Myasthenia Gravis Drug Discovery Service
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Overview
Myasthenia gravis (MG) is an autoimmune syndrome caused by neuromuscular transmission failure due to the binding of autoantibodies to proteins involved in neuromuscular junction (NMJ) signaling. MG is the best-characterized autoimmune disease with clearly pathogenic antibodies that impair function by destroying and inhibiting muscle cell acetylcholine receptor (AchR). MG treatment is firmly established as the domain of neurologists.
Fig.1 The neuromuscular junction. (Gilhus, 2015)
Autoantibodies in MG
AChR antibodies are highly specific for MG, and their presence combined with muscle weakness confirms the disease. muscle-specific kinase (MuSK) antibodies are directly pathogenic in experimental animal models. LRP4 (lipoprotein receptor-related protein-4) antibody binds to the membrane protein in vivo and blocks the interaction of agrin-LRP4, thus inhibiting the aggregation of AChR on the membrane. Agrin is essential for AChR function, but whether these antibodies cause muscle weakness in the disease remains unclear. Titin and ryanodine receptor antibodies probably do not enter the muscle cell in vivo and might not mediate any muscle weakness, but rather could be disease markers.
Fig.2 Disruption of postsynaptic differentiation pathway by MuSK autoantibodies. (Phillips, 2016)
Creative Biolabs' Mechanism of Action (MoA) Studies for Pathogenesis of MG
- Effector Mechanisms of Anti-AChR Antibodies
Anti-AChR Abs affect neuromuscular transmission by at least 3 mechanisms: i) complement binding and activation at the NMJ; ii) antigenic modulation; iii) functional AChR block-preventing normal ACh to attach and act on AChR.
- Role of CD4+ T Cells in MG
Pathogenic anti-AChR Abs are high-affinity IgGs-and their synthesis requires activated CD4+ T cells to interact with and stimulate B cells. Therefore, thymectomy, with the resultant removal of AChR-specific CD4+ T cells, helps alleviate symptoms in MG patients.
- Role of CD4+ T-Cell Subtypes and Cytokines in MG and EAMG
CD4+ T cells are classified into two main subtypes: Th1 and Th2 cells. Therapies against Th1 cytokines (TNF-α and IFN-γ) have been proven in animal models to improve EAMG symptoms.
- Other Autoantigens in MG
Anti-MuSK antibodies affect the maintenance of the agrin-dependent AChR cluster on the NMJ, resulting in a decrease in the number of AChR. Other anti-muscle cell protein antibodies are also postulated to have pathogenic roles in MG.
Treatment of MG
- Symptomatic Drug Treatment
Drugs that increase the amount of acetylcholine at neuromuscular endplates after motor nerve stimulation improve muscle weakness in all myasthenia gravis subgroups; pyridostigmine is the preferred drug for symptomatic treatment.
- Immunosuppressive Drug Treatment
A combination of immunosuppressive drugs is preferable for most patients.
- Thymectomy
Many studies have reported a substantial effect of thymectomy in MG.
Creative Biolabs' Services for MG Preclinical Drug Discovery
- In Vitro Services
- In Vivo Services
- Ex Vivo Services
- Discovery Services
- Development Services
Creative Biolabs will work with you as part of your team to not only provide comprehensive quality data but also timely and effective solutions to any challenges that you face. We are happy to discuss your objectives so that we can determine which approach and technologies can best be used to get the most reliable answer efficiently. Please do not hesitate to contact us for more details.
References
- Gilhus, N.E.; Verschuuren, J.J. Myasthenia gravis: subgroup classification and therapeutic strategies. The Lancet Neurology. 2015, 14(10): 1023-1036.
- Phillips, W.D.; Vincent, A. Pathogenesis of myasthenia gravis: update on disease types, models, and mechanisms. F1000Research. 2016, 5.
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