Autonomic Rare Diseases Clinical Research Consortium

 描述（由申请人提供）：这个关于罕见自主神经疾病的RDCRC包括5个主要中心：范德比尔特大学、马约/罗切斯特、纽约大学、贝丝以色列女执事/哈佛和NINDS/临床中心。自主神经紊乱的主要支持团体参与和参与。在更新期间，我们的研究工作将集中在罕见的多系统萎缩（MSA），纯自主神经功能衰竭（PAF）和高肾上腺素能体位性心动过速综合征（POTS），以及路易体痴呆和其他突触核蛋白病的自主神经疾病。我们联盟的总体目标是提高我们对这些疾病的病理生理学的理解，开发新的疗法，不仅缓解患者的症状，而且干预疾病进展，并希望在可能的情况下找到治愈方法。在过去四年中，我们几乎实现了初始供资周期的所有具体目标。我们开发了一个网站，对患者、研究人员和临床医生进行教育，并协助招募各种联盟研究的人员。我们在正在进行的神经源性直立性低血压自然史研究中招募了469例患者（所有项目中共有656例）。我们在一项随机、双盲、安慰剂对照的利福平治疗MSA患者的试验中提前达到了目标招募。虽然利福平没有改善MSA，但这项研究教会了我们很多，提供了宝贵的见解和策略，这些见解和策略已纳入我们更新的临床项目设计中。我们还完成了一项概念验证研究的入组，以检查去甲肾上腺素再摄取阻滞作为神经源性直立性低血压患者的诊断和治疗工具的作用。对于这次更新，除了继续进行扩展的表型和自然史研究外，我们还提出了三个新的临床项目和三个新的试点项目。间充质干细胞的试验旨在对抗最近在MSA中发现的生长因子缺乏症。我们的研究表明，托莫西汀可以改善立位耐力。我们提出了类似的研究，减少内脏电容在神经源性直立性低血压，利用残余交感神经紧张与3，4-二氨基吡啶在MSA和一种新的迷走神经刺激策略在肾上腺素能POTS。这些研究将与扩大自主生物标志物的发展相联系。自主RDCRC的继续将使我们能够建立在我们最近的新知识，以了解并希望改变这些疾病的过程。我们将与患者倡导团体合作。我们将解决信息生物标志物和阐明机制，以找到真正有效的药物罕见的自主神经疾病。

 DESCRIPTION (provided by applicant): This RDCRC on Rare Autonomic Diseases encompasses 5 major centers: Vanderbilt University, Mayo/Rochester, New York University, Beth Israel Deaconess/Harvard, and the NINDS/Clinical Center. Major support groups for autonomic disorders are engaged and participate. During the renewal period, our research efforts will focus on the rare autonomic diseases of multiple system atrophy (MSA), pure autonomic failure (PAF), and hyperadrenergic postural tachycardia syndrome (POTS), as well as dementia with Lewy bodies and other synucleinopathies. The overall objectives of our Consortium are to improve our understanding of the pathophysiology of these diseases to develop novel therapies to not only alleviate patients' symptoms but also to intervene in disease progression, and hopefully when possible to find a cure. Over the past four years, we met virtually all specific goals of our initial funding cycle. We developed a website that educates patients, researchers and clinicians, and assists with recruitment for the various consortium studies. We enrolled 469 patients in the ongoing natural history study of neurogenic orthostatic hypotension (and a total of 656 in all projects). We met target enrollment ahead of schedule in a randomized, double-blind, placebo-controlled trial of rifampicin in patients with MSA. While rifampicin did not improve MSA, this study taught us much, providing valuable insights and strategies that have been incorporated into the design of the clinical projects in our renewal. We also completed enrollment in a proof-of-concept study to examine the role of norepinephrine reuptake blockade as both a diagnostic and therapeutic tool in patients with neurogenic orthostatic hypotension. For this renewal, in addition to continuing with an expanded phenotyping and natural history study, we propose three new clinical projects and three new pilot projects. A trial of mesenchymal stem cells is directed at combating the growth factor deficiency recently identified in MSA. Our studies suggest that atomoxetine can improve orthostatic tolerance. We are proposing similar studies with reducing splanchnic capacitance in neurogenic orthostatic hypotension, harnessing residual sympathetic tone with 3,4- diaminopyridine in MSA and a novel vagal stimulation strategy in hyperadrenergic POTS. These studies will be linked with efforts to expand our development of autonomic biomarkers. Continuation of the Autonomic RDCRC will enable us to build on our recent new knowledge to understand and hopefully alter the course of these diseases. We will work collaboratively with patient advocacy groups. We will address informative biomarkers and elucidate mechanisms to find genuinely effective agents for the rare autonomic diseases.