The Clinical Development of Taldefgrobep Alfa: An Anti-Myostatin Adnectin for the Treatment of Duchenne Muscular Dystrophy.

Introduction: Duchenne muscular dystrophy (DMD) is a genetic muscle disorder that manifests during early childhood and is ultimately fatal. Recently approved treatments targeting the genetic cause of DMD are limited to specific subpopulations of patients, highlighting the need for therapies with wider applications. Pharmacologic inhibition of myostatin, an endogenous inhibitor of muscle growth produced almost exclusively in skeletal muscle, has been shown to increase muscle mass in several species, including humans.

Long-term follow-up of patients with type 2 and non-ambulant type 3 spinal muscular atrophy (SMA) treated with olesoxime in the OLEOS trial.

In a previous Phase 2 study, olesoxime had a favorable safety profile. Although the primary endpoint was not met, analyses suggested that olesoxime might help in the maintenance of motor function in patients with Types 2/3 SMA. This open-label extension study (OLEOS) further characterizes the safety, tolerability and efficacy of olesoxime over longer therapy durations.

Chitosan-Shelled Nanobubbles Irreversibly Encapsulate Morpholino Conjugate Antisense Oligonucleotides and Are Ineffective for Phosphorodiamidate Morpholino-Mediated Gene Silencing of .

Orphan drugs, including antisense oligonucleotides (AONs), siRNAs/miRNAs, Cas9 nuclease, and recombinant genes, have recently been made available for rare diseases. However, the main bottleneck for these new therapies is delivery. Drugs/synthetic genes need to reach the affected tissues with minimal off-target effects and immune reactions.

Publisher Correction: Necroptosis mediates myofibre death in dystrophin-deficient mice.

The original version of this article contained an error in Fig. 3. In panel c, the labels 'mdx' and 'mdx Ripk3-/-' were inadvertently inverted.

Necroptosis mediates myofibre death in dystrophin-deficient mice.

Duchenne muscular dystrophy (DMD) is a severe degenerative disorder caused by mutations in the dystrophin gene. Dystrophin-deficient muscles are characterised by progressive myofibre necrosis in which inflammation plays a deleterious role. However, the molecular mechanisms underlying inflammation-induced necrosis in muscle cells are unknown.

Targeting the Polyadenylation Signal of Pre-mRNA: A New Gene Silencing Approach for Facioscapulohumeral Dystrophy.

Facioscapulohumeral dystrophy (FSHD) is characterized by the contraction of the D4Z4 array located in the sub-telomeric region of the chromosome 4, leading to the aberrant expression of the DUX4 transcription factor and the mis-regulation of hundreds of genes. Several therapeutic strategies have been proposed among which the possibility to target the polyadenylation signal to silence the causative gene of the disease. Indeed, defects in mRNA polyadenylation leads to an alteration of the transcription termination, a disruption of mRNA transport from the nucleus to the cytoplasm decreasing the mRNA stability and translation efficiency.

Loss-of-function nuclear factor κB subunit 1 (NFKB1) variants are the most common monogenic cause of common variable immunodeficiency in Europeans.

Background: The genetic cause of primary immunodeficiency disease (PID) carries prognostic information.

Objective: We conducted a whole-genome sequencing study assessing a large proportion of the NIHR BioResource-Rare Diseases cohort.

Methods: In the predominantly European study population of principally sporadic unrelated PID cases (n = 846), a novel Bayesian method identified nuclear factor κB subunit 1 (NFKB1) as one of the genes most strongly associated with PID, and the association was explained by 16 novel heterozygous truncating, missense, and gene deletion variants.

Downregulation of myostatin pathway in neuromuscular diseases may explain challenges of anti-myostatin therapeutic approaches.

Muscular dystrophies are characterized by weakness and wasting of skeletal muscle tissues. Several drugs targeting the myostatin pathway have been used in clinical trials to increase muscle mass and function but most showed limited efficacy. Here we show that the expression of components of the myostatin signaling pathway is downregulated in muscle wasting or atrophying diseases, with a decrease of myostatin and activin receptor, and an increase of the myostatin antagonist, follistatin.

DNA Diagnostics of Hereditary Hearing Loss: A Targeted Resequencing Approach Combined with a Mutation Classification System.

Although there are nearly 100 different causative genes identified for nonsyndromic hearing loss (NSHL), Sanger sequencing-based DNA diagnostics usually only analyses three, namely, GJB2, SLC26A4, and OTOF. As this is seen as inadequate, there is a need for high-throughput diagnostic methods to detect disease-causing variations, including single-nucleotide variations (SNVs), insertions/deletions (Indels), and copy-number variations (CNVs). In this study, a targeted resequencing panel for hearing loss was developed including 79 genes for NSHL and selected forms of syndromic hearing loss.

