IκB kinase (IKK) contributes to the pathogenesis of multiple inflammatory and degenerative diseases as well as cancer. An 11-amino acid peptide containing the NF-κB essential modulator (NEMO)-binding domain (NBD) derived from the C-terminus of ß subunit of IKK, functions as a highly selective inhibitor of the IKK complex by disrupting the association of IKKß and the IKKγ subunit NEMO. A structure-based pharmacophore model was developed to identify NBD mimetics by in silico screening. Two optimized lead NBD mimetics, SR12343 and SR12460, inhibited tumor necrosis factor α (TNF-α)- and lipopolysaccharide (LPS)-induced NF-κB activation by blocking the interaction between IKKß and NEMO and suppressed LPS-induced acute pulmonary inflammation in mice. Chronic treatment of a mouse model of Duchenne muscular dystrophy (DMD) with SR12343 and SR12460 attenuated inflammatory infiltration, necrosis and muscle degeneration, demonstrating that these small-molecule NBD mimetics are potential therapeutics for inflammatory and degenerative diseases.
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Materiales Biomiméticos/farmacología , Quinasa I-kappa B/antagonistas & inhibidores , Distrofia Muscular de Duchenne/tratamiento farmacológico , Neumonía/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Animales , Materiales Biomiméticos/química , Línea Celular , Femenino , Células HEK293 , Humanos , Quinasa I-kappa B/química , Quinasa I-kappa B/metabolismo , Inflamación/tratamiento farmacológico , Lipopolisacáridos , Ratones , Ratones Endogámicos C57BL , Necrosis/tratamiento farmacológico , Dominios Proteicos , Células RAW 264.7RESUMEN
BACKGROUND: Treatment with corticosteroids is recommended for Duchenne muscular dystrophy (DMD) patients to slow the progression of weakness. However, chronic corticosteroid treatment causes significant morbidities. Vamorolone is a first-in-class anti-inflammatory investigational drug that has shown evidence of efficacy in DMD after 24 weeks of treatment at 2.0 or 6.0 mg/kg/day. Here, open-label efficacy and safety experience of vamorolone was evaluated over a period of 18 months in trial participants with DMD. METHODS AND FINDINGS: A multicenter, open-label, 24-week trial (VBP15-003) with a 24-month long-term extension (VBP15-LTE) was conducted by the Cooperative International Neuromuscular Research Group (CINRG) and evaluated drug-related effects of vamorolone on motor outcomes and corticosteroid-associated safety concerns. The study was carried out in Canada, US, UK, Australia, Sweden, and Israel, from 2016 to 2019. This report covers the initial 24-week trial and the first 12 months of the VBP15-LTE trial (total treatment period 18 months). DMD trial participants (males, 4 to <7 years at entry) treated with 2.0 or 6.0 mg/kg/day vamorolone for the full 18-month period (n = 23) showed clinical improvement of all motor outcomes from baseline to month 18 (time to stand velocity, p = 0.012 [95% CI 0.010, 0.068 event/second]; run/walk 10 meters velocity, p < 0.001 [95% CI 0.220, 0.491 meters/second]; climb 4 stairs velocity, p = 0.001 [95% CI 0.034, 0.105 event/second]; 6-minute walk test, p = 0.001 [95% CI 31.14, 93.38 meters]; North Star Ambulatory Assessment, p < 0.001 [95% CI 2.702, 6.662 points]). Outcomes in vamorolone-treated DMD patients (n = 46) were compared to group-matched participants in the CINRG Duchenne Natural History Study (corticosteroid-naïve, n = 19; corticosteroid-treated, n = 68) over a similar 18-month period. Time to stand was not significantly different between vamorolone-treated and corticosteroid-naïve participants (p = 0.088; least squares [LS] mean 0.042 [95% CI -0.007, 0.091]), but vamorolone-treated participants showed significant improvement compared to group-matched corticosteroid-naïve participants for run/walk 10 meters velocity (p = 0.003; LS mean 0.286 [95% CI 0.104, 0.469]) and climb 4 stairs velocity (p = 0.027; LS mean 0.059 [95% CI 0.007, 0.111]). The vamorolone-related improvements were similar in magnitude to corticosteroid-related improvements. Corticosteroid-treated participants showed stunting of growth, whereas vamorolone-treated trial participants did not (p < 0.001; LS mean 15.86 [95% CI 8.51, 23.22]). Physician-reported incidences of adverse events (AEs) for Cushingoid appearance, hirsutism, weight gain, and behavior change were less for vamorolone than published incidences for prednisone and deflazacort. Key limitations to the study were the open-label design, and use of external comparators. CONCLUSIONS: We observed that vamorolone treatment was associated with improvements in some motor outcomes as compared with corticosteroid-naïve individuals over an 18-month treatment period. We found that fewer physician-reported AEs occurred with vamorolone than have been reported for treatment with prednisone and deflazacort, and that vamorolone treatment did not cause the stunting of growth seen with these corticosteroids. This Phase IIa study provides Class III evidence to support benefit of motor function in young boys with DMD treated with vamorolone 2.0 to 6.0 mg/kg/day, with a favorable safety profile. A Phase III RCT is underway to further investigate safety and efficacy. TRIAL REGISTRATION: Clinical trials were registered at www.clinicaltrials.gov, and the links to each trial are as follows (as provided in manuscript text): VBP15-002 [NCT02760264] VBP15-003 [NCT02760277] VBP15-LTE [NCT03038399].
