RRNMF Neuromuscular Journal最新文献

{"title":"Promising Antigen-specific Immunotherapy for the Treatment of Myasthenia Gravis","authors":"Eleni Ntoukaki, María Fernández-Santoscoy, Vasiliki Baltatzidou, B. Löwenadler, Charlotte Fribert, K. Lazaridis","doi":"10.17161/rrnmf.v4i3.19494","DOIUrl":"https://doi.org/10.17161/rrnmf.v4i3.19494","url":null,"abstract":"Myasthenia gravis (MG) is a T cell-dependent, antibody-mediated, autoimmune disorder with well-established antigenic targets at the neuromuscular junction. MG autoantibodies mainly target the nicotinic acetylcholine receptor (AChR) and especially epitopes located in the extracellular domain of the α1 subunit (α1-ECD). Today, most therapeutic regimens for MG are non-specific and not curative, requiring chronic treatments that are associated with significant side effects. We aim to develop an antigen-specific therapeutic approach, based on reestablishing tolerance towards the AChR, the dominant autoantigen in MG. To this end, we used a soluble mutated form of the human α1-ECD, which incorporates a major fraction of MG autoreactive T cell epitopes and examined the therapeutic efficiency of intravenous administration in a rat experimental autoimmune MG model. We found that repeated intravenous administration of α1-ECD for up to 12 days led to a robust amelioration of disease symptoms in a dose and time-dependent manner. The observed therapeutic effect of α1-ECD was significantly better than the effect of two current mainstay drugs for MG treatment. There were no signs of toxicity in α1-ECD-treated animals and further studies are underway to fully elucidate the immunological mechanism underlying the treatment effect. Taken together, our preclinical data strongly suggest that intravenous administration of α1-ECD may represent an efficacious and safe strategy to treat MG and thus α1-ECD represents a new drug candidate for clinical application in MG. ","PeriodicalId":309700,"journal":{"name":"RRNMF Neuromuscular Journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"124514611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exercise Training for autoimmune myasthenia gravis: A review of safety and effectiveness based on existing literature","authors":"S. Birnbaum, T. Sharshar, J. Hogrel","doi":"10.17161/rrnmf.v4i3.18699","DOIUrl":"https://doi.org/10.17161/rrnmf.v4i3.18699","url":null,"abstract":"No abstract is required for a review article as per instructions","PeriodicalId":309700,"journal":{"name":"RRNMF Neuromuscular Journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"131787629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacological treatment of Lambert-Eaton Myasthenic Syndrome","authors":"Wisse Bakker, L. Remijn-Nelissen, Kirsten J.M. Schimmel, M. Tannemaat, J. Verschuuren, T. van Gelder","doi":"10.17161/rrnmf.v4i3.19550","DOIUrl":"https://doi.org/10.17161/rrnmf.v4i3.19550","url":null,"abstract":"Lambert-Eaton myasthenic syndrome (LEMS) is a very rare antibody-mediated autoimmune disease of the neuromuscular junction. Therapy can be divided in symptomatic treatment and immunosuppressive treatment. Symptomatic treatment with amifampridine is the only therapy currently authorized for use in LEMS patients. In the Netherlands the first choice drug is amifampridine base in an extended release formulation instead of the currently authorized amifampridine phosphate. This formulation has lower costs and is possibly safer due to lower peak concentrations. Other therapy used in LEMS patients is prescribed off-label and is based on experience in patients with myasthenia gravis. In many cases pyridostigmine is added as symptomatic treatment. In almost half of patients immunosuppressive therapy is started, mostly corticosteroids with or without azathioprine. Intravenous immunoglobulins and plasma exchange are used as emergency treatment. \u0000Currently no randomized clinical trials with new therapies are ongoing or announced in patients with LEMS, although multiple new therapies for myasthenia gravis are being investigated. These future therapies can be differentiated in symptomatic and immunomodulating drugs. The immunomodulating drugs can be further differentiated in early stage drugs which target the B-cell, later stage drugs which target the circulating antibodies and targeted therapy which have a disease-specific target. Some early and later stage immunomodulating drugs show promising results in myasthenia gravis although high cost and uncertain long term safety may be limiting for incorporating these drugs in LEMS treatment guidelines. \u0000Clinical trials in LEMS patients are lacking due to the rarity of the disease and we suggest the following requirements for future trials of potential new treatments: Sufficient power by performing multicenter or n-of-1 trials when appropriate, a cross-over design to reduce the number of patients and using a LEMS-specific quantitative primary outcome measure like the 3TUG score.","PeriodicalId":309700,"journal":{"name":"RRNMF Neuromuscular Journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"128939288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MGFA Meeting Proceedings: Editor's Introduction","authors":"Carolina Barnett-Tapia, Kevin O'Connor, R. Barohn","doi":"10.17161/rrnmf.v4i3.21241","DOIUrl":"https://doi.org/10.17161/rrnmf.v4i3.21241","url":null,"abstract":"Introduction to the MGFA