NIH ALS Conference: Clinical Research to Find the Pathogenesis and Cause of ALS

描述(申请人提供)：肌萎缩侧索硬化症(ALS)是一种毁灭性的神秘疾病，无法治愈。唯一获得批准的可用药物利鲁唑只能适度减缓疾病的进展。在过去的20年里，基于不同的假说开发的近30种潜在的药物被广泛尝试，但都没有成功。另一方面，动物模型、分子生物学和神经科学的令人难以置信的进步导致了一些家族性ALS遗传原因的确定，并在ALS中产生了许多令人兴奋的假说。然而，我们对ALS的发病机制和病因的认识仍然存在着明显的不足。因此，如果我们要了解和有效治疗这种疾病，我们需要进一步研究ALS患者的发病机制和病因。我们坚信，解开这一谜团的关键很可能在于患者本身。然而，研究ALS患者面临许多挑战，因为1)ALS相对罕见(每100,000人中有1至2例)，2)由于其快速发展，确诊后几乎没有时间进行研究，3)患者通常在成年后被诊断出来，几乎没有直系亲属可供研究，以及4)获得中枢神经系统组织的机会非常有限。尽管有这些局限性和巨大的方法学挑战，ALS医生和内科科学家仍然处于最好的地位，直接在患者身上研究ALS的病因和发病机制。此外，我们不仅需要找到创造性和创新性的方法来研究这种疾病，而且还需要与基础科学家作为密切合作伙伴进行合作。因此，我们建议召开一次会议，以促进ALS的临床或以患者为导向的研究。我们的具体目标是：1)将ALS医生、内科科学家和基础科学家聚集在一起，讨论一个集中的主题，即临床研究(而不是临床试验)；2)综述ALS的发病机制和病因的现状，包括临床特征、生物标志物、流行病学以及遗传和表观遗传学研究，其中大部分适合临床研究；3)鼓励医生与基础科学家合作，以考虑开展临床研究的可行性，目的是发现ALS的病因(S)和发病机制。此外，我们将讨论推动临床研究必须克服的方法和资金问题；以及4)将会议的结果和建议作为补充或白皮书发表在主要的神经学杂志上。会议的设计将允许开放的思想交流，并有望制定出未来发展非常积极的临床研究的战略。医生和科学家必须认识到，在ALS中比以往任何时候都更需要这样的合作。我们坚信，这次会议将是朝着找到发病机制和病因(S)，并最终治愈这种可怕的疾病--肌萎缩侧索硬化症--迈出的一步。 公共卫生相关性：肌萎缩侧索硬化症(ALS)是最具破坏性的神经系统疾病之一，目前尚无治愈方法。其发病机制和病因尚不清楚。我们建议召开一次NIH ALS会议，在会上，两位专门研究ALS的内科医生和基础科学家将聚集在一起，讨论如何促进和激励临床研究，以发现未来ALS的发病机制和病因。这将是导致ALS治愈的重要一步。

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a devastating and enigmatic disease with no cure. The single approved, available medication, Riluzole, only modestly slows disease progression. Nearly 30 potential medications, developed based on diverse hypotheses, have been extensively tried in the past 20 years, but this has been without success. On the other hand, incredible progress in animal models, molecular biology and neuroscience has led to the identification of a number of hereditary causes of familial ALS and generated many exciting hypotheses in ALS. Nevertheless, there is still a glaring deficit in our knowledge of the pathogenesis and cause of ALS. Consequently, if we are to understand and effectively treat this disease, we need to further investigate the disease mechanisms and cause in our ALS patients. We strongly believe that the key to this mystery is likely to exist in the patients themselves. However, studying patients with ALS poses many challenges because 1) ALS is relatively rare (1 to 2 cases per 100,000 population), 2) given its rapid progression, there is little time for research after diagnosis, 3) patients are generally diagnosed late in adulthood, leaving few immediate family members for study, and 4) access to the central nervous system tissue is highly limited. Despite these limitations and tremendous methodological challenges, ALS physicians and physician-scientists are still in the best position to study the cause and pathogenesis of ALS directly in patients. Further, we need not only to find creative and innovative ways to investigate this disease, but also, to work with basic scientists as close partners. Therefore, we propose to hold a conference to energize clinical or patient-oriented research in ALS. We specifically aim to: 1) bring ALS physicians, physician-scientists and basic scientists together to discuss a focused topic, clinical research (not clinical trials); 2) review the current status of the pathogenesis and cause of ALS including clinical characteristics, biomarkers, epidemiology, and genetic and epigenetic studies, most of which are amenable to clinical research; 3) encourage physicians to collaborate with basic scientists in order to consider the feasibility of developing clinical research with the aim of discovering the cause(s) and pathogenesis of ALS. Further, we will discuss methodological and funding issues that must be overcome in order to move clinical research forward; and 4) publish the results and recommendations from the conference as a supplement or as a white paper in a major neurology journal. The meeting will be designed to allow for the open exchange of ideas, and will hopefully work out strategies for developing very active clinical research in the future. It is imperative that physicians and scientists realize that, more than ever before, there is a serious need for such collaboration in ALS. We strongly believe that this meeting will be a step forward to finding the pathogenesis and cause(s), and eventually, the cure for this dreaded disease, ALS. PUBLIC HEALTH RELEVANCE: Amyotrophic lateral sclerosis (ALS) is one of the most devastating neurological diseases with no cure. Its pathogenesis and cause are not yet established. We propose an NIH ALS Conference in which physicians and basic scientists, who both specialize in ALS, will come together and discuss how to facilitate and energize clinical research to find the pathogenesis and cause of ALS in the future. This will be an important step to lead to the cure for ALS.