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Actividad Motora/efectos de los fármacos , Distrofia Muscular de Duchenne/tratamiento farmacológico , Pregnadienodioles/uso terapéutico , Corticoesteroides/efectos adversos , Niño , Preescolar , Progresión de la Enfermedad , Glucocorticoides/efectos adversos , Humanos , Masculino , Prednisona/uso terapéutico , Pregnadienodioles/metabolismo , Resultado del Tratamiento , Caminata/fisiologíaRESUMEN
We performed an observational, natural history study of males with in-frame dystrophin gene deletions causing Becker muscular dystrophy (BMD). A prospective natural history study collected longitudinal medical, strength, and timed function assessments. Eighty-three participants with genetically confirmed BMD were enrolled (age range 5.6-75.4 years). Lower extremity function and the percentage of participants who retained ambulation declined across the age span. The largest single group of participants had in-frame deletions that corresponded to an out-of-frame deletion treated with an exon 45 skip to restore the reading frame. This group of 54 participants showed similarities in baseline motor functional assessments when compared to the group of all others in the study. A prospective natural history cohort with in-frame dystrophin gene deletions offers the potential to contribute to clinical trial readiness for BMD and to analyze therapeutic benefit of exon skipping for Duchenne muscular dystrophy.
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Distrofina/genética , Distrofia Muscular de Duchenne/diagnóstico , Adolescente , Adulto , Anciano , Niño , Preescolar , Progresión de la Enfermedad , Eliminación de Gen , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/fisiopatología , Fenotipo , Estudios Prospectivos , Evaluación de Síntomas , Adulto JovenRESUMEN
Identification of variants in the acid α-glucosidase (GAA) gene in Pompe disease provides valuable insights and systematic overviews are needed. We report on the number, nature, frequency, and geographic distribution of GAA sequence variants listed in the Pompe Registry, a long-term, observational program and the largest global repository of Pompe disease data. Variant information was reviewed and compared with publicly available GAA databases/resources. Among 1,079 eligible patients, 2,075 GAA variants (80 unique novel) were reported. Variants were listed by groups representing Pompe disease phenotypes. Patients were classified as Group A: Symptom onset ≤ 12 months of age with cardiomyopathy; Group B: Symptom onset ≤ 12 years of age (includes patients with symptom onset ≤ 12 months of age without cardiomyopathy); or Group C: Symptom onset > 12 years of age. Likely impact of novel variants was predicted using bioinformatics algorithms. Variants were classified by pathogenicity using ACMG guidelines. Data reported from the Pompe Registry provide new information about the distribution of GAA variants globally and across the clinical spectrum, add to the number and diversity of GAA variants registered in public databases through published data sharing, provide a first indication of the severity of novel variants, and assist in diagnostic practice and outcome prediction.
