Identification of disease-specific extracellular vesicle-associated plasma protein biomarkers for Duchenne Muscular Dystrophy and Facioscapulohumeral Muscular Dystrophy.

Objective: Reliable, circulating biomarkers for Duchenne, Becker and facioscapulohumeral muscular dystrophies (DBMD and FSHD) remain unvalidated. Here, we investigated the plasma extracellular vesicle (EV) proteome to identify disease-specific biomarkers that could accelerate therapy approvals.

Methods: We extracted EVs from the plasma of DBMD and FSHD patients and healthy controls using size-exclusion chromatography, conducted mass spectrometry on the extracted EV proteins, and performed comparative analysis to identify disease-specific biomarkers.

Evaluation of safety and early efficacy of AAV gene therapy in mouse models of vanishing white matter disease.

Leukoencephalopathy with vanishing white matter (VWM) is a progressive incurable white matter disease that most commonly occurs in childhood and presents with ataxia, spasticity, neurological degeneration, seizures, and premature death. A distinctive feature is episodes of rapid neurological deterioration provoked by stressors such as infection, seizures, or trauma. VWM is caused by autosomal recessive mutations in one of five genes that encode the eukaryotic initiation factor 2B complex, which is necessary for protein translation and regulation of the integrated stress response.

Increase in Full-Length Dystrophin by Exon Skipping in Duchenne Muscular Dystrophy Patients with Single Exon Duplications: An Open-label Study.

Single exon duplications account for disease in a minority of Duchenne muscular dystrophy patients. Exon skipping in these patients has the potential to be highly therapeutic through restoration of full-length dystrophin expression. We conducted a 48-week open label study of casimersen and golodirsen in 3 subjects with an exon 45 or 53 duplication.

Draft Guidance for Industry Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, and Related Dystrophinopathies - Developing Potential Treatments for the Entire Spectrum of Disease.

Background: Duchenne muscular dystrophy (DMD) and related dystrophinopathies are neuromuscular conditions with great unmet medical needs that require the development of effective medical treatments.

Objective: To aid sponsors in clinical development of drugs and therapeutic biological products for treating DMD across the disease spectrum by integrating advancements, patient registries, natural history studies, and more into a comprehensive guidance.

Methods: This guidance emerged from collaboration between the FDA, the Duchenne community, and industry stakeholders.

Exome sequencing in the pediatric neuromuscular clinic leads to more frequent diagnosis of both neuromuscular and neurodevelopmental conditions.

Introduction/aims: Exome sequencing (ES) has proven to be a valuable diagnostic tool for neuromuscular disorders, which often pose a diagnostic challenge. The aims of this study were to investigate the clinical outcomes associated with utilization of ES in the pediatric neuromuscular clinic and to determine if specific phenotypic features or abnormal neurodiagnostic tests were predictive of a diagnostic result.

Methods: This was a retrospective medical record review of 76 pediatric neuromuscular clinic patients who underwent ES.

Promising AAV.U7snRNAs vectors targeting improve DM1 hallmarks in patient-derived cell lines.

Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults and affects mainly the skeletal muscle, heart, and brain. DM1 is caused by a CTG repeat expansion in the 3'UTR region of the gene that sequesters muscleblind-like proteins, blocking their splicing activity and forming nuclear RNA . Consequently, many genes have their splicing reversed to a fetal pattern.

Developmental exposure to corn grown on Lake Erie dredged material: a preliminary analysis.

While corn is considered to be a healthy food option, common agricultural practices, such as the application of soil amendments, might be introducing contaminants of concern (COC) into corn plants. The use of dredged material, which contain contaminants such as heavy metals, polychlorinated biphenyls (PCBs) and polycyclic aromatic hydrocarbons (PAHs), as a soil amendment is increasing. Contaminants from these amendments can accumulate in corn kernels harvested from plants grown on these sediments and potentially biomagnify in organisms that consume them.

A genome-wide association analysis of loss of ambulation in dystrophinopathy patients suggests multiple candidate modifiers of disease severity.

The major determinant of disease severity in Duchenne muscular dystrophy (DMD) or milder Becker muscular dystrophy (BMD) is whether the dystrophin gene (DMD) mutation truncates the mRNA reading frame or allows expression of a partially functional protein. However, even in the complete absence of dystrophin, variability in disease severity is observed, and candidate gene studies have implicated several genes as modifiers. Here we present the largest genome-wide search to date for loci influencing severity in N = 419 DMD patients.

Inherited myopathy plus: Double-trouble from rare neuromuscular disorders.

A rare disorder in the USA is one that affects <200,000 people, making inherited myopathies rare diseases. Increasing access to genetic testing has been instrumental for the diagnosis of inherited myopathies. Genetic findings, however, require clinical correlation due to variable phenotype, polygenic etiology of certain inherited disorders, and possible co-existing independent neuromuscular disorders.

