project 4 - Autonomic Rare Diseases Clinical Research Consortium

多系统萎缩(MSA)是一种散发性的多系统进行性疾病，且一致致死。 以自主神经衰竭为特征，伴有直立性低血压、神经性膀胱/勃起功能障碍、小脑性共济失调、皮质脊髓功能障碍，并伴有帕金森氏症或小脑变性。 在神经病理学上，MSA的特征是异常聚集的o-突触核蛋白(a-syn)的胶质细胞质包涵体(GCI)。目前旨在缓解症状的治疗方法无法阻止疾病和死亡的进展，因此，战略已转向旨在阻止或逆转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。在髓鞘碱性蛋白(MBP)启动子下表达人a-syn的转基因(TG)小鼠模型现已可用。这些MBP-a-syn TG小鼠已被证明表现出a-syn的少突胶质聚集和MSA特有的运动缺陷。一些代理商在打击a-syn聚合方面表现出了希望。特别令人感兴趣的是利福平，因为它有能力抑制a-突触核蛋白纤维的形成，并已经解聚了纤维。 形成了。这导致了一种假设，即抗生素将延缓MSA的进展或逆转神经和自主神经功能和症状。这一方法得到了最近一些研究的支持，这些研究证明了病理和功能的逆转。 我们提出了一项双盲安慰剂对照临床试验，利福平每天600毫克，持续12个月，用于60名患有MSA的TOLO患者。研究队列将包括由病程(4年)和严重程度定义的相对较早的MSA患者，以优化改善的机会。主端点将是统一MSA评级量表(UMSARS1)的第1部分。次要终端将包括自主症状评分(COMPASS_CHANGE_SELECT)和其他自主指数的变化。该联盟汇集了具有专业知识的自主神经专家的独特合作，对MSA的发病机制进行了关键研究。这项研究之所以有可能，是因为该联盟与4所院校(范德比尔特、梅奥、哈佛、纽约)建立了协作协同关系，并与MSA PPG进行了合作。

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.