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Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Enfermedad del Almacenamiento de Glucógeno Tipo II/genética , Mutación , Fenotipo , alfa-Glucosidasas/genética , Alelos , Bases de Datos Genéticas , Estudios de Asociación Genética/métodos , Sitios Genéticos , Variación Genética , Genotipo , Salud Global , Enfermedad del Almacenamiento de Glucógeno Tipo II/diagnóstico , Enfermedad del Almacenamiento de Glucógeno Tipo II/epidemiología , Humanos , Sistema de RegistrosRESUMEN
BACKGROUND: Glucocorticoid treatment is recommended as a standard of care in Duchenne muscular dystrophy; however, few studies have assessed the long-term benefits of this treatment. We examined the long-term effects of glucocorticoids on milestone-related disease progression across the lifespan and survival in patients with Duchenne muscular dystrophy. METHODS: For this prospective cohort study, we enrolled male patients aged 2-28 years with Duchenne muscular dystrophy at 20 centres in nine countries. Patients were followed up for 10 years. We compared no glucocorticoid treatment or cumulative treatment duration of less than 1 month versus treatment of 1 year or longer with regard to progression of nine disease-related and clinically meaningful mobility and upper limb milestones. We used Kaplan-Meier analyses to compare glucocorticoid treatment groups for time to stand from supine of 5 s or longer and 10 s or longer, and loss of stand from supine, four-stair climb, ambulation, full overhead reach, hand-to-mouth function, and hand function. Risk of death was also assessed. This study is registered with ClinicalTrials.gov, number NCT00468832. FINDINGS: 440 patients were enrolled during two recruitment periods (2006-09 and 2012-16). Time to all disease progression milestone events was significantly longer in patients treated with glucocorticoids for 1 year or longer than in patients treated for less than 1 month or never treated (log-rank p<0·0001). Glucocorticoid treatment for 1 year or longer was associated with increased median age at loss of mobility milestones by 2·1-4·4 years and upper limb milestones by 2·8-8·0 years compared with treatment for less than 1 month. Deflazacort was associated with increased median age at loss of three milestones by 2·1-2·7 years in comparison with prednisone or prednisolone (log-rank p<0·012). 45 patients died during the 10-year follow-up. 39 (87%) of these deaths were attributable to Duchenne-related causes in patients with known duration of glucocorticoids usage. 28 (9%) deaths occurred in 311 patients treated with glucocorticoids for 1 year or longer compared with 11 (19%) deaths in 58 patients with no history of glucocorticoid use (odds ratio 0·47, 95% CI 0·22-1·00; p=0·0501). INTERPRETATION: In patients with Duchenne muscular dystrophy, glucocorticoid treatment is associated with reduced risk of losing clinically meaningful mobility and upper limb disease progression milestones across the lifespan as well as reduced risk of death. FUNDING: US Department of Education/National Institute on Disability and Rehabilitation Research; US Department of Defense; National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases; and Parent Project Muscular Dystrophy.
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Glucocorticoides/uso terapéutico , Distrofia Muscular de Duchenne/tratamiento farmacológico , Adolescente , Adulto , Niño , Preescolar , Discapacidades del Desarrollo/etiología , Discapacidades del Desarrollo/mortalidad , Discapacidades del Desarrollo/prevención & control , Progresión de la Enfermedad , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Cuidados a Largo Plazo , Masculino , Trastornos del Movimiento/etiología , Trastornos del Movimiento/mortalidad , Trastornos del Movimiento/prevención & control , Distrofia Muscular de Duchenne/mortalidad , Estudios Prospectivos , Calidad de Vida , Adulto JovenRESUMEN
For many neuromuscular diseases (NMDs), cardiac disease represents a major cause of morbidity and mortality. The management of cardiac disease in NMDs is made challenging by the broad clinical heterogeneity that exists among many NMDs and by limited knowledge about disease-specific cardiovascular pathogenesis and course-modifying interventions. The overlay of compromise in peripheral muscle function and other organ systems, such as the lungs, also makes the simple application of endorsed adult or pediatric heart failure guidelines to the NMD population problematic. In this statement, we provide background on several NMDs in which there is cardiac involvement, highlighting unique features of NMD-associated myocardial disease that require clinicians to tailor their approach to prevention and treatment of heart failure. Undoubtedly, further investigations are required to best inform future guidelines on NMD-specific cardiovascular health risks, treatments, and outcomes.
