project 4 - Autonomic Rare Diseases Clinical Research Consortium

多系统萎缩症是一种散发性、多系统、渐进性、致死性的疾病 其特征在于自主神经衰竭，伴有直立性低血压、神经源性膀胱/勃起功能障碍、小脑共济失调、皮质脊髓功能障碍，加上帕金森综合征或小脑变性。 在神经病理学上，MSA的特征在于异常聚集的α-突触核蛋白（α-syn）的胶质细胞胞质内含物（GCI）。目前旨在缓解症状的治疗方法不能阻止疾病进展和死亡，因此策略已转向旨在停止或逆转MSA发病机制的方法。许多证据强调了a-syn聚集的病理重要性。有证据支持线粒体的作用！功能障碍和氧化应激。现在可获得在髓鞘碱性蛋白（MBP）启动子下表达人a-syn的转基因（tg）小鼠模型。这些MBP-a-syn tg小鼠已显示出表现出MSA特征性的a-syn的少突胶质细胞聚集和运动缺陷。许多药剂已经显示出对抗α-syn聚集的前景。特别令人感兴趣的是利福平，因为它能够抑制α-突触核蛋白原纤维的形成，并使原纤维解聚， 形成了这导致了一种假设，即抗生素将延缓MSA的进展或逆转MSA的神经和自主神经功能和症状。这种方法得到了最近的研究的支持，这些研究证明了病理学和功能的逆转。 我们提出了一个双盲安慰剂对照临床试验利福平600毫克每天12个月60 100例MSA患者。研究组群将包括具有相对早期MSA的患者，根据疾病持续时间（<4年）和严重程度定义，以优化改善的机会。主要终点为统一MSA评定量表（UMSARS 1）的第1部分。次要终点将包括自主神经症状评分（COMPASS_change_select）和其他自主神经指数的变化。该联盟汇集了具有专业知识的自主专家的独特合作，对MSA的发病机制进行了关键研究。这样的研究可能是唯一可能的，因为这个联盟能够与4个机构（范德比尔特，马约，哈佛，纽约）和它的合作与MSA PPG的协作协同关系。

Multiple system atrophy (MSA) is a sporadic multi-system progressive and uniformly fatal disorder characterized by autonomic failure, with orthostatic hypotension, neurogenic bladder/erectile dysfunction, cerebellar ataxia, corticospinal dysfunction, plus parkinsonism or cerebellar degeneration. Neuropathologically, MSA is characterized by glial cytoplasmic inclusions (GCI) of abnormally aggregated o synuclein (a-syn). Current treatments approaches aimed at symptomatic relief do not stay progression of disease and death, so that strategy has shifted to approaches aimed at halting or reversing pathogenesis of MSA. Many lines of evidence highlight the pathological importance of a-syn aggregation. There is evidence to support roles for mitochondria! dysfunction and oxidative stress. A transgenic (tg) mouse model expressing human a-syn under the myelin basic protein (MBP) promoter is now available. These MBP-a-syn tg mice have been shown to exhibit the oligodendroglial aggregates of a-syn and motor deficits characteristic of MSA. A number of agents have shown promise in combating a-syn aggregation. Of particular interest is rifampicin, because of its ability to inhibit the formation of a-synuclein fibrils and disaggregate fibrils already formed. This has led to the hypothesis that the antibiotic will delay progression or reverse neurologic and autonomic functions and symptoms in MSA. This approach has been supported by recent studies demonstrating a reversal of pathology and function. We propose a double blind placebo controlled clinical trial of Rifampicin 600 mg per day for 12 months in 60 tolOO patients with MSA. The study cohort will comprise patients with relatively early MSA, defined by duration of disease (<4 years) and severity, to optimize chances of improvement. The primary endpoint will be part 1 of the Unified MSA Rating Scale (UMSARS1). Secondary endpoints will comprise changes in autonomic symptom scores (COMPASS_change_select), and other autonomic indices. This consortium brings together a unique collaboration of autonomic experts with expertise to undertake a key study on the pathogenesis of MSA. Such a study may only be possible because this consortium enables a collaborative synergistic relationship with the 4 institutions (Vanderbilt, Mayo, Harvard, New York) and its collaboration with the MSA PPG.