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Frontiers in Neurology 2023Myasthenia gravis (MG) is an autoimmune disorder characterized by autoantibodies specifically directed against proteins located within the postsynaptic membrane of the... (Review)
Review
Myasthenia gravis (MG) is an autoimmune disorder characterized by autoantibodies specifically directed against proteins located within the postsynaptic membrane of the neuromuscular junction. These pathogenic autoantibodies can be reduced by therapies such as plasma exchange, IVIG infusions and other immunosuppressive agents. However, there are significant side effects associated with most of these therapies. Since there is a better understanding of the molecular structure and the biological properties of the neonatal Fc receptors (FcRn), it possesses an attractive profile in treating myasthenia gravis. FcRn receptors prevent the catabolism of IgG by impeding their lysosomal degradation and facilitating their extracellular release at physiological pH, consequently extending the IgG half-life. Thus, the catabolism of IgG can be enhanced by blocking the FcRn, leading to outcomes similar to those achieved through plasma exchange with no significant safety concerns. The available studies suggest that FcRn holds promise as a versatile therapeutic intervention, capable of delivering beneficial outcomes in patients with distinct characteristics and varying degrees of MG severity. Efgartigimod is already approved for the treatment of generalized MG, rozanolixizumab is under review by health authorities, and phase 3 trials of nipocalimab and batoclimab are underway. Here, we will review the available data on FcRn therapeutic agents in the management of MG.
PubMed: 37602255
DOI: 10.3389/fneur.2023.1229112 -
Nature Reviews. Neurology Feb 2024Myasthenia gravis (MG) is an autoimmune disorder that affects the neuromuscular junction, leading to muscle weakness and fatigue. MG is caused by antibodies against the... (Review)
Review
Myasthenia gravis (MG) is an autoimmune disorder that affects the neuromuscular junction, leading to muscle weakness and fatigue. MG is caused by antibodies against the acetylcholine receptor (AChR), the muscle-specific kinase (MuSK) or other AChR-related proteins that are expressed in the postsynaptic muscle membrane. The standard therapeutic approach for MG has relied on acetylcholinesterase inhibitors, corticosteroids and immunosuppressants, which have shown good efficacy in improving MG-related symptoms in most people with the disease; however, these therapies can carry a considerable burden of long-term adverse effects. Moreover, up to 15% of individuals with MG exhibit limited or no response to these standard therapies. The emergence of molecular therapies, including monoclonal antibodies, B cell-depleting agents and chimeric antigen receptor T cell-based therapies, has the potential to revolutionize the MG treatment landscape. This Review provides a comprehensive overview of the progress achieved in molecular therapies for MG associated with AChR antibodies and MuSK antibodies, elucidating both the challenges and the opportunities these therapies present to the field. The latest developments in MG treatment are described, exploring the potential for personalized medicine approaches.
Topics: Humans; Acetylcholinesterase; Receptor Protein-Tyrosine Kinases; Myasthenia Gravis; Receptors, Cholinergic; Autoantibodies
PubMed: 38191918
DOI: 10.1038/s41582-023-00916-w -
Science (New York, N.Y.) Mar 2024Endocannabinoid (eCB)-mediated suppression of inhibitory synapses has been hypothesized, but this has not yet been demonstrated to occur in vivo because of the...
Endocannabinoid (eCB)-mediated suppression of inhibitory synapses has been hypothesized, but this has not yet been demonstrated to occur in vivo because of the difficulty in tracking eCB dynamics and synaptic plasticity during behavior. In mice navigating a linear track, we observed location-specific eCB signaling in hippocampal CA1 place cells, and this was detected both in the postsynaptic membrane and the presynaptic inhibitory axons. All-optical in vivo investigation of synaptic responses revealed that postsynaptic depolarization was followed by a suppression of inhibitory synaptic potentials. Furthermore, interneuron-specific cannabinoid receptor deletion altered place cell tuning. Therefore, rapid, postsynaptic, activity-dependent eCB signaling modulates inhibitory synapses on a timescale of seconds during behavior.