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Cardiomiopatías/diagnóstico , Enfermedades Musculares/diagnóstico , Enfermedades Neuromusculares/diagnóstico , American Heart Association , Síndrome de Barth/diagnóstico , Síndrome de Barth/genética , Síndrome de Barth/metabolismo , Síndrome de Barth/patología , Cardiomiopatías/complicaciones , Cardiomiopatías/patología , Ataxia de Friedreich/diagnóstico , Ataxia de Friedreich/metabolismo , Ataxia de Friedreich/patología , Humanos , Enfermedades Musculares/metabolismo , Enfermedades Musculares/patología , Distrofia Muscular de Cinturas/diagnóstico , Distrofia Muscular de Cinturas/metabolismo , Distrofia Muscular de Cinturas/patología , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/patología , Distrofia Muscular de Emery-Dreifuss/diagnóstico , Distrofia Muscular de Emery-Dreifuss/metabolismo , Distrofia Muscular de Emery-Dreifuss/patología , Miopatías Estructurales Congénitas/diagnóstico , Miopatías Estructurales Congénitas/genética , Miopatías Estructurales Congénitas/metabolismo , Miopatías Estructurales Congénitas/patología , Distrofia Miotónica/diagnóstico , Distrofia Miotónica/metabolismo , Distrofia Miotónica/patología , Enfermedades Neuromusculares/complicaciones , Enfermedades Neuromusculares/patología , Factores de Riesgo , Estados UnidosRESUMEN
We report a first-in-patient study of vamorolone, a first-in-class dissociative steroidal anti-inflammatory drug, in Duchenne muscular dystrophy. This 2-week, open-label Phase IIa multiple ascending dose study (0.25, 0.75, 2.0, and 6.0 mg/kg/day) enrolled 48 boys with Duchenne muscular dystrophy (4 to <7 years), with outcomes including clinical safety, pharmacokinetics and pharmacodynamic biomarkers. The study design included pharmacodynamic biomarkers in three contexts of use: 1. Secondary outcomes for pharmacodynamic safety (insulin resistance, adrenal suppression, bone turnover); 2. Exploratory outcomes for drug mechanism of action; 3. Exploratory outcomes for expanded pharmacodynamic safety. Vamorolone was safe and well-tolerated through the highest dose tested (6.0 mg/kg/day) and pharmacokinetics of vamorolone were similar to prednisolone. Using pharmacodynamic biomarkers, the study demonstrated improved safety of vamorolone versus glucocorticoids as shown by reduction of insulin resistance, beneficial changes in bone turnover (loss of increased bone resorption and decreased bone formation only at the highest dose level), and a reduction in adrenal suppression. Exploratory biomarkers of pharmacodynamic efficacy showed an anti-inflammatory mechanism of action and a beneficial effect on plasma membrane stability, as demonstrated by a dose-responsive decrease in serum creatine kinase activity. With an array of pre-selected biomarkers in multiple contexts of use, we demonstrate the development of the first dissociative steroid that preserves anti-inflammatory efficacy and decreases steroid-associated safety concerns. Ongoing extension studies offer the potential to bridge exploratory efficacy biomarkers to clinical outcomes.
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Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Distrofia Muscular de Duchenne/tratamiento farmacológico , Pregnadienodioles/farmacología , Pregnadienodioles/uso terapéutico , Administración Oral , Antiinflamatorios/sangre , Biomarcadores/sangre , Glucemia/análisis , Niño , Preescolar , Humanos , Hidrocortisona/sangre , Insulina/sangre , Masculino , Distrofia Muscular de Duchenne/metabolismo , Pregnadienodioles/sangreRESUMEN
Serum biomarkers in Duchenne muscular dystrophy (DMD) may provide deeper insights into disease pathogenesis, suggest new therapeutic approaches, serve as acute read-outs of drug effects, and be useful as surrogate outcome measures to predict later clinical benefit. In this study a large-scale biomarker discovery was performed on serum samples from patients with DMD and age-matched healthy volunteers using a modified aptamer-based proteomics technology. Levels of 1,125 proteins were quantified in serum samples from two independent DMD cohorts: cohort 1 (The Parent Project Muscular Dystrophy-Cincinnati Children's Hospital Medical Center), 42 patients with DMD and 28 age-matched normal volunteers; and cohort 2 (The Cooperative International Neuromuscular Research Group, Duchenne Natural History Study), 51 patients with DMD and 17 age-matched normal volunteers. Forty-four proteins showed significant differences that were consistent in both cohorts when comparing DMD patients and healthy volunteers at a 1% false-discovery rate, a large number of significant protein changes for such a small study. These biomarkers can be classified by known cellular processes and by age-dependent changes in protein concentration. Our findings demonstrate both the utility of this unbiased biomarker discovery approach and suggest potential new diagnostic and therapeutic avenues for ameliorating the burden of DMD and, we hope, other rare and devastating diseases.
