Clinical, Viral/mmune Studies In Neuromuscular Diseases

神经肌肉疾病的临床、病毒/免疫研究

• 批准号: 7143799
• 负责人: Marinos Dalakas
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7143799
• 关键词: B lymphocyte; GABA receptor; T cell receptor; T lymphocyte; antiinflammatory agents; autoantibody; autoantigens; clinical trials; dermatomyositis; extrapyramidal disorder; glycogen storage disease; hereditary peripheral nervous system disorder; human subject; human therapy evaluation; immunoglobulins; immunotherapy; longitudinal human study; monoclonal antibody; muscle cells; myelinopathy; myositis; neuroprotectants; neuropsychological tests; patient oriented research; poliomyelitis; proteomics

Clinical, laboratory and therapeutic studies are conducted to determine etiology (autoimmunity, neurotoxicity, genetics) of various neuromuscular diseases and design, or apply, effective therapies. Current studies involve patients with: a) inflammatory myopathies with emphasis on inclusion body myositis (IBM); b) inherited vacuolar myopathies with emphasis on hereditary IBM due to GNE mutations and desmin-related myopathies; c) demyelinating polyneuropathies; d) postpolio syndrome; and e) the stiff-person syndrome(SPS). In inflammatory myopathies, the specificity of the T cell Receptors and the in situ clonal expansion of the endomysial T cells are examined longitudinally. The studies have shown that in IBM the T cells are driven by specific antigens. To search for putative antigen(s), T cell clones have been established from the endomysial T cell infiltrates; candidate immunodominant peptides that drive the T cell responses and serve as autoantigens are currently explored using combinatorial peptide libraries. It has been found that in IBM chemokines and costimulatory molecules such as ICOS, ICOS-L and PDI are upregulated and the muscle fiber may function as Antigen Presenting cell. Because cytokines share common antigenic determinants with the Alzheimer-like beta-APP amyloid deposits, an interrelationship between these molecules was explored. A linear relationship was found between cytokines, chemokines and amyloid-related degenerating molecules not only in vivo in the patient's muscles but also in vitro in human myotubes. At the clinical level, a longitudinal study examining the natural history of IBM has been completed. To suppress the myocytotoxic effect of T cells, a therapeutic and investigational clinical trial has begun using CAMPATH, a humanized monoclonal antibody that induces a sustained depletion of mature T cells allowing for toleragenic T cell responses. Six patients have been treated up to now. The study is ongoing. In demyelinating neuropathies associated with IgM autoantibodies to MAG and glycolipids,a new controlled therapeutic study was performed using a humanized monoclonal antibody against B cell clones. The study is now completed and all required 23 patients have been enrolled. The study correlates clinical responses with the binding affinity of IgM to various glycoconjugates on the myelin sheath. The results are currently analyzed. In an effort to find responsible autoantigens in patients with Stiff Person Syndrome (SPS), T cell clones were established from the CSF and being tested against combinatorial peptide libraries. Using proteomics in the patients' serum, an antigenic peptide GABARAP (GABA-Receptor Associated Protein) was found to be reduced. The reduction of GABARAP was subsequently found to be associated with anti-GABARAP antibodies which were detected in up to 65% of SPS patients. Because GABARAP is fundamental in stabilizing GABAA receptors, a dysfunctional GABARAP is probably associated with the reduced level of brain GABA, as detected with MRS spectroscopy, and play a role in the pathogenesis of SPS. A new double-blind clinical trial using the B cell-depleting monoclonal antibody Rituximab has began. Up to 4 patients have enrolled this year. The origin of phobias, a common feature in SPS patients, was being explored using a series of neurocognitive measurements. It was found that the phobias are secondary to disabillity and not due to the primary disease. In patients with postpolio syndrome and severe fatigue, a double blind study using Modafinil has been conducted. The results are now analyzed. In patients with hereditary IBM due to mutations in the GNE gene we observed defect in glycosylation of muscle proteins and reduction of alpha-dystroglycan. A clinical trial is now ready to begin using intravenous immunoglobulin in an effort to increase muscle glycosylation. A phenotype/genotype correlation has been completed in patients with hereditary myopathies due to pathogenic mutations in the desmin gene. It has been concluded that desmin myopathy is a distinct disease affecting intermediate filaments (filamentopathy) and that the type of mutations may dictate clinical severity or presence of cardiomyopathy.

进行临床、实验室和治疗研究，以确定各种神经肌肉疾病的病因（自身免疫、神经毒性、遗传学），并设计或应用有效的治疗方法。目前的研究涉及的患者有：a)炎症性肌病，重点是包涵体肌炎（IBM）；b)遗传性空泡性肌病，重点是由GNE突变和与死亡相关的肌病引起的遗传性IBM；C)脱髓鞘性多发性神经病；D)脊髓灰质炎后综合症；e)僵硬人综合症。