Topics: Animals; Mice; Endocannabinoids; Neuronal Plasticity; Synapses; Synaptic Transmission; Calcium Signaling; CA1 Region, Hippocampal; Inhibitory Postsynaptic Potentials; Receptor, Cannabinoid, CB1; Male; Female; Mice, Knockout
PubMed: 38422134
DOI: 10.1126/science.adk3863 -
Annual Review of Biophysics Feb 2024Dendritic spines are small, bulbous compartments that function as postsynaptic sites and undergo intense biochemical and biophysical activity. The role of the myriad... (Review)
Review
Dendritic spines are small, bulbous compartments that function as postsynaptic sites and undergo intense biochemical and biophysical activity. The role of the myriad signaling pathways that are implicated in synaptic plasticity is well studied. A recent abundance of quantitative experimental data has made the events associated with synaptic plasticity amenable to quantitative biophysical modeling. Spines are also fascinating biophysical computational units because spine geometry, signal transduction, and mechanics work in a complex feedback loop to tune synaptic plasticity. In this sense, ideas from modeling cell motility can inspire us to develop multiscale approaches for predictive modeling of synaptic plasticity. In this article, we review the key steps in postsynaptic plasticity with a specific focus on the impact of spine geometry on signaling, cytoskeleton rearrangement, and membrane mechanics. We summarize the main experimental observations and highlight how theory and computation can aid our understanding of these complex processes.Expected final online publication date for the , Volume 53 is May 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
PubMed: 38382115
DOI: 10.1146/annurev-biophys-072123-124954 -
Journal of Neurology Jul 2023Myasthenia gravis (MG) is characterized by muscle weakness caused by autoantibodies that bind to the postsynaptic membrane at the neuromuscular junction and impair... (Review)
Review
Myasthenia gravis (MG) is characterized by muscle weakness caused by autoantibodies that bind to the postsynaptic membrane at the neuromuscular junction and impair acetylcholine receptor function. Weakness of respiratory muscles represents the most severe MG manifestation, and 10-15% of all patients experience an MG crisis with the need of mechanical ventilatory support at least once in their life. MG patients with respiratory muscle weakness need active immunosuppressive drug treatment long term, and they need regular specialist follow-up. Comorbidities affecting respiratory function need attention and optimal treatment. Respiratory tract infections can lead to MG exacerbations and precipitate an MG crisis. Intravenous immunoglobulin and plasma exchange are the core treatments for severe MG exacerbations. High-dose corticosteroids, complement inhibitors, and FcRn blockers represent fast-acting treatments that are effective in most MG patients. Neonatal myasthenia is a transient condition with muscle weakness in the newborn caused by mother's muscle antibodies. In rare cases, treatment of respiratory muscle weakness in the baby is required.
Topics: Infant, Newborn; Humans; Myasthenia Gravis; Neuromuscular Junction; Neuromuscular Diseases; Muscle Weakness; Respiratory Tract Diseases
PubMed: 37101094
DOI: 10.1007/s00415-023-11733-y -
Neuropsychiatric Disease and Treatment 2023The terminal complement C5 inhibitor ravulizumab was engineered from the humanized monoclonal antibody eculizumab to have an extended half-life and duration of action.... (Review)
Review
The terminal complement C5 inhibitor ravulizumab was engineered from the humanized monoclonal antibody eculizumab to have an extended half-life and duration of action. It binds to human terminal complement protein C5, inhibiting its cleavage into C5a and C5b, thus preventing the cascade of events that lead to architectural destruction of the postsynaptic neuromuscular junction membrane by the membrane attack complex, and consequent muscle weakness in patients with anti-acetylcholine receptor (AChR) antibody-positive generalized myasthenia gravis (gMG). The 26-week randomized, placebo-controlled period (RCP) of the phase 3 CHAMPION MG study demonstrated the rapid efficacy of ravulizumab in reducing MG symptoms. Weight-based dosing of ravulizumab every 8 weeks provided sustained efficacy, in terms of patient-reported (Myasthenia Gravis-Activities of Daily Living) and clinician-reported (Quantitative Myasthenia Gravis) endpoints in patients with anti-AChR antibody-positive gMG. Pharmacokinetic and pharmacodynamic analyses showed therapeutic serum ravulizumab concentrations (>175 µg/mL) were achieved immediately after the first dose and were maintained throughout 26 weeks, irrespective of patient body weight; inhibition of serum free C5 was immediate, complete (<0.5 μg/mL), and sustained in all patients. Interim results from the open-label extension (OLE) showed that after 60 weeks, efficacy was maintained in patients continuing on ravulizumab. Rapid and sustained improvements in efficacy, similar to those seen in patients initiating ravulizumab in the RCP, were observed after initiation of ravulizumab treatment in patients who switched from placebo in the RCP to ravulizumab in the OLE. The findings from the RCP and OLE support ravulizumab's favorable safety profile. In conclusion, ravulizumab has a simple weight-based administration and long dosing interval. Its targeted mechanism of action without generalized immunosuppression is reflected in its rapid onset of symptom improvement, sustained efficacy and good safety profile in the treatment of patients with anti-AChR antibody-positive gMG.
PubMed: 38059203
DOI: 10.2147/NDT.S374694