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Biomarcadores/sangre , Proteínas Sanguíneas/metabolismo , Distrofia Muscular de Duchenne/sangre , Adolescente , Adulto , Estudios de Casos y Controles , Niño , Preescolar , Estudios de Cohortes , Humanos , Masculino , Adulto JovenRESUMEN
INTRODUCTION: An opt-out newborn screening (NBS) program for Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) was implemented at 2 hospitals in Pittsburgh, Pennsylvania, between 1987 and 1995. METHODS: For patients and their parents in families who received a diagnosis of DMD or BMD, either by NBS or by traditional diagnostics after symptom onset, attitudes toward NBS for DMD and BMD were assessed. RESULTS: All patients and most parents supported NBS for DMD and BMD. In contrast to the NBS parent cohort, the non-NBS cohort felt that diagnosis by NBS would cause anxiety. CONCLUSIONS: There was strong support of NBS for DMD and BMD in both patients and their parents in families who received a diagnosis through NBS or through traditional diagnostics. No negative psychosocial impacts of NBS were identified among those families who received a diagnosis through NBS.
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Distrofias Musculares/diagnóstico , Distrofias Musculares/psicología , Tamizaje Neonatal/métodos , Tamizaje Neonatal/tendencias , Adolescente , Adulto , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Pruebas Genéticas/métodos , Pruebas Genéticas/tendencias , Humanos , Recién Nacido , Masculino , Adulto JovenRESUMEN
In Duchenne muscular dystrophy (DMD) patients and the mdx mouse model of DMD, chronic activation of the classical nuclear factor-κB (NF-κB) pathway contributes to the pathogenesis that causes degeneration of muscle fibers, inflammation and fibrosis. Prior studies demonstrate that inhibition of inhibitor of κB kinase (IKK)-mediated NF-κB activation using L-isomer NF-κB essential modulator (NEMO)-binding domain (NBD) peptide-based approaches reduce muscle pathology in the mdx mouse. For our studies, the NBD peptide is synthesized as a fusion peptide with an eight-lysine (8K) protein transduction domain to facilitate intracellular delivery. We hypothesized that the d-isoform peptide could have a greater effect than the naturally occurring L-isoform peptide due to the longer persistence of the D-isoform peptide in vivo. In this study, we compared systemic treatment with low (1 mg/kg) and high (10 mg/kg) doses of L- and D-isomer 8K-wild-type-NBD peptide in mdx mice. Treatment with both L- or D-isoform 8K-wild-type-NBD peptide resulted in decreased activation of NF-κB and improved histology in skeletal muscle of the mdx mouse. However, we observed kidney toxicity (characterized by proteinuria), increased serum creatinine, activation of NF-κB and pathological changes in kidney cortex that were most severe with treatment with the D-isoform of 8K-wild-type-NBD peptide. The observed toxicity was also seen in normal mice.
