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Representatives of academia, patient organisations, industry and the United States Food and Drug Administration attended a workshop on dystrophin quantification methodology. The aims of the workshop were to provide an overview of methods used to quantify dystrophin levels in human skeletal muscle and their applicability to clinical trial samples, outline the gaps with regards to validating the methods for robust clinical applications prior to regulatory agency review, and to align future efforts towards further optimizing these methods. The workshop facilitated a constructive but also critical discussion on the potential and limitations of techniques currently used in the field of translational research (western blot and immunofluorescence analysis) and emerging techniques (mass spectrometry and capillary western immunoassay). Notably, all participants reported variation in dystrophin levels between muscle biopsies from different healthy individuals and agreed on the need for a common reference sample.

Nucleic acid‐based therapeutics that regulate gene expression have been developed towards clinical use at a steady pace for several decades, but in recent years the field has been accelerating. To date, there are 11 marketed products based on antisense oligonucleotides, aptamers and small interfering RNAs, and many others are in the pipeline for both academia and industry. A major technology trigger for this development has been progress in oligonucleotide chemistry to improve the drug properties and reduce cost of goods, but the main hurdle for the application to a wider range of disorders is delivery to target tissues. The adoption of delivery technologies, such as conjugates or nanoparticles, has been a game changer for many therapeutic indications, but many others are still awaiting their eureka moment. Here, we cover the variety of methods developed to deliver nucleic acid‐based therapeutics across biological barriers and the model systems used to test them. We discuss important safety considerations and regulatory requirements for synthetic oligonucleotide chemistries and the hurdles for translating laboratory breakthroughs to the clinic. Recent advances in the delivery of nucleic acid‐based therapeutics and in the development of model systems, as well as safety considerations and regulatory requirements for synthetic oligonucleotide chemistries are discussed in this review on oligonucleotide‐based therapeutics., Recent advances in the delivery of nucleic acid‐based therapeutics and in the development of model systems, as well as safety considerations and regulatory requirements for synthetic oligonucleotide chemistries are discussed in this review on oligonucleotide‐based therapeutics.

To establish the potential economic burden in caregivers to patients with DMD and the potential causative factors.Caregivers to patients with DMD were recruited through the DMD patients Register and questioned about several economic aspects using "ad-hoc" questionnaires.All families, apart from one (97.2% n = 36), incurred in monthly medical costs (44% of the families more than 50 euros/month). 97.2% of the households considered looking after a patient of DMD as financially burdensome, and 80.5% of households declared to have suffered work changes, especially the mothers (job timetable-related mainly). The presence of obsessive-compulsive disorders (OCD) in patients was significantly associated with caregivers' high financial burden as these were six times more likely to have this perception OR = 6468 IC 95% (1056-39,601), p = 0.043. Also, when patients had learning difficulties, caregivers had up to six times more chances to incur in monthly expenditure for formal care OR = 6089 IC 95% (1112-33,342), p = 0.037.Caregivers have relevant financial burden that might be conditioned by the clinical condition of the patient.Quantitative data about financial burden in DMD Spanish families providing informal care. Identification of the patient's main clinical issues associated with financial burden.

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare type of leukodystrophy characterized by dysfunction of the role of glial cells in controlling brain fluid and ion homeostasis. Patients affected by MLC present macrocephaly, cysts and white matter vacuolation, which lead to motor and cognitive impairments. To date, there is no treatment for MLC, only supportive care. MLC is caused by mutations in the MLC1 and GLIALCAM genes. MLC1 is a membrane protein with low identity to the Kv1.1 potassium channel and GlialCAM belongs to an adhesion molecule family. Both proteins form a complex with an as-yet-unknown function that is expressed mainly in the astrocytes surrounding the blood-brain barrier and in Bergmann glia. GlialCAM also acts as an auxiliary subunit of the chloride channel ClC-2, thus regulating its localization at cell-cell junctions and modifying its functional properties by affecting the common gate of ClC-2. Recent studies in Mlc1-, GlialCAM- and Clcn2-knockout mice or Mlc1-knockout zebrafish have provided fresh insight into the pathophysiology of MLC and further details about the molecular interactions between these three proteins. Additional studies have shown that GlialCAM/MLC1 also regulates other ion channels (TRPV4, VRAC) or transporters (Na+/K+-ATPase) in a not-understood manner. Furthermore, it has been shown that GlialCAM/MLC1 may influence signal transduction mechanisms, thereby affecting other proteins not related with transport such as the EGF receptor. Here, we offer a personal biochemical retrospective of the work that has been performed to gain knowledge of the pathophysiology of MLC, and we discuss future strategies that may be used to identify therapeutic solutions for MLC patients.

Cannabidiol (CBD) reduces seizures in childhood epilepsy syndromes including Dravet syndrome (DS). A formulation of CBD has obtained orphan drug designation for these syndromes and clinical trials are currently underway. The mechanism responsible for CBD effects is not known, although it could involve targets sensitive to CBD in other neurological disorders. We believe of interest to investigate whether these potential targets are altered in DS, in particular whether the endocannabinoid system is dysregulated. To this end, lymphocytes from patients and controls were used for analysis of gene expression of transmitter receptors and transporters, ion channels, and enzymes associated with CBD effects, as well as endocannabinoid genes. Plasma endocannabinoid levels were also analyzed. There were no differences between DS patients and controls in most of the CBD targets analyzed, except an increase in the voltage-dependent calcium channel alpha-1h subunit. We also found that cannabinoid type-2 (CB 2) receptor gene expression was elevated in DS patients, with no changes in other endocannabinoid-related receptors and enzymes, as well as in plasma levels of endocannabinoids. Such elevation was paralleled by an increase in CD70, a marker of lymphocyte activation, and certain trends in inflammation-related proteins (e.g., peroxisome proliferator-activated receptor-gamma receptors, cytokines). In conclusion, together with changes in the voltage-dependent calcium channel alpha-1h subunit, we found an upregulation of CB 2 receptors, associated with an activation of lymphocytes and changes in inflammation-related genes, in DS patients. Such changes were also reported in inflammatory disorders and may indirectly support the occurrence of a potential dysregulation of the endocannabinoid system in the brain.