With the near-eradication of polio, Guillain-Barr? syndrome (GBS) has become the most frequent cause of acute flaccid paralysis. Current immunomodulatory treatments are only effective in a proportion of patients. For example IVIG-a first line treatment modality in GBS-hasten recovery in only ~50% of those treated with this medication. Despite availability of current of immunotherapies, a significant proportion of patients are left with severe and permanent neurologic sequelae, including inability to walk independently. There is a dire need for newer/additional treatments that can limit the axonal damage during the acute phase of the disease and enhance repair during recovery period are desirable. For over last 20 years no new treatments have entered the clinical arena of GBS. It is in this context we want to test an Abdeg (Fc-engineered antibody that enhance IgG degradation by blocking neonatal Fc receptor (FcRn)) appropriate for human use as autoAb-specific immunotherapy in preclinical models of GBS. Anti-ganglioside antibodies (Abs) are the most frequently recognized autoimmune responses in GBS. We focus on anti-glycan Ab associated disease models in this grant as substantial experimental data support the primary pathogenic role of these autoAbs in GBS particularly in its axonal variants. Our group has developed two different passive transfer animal models with anti-glycan Abs, which will be used in the proposed studies. Our preliminary studies show that mice lacking neonatal Fc receptor (FcRn) are not susceptible to anti-ganglioside Ab-mediated nerve injury due to rapid clearance of these Abs in an animal model. Based on these observations we postulate that Abdegs would be protective in our animal models of anti-ganglioside Ab-mediated nerve injury. This hypothesis will be tested by the following specific aims:
Aim 1 will examine the efficacy of Abdeg (MST-HN) in animal studies by measuring the circulating half-life of pathogenic experimental and human anti-glycan Abs and correlate this with their pathogenic effects on intact and injured axons;
Aim 2 will compare efficacy and/or synergism of IVIG with Abdeg MST-HN in suppressing anti-glycan Ab-mediated nerve injury in animal models. For translational purposes it would be important to determine in preclinical models whether a): Abdeg (MST-HN) and IVIG do not have antagonistic effects;and b) these two medications have synergistic effects. Both these issues are relevant from ethical and trial design perspective if this therapy were to extend to human studies. This project may help in developing new treatment stratgies aiming to expedite clearnce of autoAbs and has relevance not only to GBS but other neuroimmunological disorders including myasthenia gravis and neuromyelitis optica.
Guillain-Barre syndrome (GBS) is the commonest cause of acute flaccid paralysis worldwide and current treatments are ineffective in a substantial proportion of patients. This disease is strongly associated with autoantibodies directed against cell surface glycans called gangliosides and these autoantibodies are considered pathogenic. This project proposes to test a treatment strategy that can enhance clearance of these autoantibodies in animal models relevant to GBS and results may facilitate development of new therapies for patients with GBS.
|Zhang, Gang; Lin, Jianxin; Ghauri, Sameera et al. (2017) Modulation of IgG-FcRn interactions to overcome antibody-mediated inhibition of nerve regeneration. Acta Neuropathol 134:321-324|
|Zhang, Gang; Massaad, Cynthia A; Gao, Tong et al. (2016) Sialylated intravenous immunoglobulin suppress anti-ganglioside antibody mediated nerve injury. Exp Neurol 282:49-55|
|Rozés Salvador, Victoria; Heredia, Florencia; Berardo, Andrés et al. (2016) Anti-glycan antibodies halt axon regeneration in a model of Guillain Barrè Syndrome axonal neuropathy by inducing microtubule disorganization via RhoA-ROCK-dependent inactivation of CRMP-2. Exp Neurol 278:42-53|
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