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Sustitución de Aminoácidos/genética , Distrofia Muscular de Duchenne/tratamiento farmacológico , FN-kappa B/genética , Péptidos/administración & dosificación , Animales , Modelos Animales de Enfermedad , Humanos , Quinasa I-kappa B/antagonistas & inhibidores , Quinasa I-kappa B/genética , Riñón/efectos de los fármacos , Riñón/patología , Masculino , Ratones , Ratones Endogámicos mdx , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/patología , FN-kappa B/antagonistas & inhibidores , Péptidos/genética , Transducción de Señal/efectos de los fármacos , EstereoisomerismoRESUMEN
We have previously shown that i.m. administration of bacterially expressed murine histidyl-tRNA synthetase (HRS) triggers florid muscle inflammation (relative to appropriate control proteins) in various congenic strains of mice. Because severe disease develops even in the absence of adaptive immune responses to HRS, we sought to identify innate immune signaling components contributing to our model of HRS-induced myositis. In vitro stimulation assays demonstrated HRS-mediated activation of HEK293 cells transfected with either TLR2 or TLR4, revealing an excitatory capacity exceeding that of other bacterially expressed fusion proteins. Corresponding to this apparent functional redundancy of TLR signaling pathways, HRS immunization of B6.TLR2(-/-) and B6.TLR4(-/-) single-knockout mice yielded significant lymphocytic infiltration of muscle tissue comparable to that produced in C57BL/6 wild-type mice. In contrast, concomitant elimination of TLR2 and TLR4 signaling in B6.TLR2(-/-).TLR4(-/-) double-knockout mice markedly reduced the severity of HRS-induced muscle inflammation. Complementary subfragment analysis demonstrated that aa 60-90 of HRS were absolutely required for in vitro as well as in vivo signaling via these MyD88-dependent TLR pathways--effects mediated, in part, through preferential binding of exogenous ligands capable of activating specific TLRs. Collectively, these experiments indicate that multiple MyD88-dependent signaling cascades contribute to this model of HRS-induced myositis, underscoring the antigenic versatility of HRS and confirming the importance of innate immunity in this system.
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Autoantígenos/toxicidad , Histidina-ARNt Ligasa/toxicidad , Factor 88 de Diferenciación Mieloide/fisiología , Enfermedad Autoinmune Experimental del Sistema Nervioso/fisiopatología , Transducción de Señal/fisiología , Receptor Toll-Like 2/fisiología , Receptor Toll-Like 4/fisiología , Animales , Autoantígenos/química , Autoantígenos/inmunología , Diglicéridos/metabolismo , Endotoxinas/metabolismo , Femenino , Proteína HMGB1/metabolismo , Histidina-ARNt Ligasa/química , Histidina-ARNt Ligasa/inmunología , Inmunidad Innata , Inmunización , Epítopos Inmunodominantes/química , Epítopos Inmunodominantes/inmunología , Epítopos Inmunodominantes/toxicidad , Ligandos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 88 de Diferenciación Mieloide/deficiencia , Enfermedad Autoinmune Experimental del Sistema Nervioso/etiología , Oligopéptidos/metabolismo , Fragmentos de Péptidos/inmunología , Fragmentos de Péptidos/toxicidad , Unión Proteica , Proteínas Recombinantes de Fusión/inmunología , Proteínas Recombinantes de Fusión/toxicidad , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 2/deficiencia , Receptor Toll-Like 2/efectos de los fármacos , Receptor Toll-Like 4/deficiencia , Receptor Toll-Like 4/efectos de los fármacosRESUMEN
INTRODUCTION: Cardiomyopathy is a common cause of morbidity and death in patients with Duchenne muscular dystrophy (DMD). METHODS: This investigation was a cross-sectional cross-sectional analysis of clinical data from the multi-institutional Cooperative International Neuromuscular Research Group (CINRG) DMD Natural History Study of 340 DMD patients aged 2-28 years. Cardiomyopathy was defined as shortening fraction (SF) <28% or ejection fraction (EF) <55%. RESULTS: Two hundred thirty-one participants reported a prior clinical echocardiogram study, and 174 had data for SF or EF. The prevalence of cardiomyopathy was 27% (47 of 174), and it was associated significantly with age and clinical stage. The association of cardiomyopathy with age and clinical stage was not changed by glucocorticoid use as a covariate (P > 0.68). In patients with cardiomyopathy, 57% (27 of 47) reported not taking any cardiac medications. Cardiac medications were used in 12% (15 of 127) of patients without cardiomyopathy. CONCLUSIONS: We found that echocardiograms were underutilized, and cardiomyopathy was undertreated in this DMD natural history cohort.