Meeting Proceedings.","PeriodicalId":309700,"journal":{"name":"RRNMF Neuromuscular Journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"130140862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Complement inhibition in Myasthenia – from basics to RCT data","authors":"S. Jacob","doi":"10.17161/rrnmf.v4i3.19516","DOIUrl":"https://doi.org/10.17161/rrnmf.v4i3.19516","url":null,"abstract":"Myasthenia gravis (MG) is the prototypic autoimmune neurological disorder causing fatiguable muscle weakness either limited to the ocular muscles or becoming generalised involving the limb and bulbar muscles. Nine out of 10 generalised MG patients have IgG1 or IgG3 antibodies against the acetylcholine receptor (AChR). AChR antibodies cause neuromuscular weakness by internalisation of AChR, receptor blockade and by activating the complement pathway. Complement activation causes formation of the membrane attack complex (MAC) leading to degradation of the neuromuscular junction (NMJ). Several animal models have confirmed the role of complement in the pathogenesis of MG, with the experimental models (EAMG) often needing complement inhibitory therapies to prevent or reverse the disease. Various molecules that target the complement system have now been developed to treat myasthenia gravis. The vast majority of the currently studied molecules target the C5 protein, thereby preventing the formation of MAC and subsequent NMJ destruction. The currently studied anti-complement therapies for MG include Eculizumab, Zilucoplan, Ravulizumab, Pozelimab, Cemdisiran, Gefurilimab, Danicopan and few others in the pipeline.  Eculizumab has been shown in clinical trials to be effective in the treatment of refractory MG, but further sub-group analysis and real-life experience have shown that this can be beneficial in various patients including those receiving regular IVIG, plasma exchange or Rituximab. It was approved for use by FDA in Oct 2017. Ravulizumab is a long-acting monoclonal antibody which has similar mechanism of action to Eculizumab and was approved for use in MG by FDA in April 2022. Zilucoplan is a macrocyclic peptide which binds to C5 and C5b thus preventing terminal complement activation, which can be given subcutaneously (FDA new drug application accepted in Nov 2022). Many of these have also been shown to have long term benefit in different sub-groups of patients with MG. Patients would need to be vaccinated against Neisseria meningitidis because of the risk of Gram-negative septicaemia, although no major safety signatures have been noted in the studies so far. Future studies may be able to identify specific biomarkers which might aid in selecting the most appropriate patients who might respond to these therapies.","PeriodicalId":309700,"journal":{"name":"RRNMF Neuromuscular Journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"115388625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the safety factor for neuromuscular transmission to treat myasthenia gravis","authors":"G. L. Odierna, William Phillips","doi":"10.17161/rrnmf.v4i3.19543","DOIUrl":"https://doi.org/10.17161/rrnmf.v4i3.19543","url":null,"abstract":"In myasthenia gravis autoantibodies attack the postsynaptic membrane of the neuromuscular junction causing fatiguing weakness that can wax and wane. Weakness occurs when the safety factor for neuromuscular transmission becomes marginal, meaning that the (postsynaptic) endplate potential is no longer sufficient to reliably trigger action potentials in the muscle fiber. Cholinesterase inhibitor drugs provide temporary relief by increasing the endplate potential amplitude, but additional symptomatic treatment options are needed. Here we discuss our recent experience in early preclinical testing of candidate compounds. Using an ex vivo mouse nerve-muscle contraction assay, followed up by endplate potential recordings, we examined the effects of cannabinoids. Our findings highlighted the potentially confounding effects of dimethylsulfoxide (DMSO) when used as a solubilizing agent. DMSO produced a dose-dependent restoration of force to curarized muscle and enhanced miniature endplate potential amplitude, thus enhancing the safety factor for neuromuscular transmission at concentrations as low as 0.1% v/v. When examined in the absence of curare, the DMSO-induced increase in quantal amplitude was opposed by a homeostatic reduction in the number of quanta of acetylcholine released by the nerve terminal. In contrast to DMSO, cannabinoids appear to work via cannabinoid receptor type 1 to reduce quantal number, thereby weakening the safety factor. Our results highlight the need to consider the effects of solubilizing agents per se when screening new therapeutics for neurological diseases. They also demonstrate the need to take synaptic homeostasis into account, which can otherwise distort or mask the effects of bioactive agents upon neurotransmission.","PeriodicalId":309700,"journal":{"name":"RRNMF Neuromuscular Journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"133323761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circulating microRNA in Myasthenia gravis (MG)","authors":"A. Punga, T. Punga","doi":"10.17161/rrnmf.v4i3.19486","DOIUrl":"https://doi.org/10.17161/rrnmf.v4i3.19486","url":null,"abstract":"One of the main difficulties in predicting the clinical course of Myasthenia Gravis (MG) is the