Seizure outcome after extratemporal epilepsy surgery in childhood.

Aim: The aim of the study was to describe seizure outcome following surgery for focal extratemporal epilepsy and identify factors associated with prolonged postsurgical freedom from seizures.

Method: In this retrospective cohort study, children with drug-resistant focal extratemporal epilepsy were treated surgically and followed up in a single tertiary care centre between 1997 and 2008.

Results: Eighty children were identified for inclusion in the study (42 males, 38 females; median age 9y 1mo, range 3mo-18y 7mo).

Neuraxial analgesia in neonates and infants: a review of clinical and preclinical strategies for the development of safety and efficacy data.

Neuraxial drugs provide robust pain control, have the potential to improve outcomes, and are an important component of the perioperative care of children. Opioids or clonidine improves analgesia when added to perioperative epidural infusions; analgesia is significantly prolonged by the addition of clonidine, ketamine, neostigmine, or tramadol to single-shot caudal injections of local anesthetic; and neonatal intrathecal anesthesia/analgesia is increasing in some centers. However, it is difficult to determine the relative risk-benefit of different techniques and drugs without detailed and sensitive data related to analgesia requirements, side effects, and follow-up.

Renal malformations associated with mutations of developmental genes: messages from the clinic.

Renal tract malformations (RTMs) account for about 40% of children with end-stage renal failure. RTMs can be caused by mutations of genes normally active in the developing kidney and lower renal tract. Moreover, some RTMs occur in the context of multi-organ malformation syndromes.

Aminoglycoside-induced deafness during treatment of acute leukaemia.

Three unrelated children from ethnically diverse backgrounds who were treated for acute leukaemia became profoundly and irreversibly deaf during treatment. Aminoglycoside levels were within the therapeutic range. Genetic testing showed all three to have a maternally inherited mutation of mitochondrial DNA, m.

Pain in children: recent advances and ongoing challenges.

Significant advances in the assessment and management of acute pain in children have been made, and are supported by an increase in the availability and accessibility of evidence-based data. However, methodological and practical issues in the design and performance of clinical paediatric trials limit the quantity, and may influence the quality, of current data, which lags behind that available for adult practice. Collaborations within research networks, which incorporate both preclinical and clinical studies, may increase the feasibility and specificity of future trials.

Striatal encephalitis after varicella zoster infection complicated by Tourettism.

We describe a case of encephalitis after primary varicella zoster infection with localised basal ganglia imaging abnormalities. The patient subsequently developed a chronic tic disorder with attention deficit disorder. This case furthers the proposed association between Tourettism and the basal ganglia.

Interleukin-6 and oligoclonal IgG synthesis in children with acute disseminated encephalomyelitis.

Interleukin-6 (IL-6) has a number of roles including recruitment of T lymphocytes and differentiation of B lymphocytes into IgG-secreting plasma cells. Furthermore, IL-6 is a neuropoietic cytokine with effects on neuronal differentiation, function and survival. We studied IL-6 concentrations in children with acute disseminated encephalomyelitis (ADEM; n = 14), and compared the values with those obtained from control patients with other inflammatory (OIND; n = 13) and non-inflammatory (NIND; n = 10) neurological disorders.

Acute disseminated encephalomyelitis.

Acute disseminated encephalomyelitis (ADEM) is a monophasic inflammatory disorder of the central nervous system (CNS). Unlike viral encephalitis, microorganisms do not invade the CNS. Instead, ADEM is a postinfectious disease mediated by auto-reactive cells or molecules.

Influence of jacket tightness and pressure on raised lung volume forced expiratory maneuvers in infants.

While the use of the raised volume rapid thoraco-abdominal compression (RVRTC) technique has been shown to provide new insights into airway and pulmonary pathophysiology in infants, and appears to resemble the spirometric techniques used in older subjects, there is as yet no consensus regarding measurement procedures, which are known to vary considerably between laboratories (Gappa [1999] Pediatr Pulmonol 28:391-393). The aims of this study were to assess the effects of tightness of jacket fit, the efficiency with which pressure is transmitted from the jacket to the intrathoracic airways, and the effect of jacket pressure on parameters derived from the RVRTC technique. Paired forced expiratory maneuvers were performed in 20 infants with the jacket snugly or loosely wrapped around the infant's torso, and in a further 21 infants using "optimal" or a higher jacket pressure (P(j)) (1-2 kPa above "optimal" P(j)).

Effect of airway inflation pressure on forced expiratory maneuvers from raised lung volume in infants.

The raised lung volume technique is increasingly used to measure forced expiratory maneuvers in infants. However, there is no consensus regarding the optimal airway inflation pressure (P(inf)) required for such maneuvers, or the influence of small changes in P(inf) within and between infants. The aim of this study was to assess the effect of small differences (0.