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Investigación Biomédica , Cardiomiopatías , Cooperación Internacional , Distrofia Muscular de Duchenne/complicaciones , Adolescente , Adulto , Factores de Edad , Cardiomiopatías/diagnóstico , Cardiomiopatías/etiología , Cardiomiopatías/terapia , Niño , Preescolar , Femenino , Glucocorticoides/uso terapéutico , Humanos , Masculino , Estadísticas no Paramétricas , Adulto JovenRESUMEN
INTRODUCTION: Disease inclusion in the newborn screening (NBS) panel should consider the opinions of those most affected by the outcome of screening. We assessed the level and factors that affect parent attitudes regarding NBS panel inclusion of Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and spinal muscular atrophy (SMA). METHODS: The attitudes toward NBS for DMD, BMD, and SMA were surveyed and compared for 2 categories of parents, those with children affected with DMD, BMD, or SMA and expectant parents unselected for known family medical history. RESULTS: The level of support for NBS for DMD, BMD, and SMA was 95.9% among parents of children with DMD, BMD, or SMA and 92.6% among expectant parents. CONCLUSIONS: There was strong support for NBS for DMD, BMD, and SMA in both groups of parents. Given advances in diagnostics and promising therapeutic approaches, discussion of inclusion in NBS should continue.
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Actitud Frente a la Salud , Distrofia Muscular de Duchenne/diagnóstico , Tamizaje Neonatal/psicología , Padres/psicología , Atrofias Musculares Espinales de la Infancia/diagnóstico , Adulto , Ansiedad/psicología , Estudios de Cohortes , Diagnóstico Precoz , Emociones , Femenino , Encuestas Epidemiológicas , Humanos , Recién Nacido , Masculino , Encuestas y CuestionariosRESUMEN
OBJECTIVES: Public access databases such as clinicaltrials.gov achieve dissemination of clinical trial design and aggregated study results. However, return of participant-level data is rarely done. A key barrier includes the proprietary ownership of data by the sponsor. Additionally, investigators may not have access to centralised data, and per International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice, must maintain the confidentiality of participants. This study piloted an approach to return both individual and aggregate clinical trial data to parents of children participating in a series of open-label clinical trials. SETTING AND DESIGN: A small biotech company obtained central ethics approval (centralised institutional review board [IRB], non-exempt). The study was advertised via parent advocacy groups. Parents of trial participants were offered the option to contact an employee (coordinator) within the company, requesting return of their child's study results. Ethics approval covered participation in six countries. The study focused on the sequential clinical trials of vamorolone VBP15-002 (NCT02760264) and VBP15-003 (NCT02760277) (post-results). INTERVENTIONS: Contact initiated by the parent enabled the coordinator to obtain informed consent (and separate General Data Protection Regulations consent), with phone translation when needed. Using date of birth and study site location provided by the parent, the data manager reported the participant number to the coordinator. The coordinator retrieved and compiled data, along with an aggregate summary, which was mailed via a password protected and encrypted memory device to the parent. Prereturn and postreturn surveys were sent to consented parents (n=19; 40% of 48 total trial participants) and investigators. RESULTS: Prereturn surveys indicated a request for as much data as offered, in all formats offered. Postreturn survey showed high satisfaction with the process and data returned. Survey of the physician site investigators (n=10; 100% participation of investigators) voiced general satisfaction with the process, with some reservations. CONCLUSIONS: This pilot study demonstrates an innovative, cost-effective, centralised and labour conservative approach to return of participant-level and aggregate data to participants in studies.