heterogeneity of the disease, where disease progression differs greatly depending on the patient's subgroup. MG subgroups are classified according to the age of onset [early onset MG (EOMG; onset ≤ 50 years) versus late-onset MG (LOMG; onset >50 years]; the presence of a thymoma (thymoma associated MG), antibody subtype [acetylcholine receptor antibody seropositive (AChR+), muscle-specific tyrosine kinase antibody seropositive (MuSK+)], or presence of antibodies against low-density lipoprotein receptor-related protein 4 (Lrp4) or agrin as well as clinical subtypes (ocular versus generalized MG). The diagnostic tests for MG, such as antibody titers, neurophysiological tests, and objective clinical fatigue scores, do not necessarily reflect disease progression. Hence, there is a great need for reliable, objective biomarkers in MG to follow the disease course and the individualized response to therapy toward personalized medicine. In this regard, circulating microRNAs (miRNAs) have emerged as promising potential biomarkers due to their accessibility in body fluids and unique profiles in different diseases, including autoimmune disorders. Several studies on circulating miRNAs in MG subtypes have revealed specific miRNA profiles in patient sera. In generalized AChR+ EOMG, miR-150-5p and miR-21-5p are the most elevated miRNAs, with lower levels observed upon treatment with immunosuppression and thymectomy. In AChR+ generalized LOMG, miR-150-5p, miR-21-5p, and miR-30e-5p levels are elevated and decreased by the clinical response after immunosuppression. In ocular MG, higher levels of miR-30e-5p discriminate patients who will later generalize from those remaining ocular. In contrast, in MuSK+ MG, the levels of the let-7 miRNA family members are elevated. Studies of circulating miRNA profiles in Lrp4 or agrin antibody seropositive MG are still lacking. This review summarizes the present knowledge of circulating miRNAs in different subgroups of MG.","PeriodicalId":309700,"journal":{"name":"RRNMF Neuromuscular Journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"127756582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MuSK-CAART: A novel precision cellular therapy for muscle-specific tyrosine kinase myasthenia gravis","authors":"A. Payne, Sangwook Oh","doi":"10.17161/rrnmf.v4i3.19417","DOIUrl":"https://doi.org/10.17161/rrnmf.v4i3.19417","url":null,"abstract":"Chimeric autoantibody receptor (CAAR) T cells are a novel genetically-engineered T cell immunotherapy that aims to durably eliminate antigen-specific B cells while sparing healthy B cells, ideally leading to safe and lasting remission of B cell-mediated autoimmune diseases with a one-time infusion. We describe the preclinical development of muscle-specific tyrosine kinase CAAR T cells (MuSK-CAART) for the treatment of MuSK myasthenia gravis, a debilitating autoantibody-mediated disease that causes potentially life-threatening muscle weakness.","PeriodicalId":309700,"journal":{"name":"RRNMF Neuromuscular Journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"128953336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Myasthenia research over the last 50 years – a personal perspective","authors":"A. Vincent","doi":"10.17161/rrnmf.v4i3.19551","DOIUrl":"https://doi.org/10.17161/rrnmf.v4i3.19551","url":null,"abstract":"Myasthenia gravis (MG) research has, in many respects, been a trail blazer for the growing number of autoantibody-mediated disorders that affect the nervous system. The breakthroughs in MG understanding were made in the 1970s and even 50 years later, MG still remains a topic which scientists, clinicians and, most recently Pharma, return to as the most common and well-studied disorder.  Here, some of the main discoveries will be reviewed very briefly focusing on how the knowledge of the disease evolved during the first decades after the discovery of acetylcholine receptor antibodies.  It should be noted that this is a personal perspective and not a systematic or fully referenced review.","PeriodicalId":309700,"journal":{"name":"RRNMF Neuromuscular Journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"116638722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of Rare Membrane Antigen Specific Human B Cells","authors":"N. Sanderson","doi":"10.17161/rrnmf.v4i3.19523","DOIUrl":"https://doi.org/10.17161/rrnmf.v4i3.19523","url":null,"abstract":"The experimentally well supported model that MG pathology is caused by antibodies of the IgG class that bind to AChR at the neuromuscular junction, activate complement, and possibly cause internalization of receptors or their functional blockade has enabled the development of a range of reasonably effective treatments. A better understanding of which B cells are responsible for producing these pathogenic antibodies, and why such B cells develop would enable the development of more targeted therapies. Studies of antibodies isolated from single B cells from patients have provided some of this information that was not available from studies of polyclonal antibodies in sera, but perhaps future studies of the B cells themselves will provide deeper insight into the causes of the disease and thereby enable its prevention.","PeriodicalId":309700,"journal":{"name":"RRNMF Neuromuscular Journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"122504385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}