Autonomic Rare Diseases Clinical Research Consortium

 描述(由申请人提供)：这个关于罕见自主疾病的RDCRC包括5个主要中心：范德比尔特大学、梅奥/罗切斯特、纽约大学、贝丝以色列女执事/哈佛大学和NINDS/临床中心。自主神经障碍的主要支持团体正在参与和参与。在更新期间，我们的研究重点将集中在罕见的自主神经疾病，如多系统萎缩(MSA)、纯自主神经衰竭(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了解，开发新的治疗方法，不仅可以缓解患者的症状，还可以干预疾病的发展，并希望在可能的情况下找到治愈方法。在过去四年中，我们几乎实现了最初筹资周期的所有具体目标。我们开发了一个网站，教育患者、研究人员和临床医生，并协助为各种联盟研究招募人员。我们招募了469名患者参加正在进行的神经源性直立性低血压的自然病史研究(所有项目中共有656名患者)。在利福平治疗MSA患者的随机、双盲、安慰剂对照试验中，我们提前达到了目标入选人数。虽然利福平没有改善MSA，但这项研究教会了我们很多，提供了有价值的见解和策略，已被纳入我们更新的临床项目的设计中。我们还完成了一项概念验证研究，以检验去甲肾上腺素再摄取阻断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，除了继续进行扩大的表型和自然病史研究外，我们还提出了三个新的临床项目和三个新的试点项目。间充质干细胞的一项试验旨在对抗最近在MSA中发现的生长因子缺乏。我们的研究表明，托莫西汀可以提高立位耐力。我们正在进行类似的研究，包括在神经源性直立性低血压中减少内脏电容，在MSA中用3，4-二氨基吡啶控制残余交感神经张力，在高肾上腺素能POTS中采用新的迷走神经刺激策略。这些研究将与我们扩大自主生物标记物开发的努力联系起来。继续开展自主性疾病控制与发展合作伙伴关系将使我们能够以我们最近的新知识为基础，了解并有望改变这些疾病的进程。我们将与患者权益倡导团体合作。我们将处理信息丰富的生物标记物，并阐明机制，以寻找真正有效的药物治疗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.