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Consentimiento Informado , Niño , Humanos , Proyectos Piloto , Encuestas y Cuestionarios , Ensayos Clínicos como AsuntoRESUMEN
CONTEXT: Vamorolone, a novel "dissociative" steroid, demonstrated similar efficacy in muscle function relative to prednisone 0.75 mg/kg/day but improved linear growth and bone turnover markers in a randomized trial of pediatric Duchenne muscular dystrophy (DMD). OBJECTIVES: To determine the frequency of adrenal suppression (AS) induced by vamorolone and prednisone in pediatric DMD, and to assess cortisol thresholds using a monoclonal antibody immunoassay. METHODS: Post-hoc analysis of cortisol levels was performed on data from a randomized, double-blind, placebo- and prednisone-controlled 24-week trial of vamorolone with a 24-week crossover extension. Morning and ACTH-stimulated cortisol levels were measured using the Elecsys II immunoassay, with AS defined as a stimulated cortisol of <500nmol/L ("historical threshold") and <400nmol/L ("revised threshold"). RESULTS: Mean age at enrolment was 5.41±0.86 years (N=118). At Week 24, proportion of participants with AS using the historical and revised cortisol thresholds, respectively, were as follows: prednisone 0.75 mg/kg/day=100% (25/25) and 92.0% (23/25); vamorolone 6 mg/kg/day=95.2% (20/21) and 90.5% (19/21); vamorolone 2 mg/kg/day=84.2% (16/19) and 47.5% (9/19); and placebo=20.0% (4/20) and 0% (0/20). Morning and peak ACTH-stimulated cortisol were strongly correlated in steroid-treated boys (Spearman correlation week 48=0.83). CONCLUSIONS: AS after vamorolone and prednisone was frequent and vamorolone-associated AS appeared dose-dependent. A lower stimulated cortisol threshold may be appropriate when using a monoclonal assay. We recommend hydrocortisone for glucocorticoid stress dosing in patients receiving vamorolone.
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Human genetic variation (polymorphisms) in genes coding proteins involved in the absorption, distribution, metabolism, and elimination (ADME) of drugs can have a strong effect on drug exposure and downstream efficacy and safety outcomes. Vamorolone, a dissociative steroidal anti-inflammatory drug for treating Duchenne muscular dystrophy (DMD), primarily undergoes oxidation by CYP3A4 and CYP3A5 and glucuronidation by UDP-glucuronosyltransferases. This work assesses the pharmacokinetics (PKs) of vamorolone and sources of interindividual variability (IIV) in 81 steroid-naïve boys with DMD aged 4 to <7 years old considering the genetic polymorphisms of CYPS3A4 (CYP3A4*22, CYP3A4*1B), CYP3A5 (CYP3A5*3), and UGT1A1 (UGT1A1*60) utilizing population PK modeling. A one-compartment model with zero-order absorption (Tk0, duration of absorption), linear clearance (CL/F), and volume (V/F) describes the plasma PK data for boys with DMD receiving a wide range of vamorolone doses (0.25-6 mg/kg/day). The typical CL/F and V/F values of vamorolone were 35.8 L/h and 119 L, with modest IIV. The population Tk0 was 3.14 h yielding an average zero-order absorption rate (k0) of 1.16 mg/kg/h with similar absorption kinetics across subjects at the same vamorolone dose (i.e., no IIV on Tk0). The covariate analysis showed that none of the genetic covariates had any significant impact on the PKs of vamorolone in boys with DMD. Thus, the PKs of vamorolone is very consistent in these young boys with DMD.
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BACKGROUND: Becker muscular dystrophy is an X-linked, genetic disorder causing progressive degeneration of skeletal and cardiac muscle, with a widely variable phenotype. OBJECTIVE: A 3-year, longitudinal, prospective dataset contributed by patients with confirmed Becker muscular dystrophy was analyzed to characterize the natural history of this disorder. A better understanding of the natural history is crucial to rigorous therapeutic trials. METHODS: A cohort of 83 patients with Becker muscular dystrophy (5-75 years at baseline) were followed for up to 3 years with annual assessments. Muscle and pulmonary function outcomes were analyzed herein. Age-stratified statistical analysis and modeling were conducted to analyze cross-sectional data, time-to-event data, and longitudinal data to characterize these clinical outcomes. RESULTS: Deletion mutations of dystrophin exons 45-47 or 45-48 were most common. Subgroup analysis showed greater pairwise association between motor outcomes at baseline than association between these outcomes and age. Stronger correlations between outcomes for adults than for those under 18 years were also observed. Using cross-sectional binning analysis, a ceiling effect was seen for North Star Ambulatory Assessment but not for other functional outcomes. Longitudinal analysis showed a decline in percentage predicted forced vital capacity over the life span. There was relative stability or improved median function for motor functional outcomes through childhood and adolescence and decreasing function with age thereafter. CONCLUSIONS: There is variable progression of outcomes resulting in significant heterogeneity of the clinical phenotype of Becker muscular dystrophy. Disease progression is largely manifest in adulthood. There are implications for clinical trial design revealed by this longitudinal analysis of a Becker natural history dataset.