Systemic PPMO-mediated dystrophin expression in the Dup2 mouse model of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a devastating muscle-wasting disease that arises due to the loss of dystrophin expression, leading to progressive loss of motor and cardiorespiratory function. Four exon-skipping approaches using antisense phosphorodiamidate morpholino oligomers (PMOs) have been approved by the FDA to restore a open reading frame, resulting in expression of a functional but internally deleted dystrophin protein, but in patients with single-exon duplications, exon skipping has the potential to restore full-length dystrophin expression. Cell-penetrating peptide-conjugated PMOs (PPMOs) have demonstrated enhanced cellular uptake and more efficient dystrophin restoration than unconjugated PMOs.

A first-in-human phase I/IIa gene transfer clinical trial for Duchenne muscular dystrophy using rAAVrh74.MCK..

In a phase 1/2, open-label dose escalation trial, we delivered rAAVrh74.MCK. (also ) bilaterally to the legs of two boys with Duchenne muscular dystrophy using intravascular limb infusion.

Systemic delivery of an AAV9 exon-skipping vector significantly improves or prevents features of Duchenne muscular dystrophy in the Dup2 mouse.

Duchenne muscular dystrophy (DMD) is typically caused by mutations that disrupt the reading frame, but nonsense mutations in the 5' part of the gene induce utilization of an internal ribosomal entry site (IRES) in exon 5, driving expression of a highly functional N-truncated dystrophin. We have developed an AAV9 vector expressing U7 small nuclear RNAs targeting exon 2 and have tested it in a mouse containing a duplication of exon 2, in which skipping of both exon 2 copies induces IRES-driven expression, and skipping of one copy leads to wild-type dystrophin expression. One-time intravascular injection either at postnatal days 0-1 or at 2 months results in efficient exon skipping and dystrophin expression, and significant protection from functional and pathologic deficits.

Housing Environment Affects Pubertal Onset, Anxiety-like Behavior, and Object Interaction in Male and Female Long Evans Rats.

Rodents used for research can be humanely housed in a variety of ways. As such, a vast number of different housing environments are used, but are often not described in research publications. However, many elements of housing environments, including bedding, diet, water bottles, and cage material, can expose rodents to natural and synthetic compounds that can have lasting effects on the body, brain, and behavior.

Intron mutations and early transcription termination in Duchenne and Becker muscular dystrophy.

DMD pathogenic variants for Duchenne and Becker muscular dystrophy are detectable with high sensitivity by standard clinical exome analyses of genomic DNA. However, up to 7% of DMD mutations are deep intronic and analysis of muscle-derived RNA is an important diagnostic step for patients who have negative genomic testing but abnormal dystrophin expression in muscle. In this study, muscle biopsies were evaluated from 19 patients with clinical features of a dystrophinopathy, but negative clinical DMD mutation analysis.

Phenotypic Spectrum of Dystrophinopathy Due to Duchenne Muscular Dystrophy Exon 2 Duplications.

Background And Objectives: To describe the phenotypic spectrum of dystrophinopathy in a large cohort of individuals with exon 2 duplications (Dup2), who may be particularly amenable to therapies directed at restoring expression of either full-length dystrophin or nearly full-length dystrophin through utilization of the exon 5 internal ribosome entry site (IRES).

Methods: In this retrospective observational study, we analyzed data from large genotype-phenotype databases (the United Dystrophinopathy Project [UDP] and the Italian DMD network) and classified participants into Duchenne muscular dystrophy (DMD), intermediate muscular dystrophy (IMD), or Becker muscular dystrophy (BMD) phenotypes. Log-rank tests for time-to-event variables were used to compare age at loss of ambulation (LOA) in participants with Dup2 vs controls without Dup2 in the UDP database and for comparisons between steroid-treated vs steroid-naive participants with Dup2.

Automated immunofluorescence analysis for sensitive and precise dystrophin quantification in muscle biopsies.

Aims: Dystrophin, the protein product of the DMD gene, plays a critical role in muscle integrity by stabilising the sarcolemma during contraction and relaxation. The DMD gene is vulnerable to a variety of mutations that may cause complete loss, depletion or truncation of the protein, leading to Duchenne and Becker muscular dystrophies. Precise and reproducible dystrophin quantification is essential in characterising DMD mutations and evaluating the outcome of efforts to induce dystrophin through gene therapies.

Visual control of refuge recognition in the whip spider Phrynus marginemaculatus.

Amblypygids, or whip spiders, are nocturnally active arachnids which live in structurally complex environments. Whip spiders are excellent navigators that can re-locate a home refuge without relying on visual input. Therefore, an open question is whether visual input can control any aspect of whip spider spatial behavior.

Evaluating longitudinal therapy effects via the North Star Ambulatory Assessment.

Introduction/aims: In comparative studies, treatment effects are typically evaluated at a specific time point. When data are collected periodically, an alternative, clinically meaningful approach could be used to assess the totality of treatment effects. We applied a well-developed analytical procedure for evaluating longitudinal treatment effects using North Star Ambulatory Assessment (NSAA) data for illustration.

Validity and Reliability of the Neuromuscular Gross Motor Outcome.

Background: Approved treatments in spinal muscular atrophy (SMA) have resulted in unprecedented gains for many individuals. Use of available outcomes, typically developed for a specific type of SMA, do not cover the range of progression, often resulting in a battery of functional testing being completed at visits. Our objective was to validate the Neuromuscular Gross Motor Outcome (GRO) as a tool to quantify function in SMA across the span of abilities.