National Center for Drug Discovery in Neurodegeneration

描述(由申请人提供)： 神经退行性疾病是以神经元进行性细胞死亡为特征的中枢神经系统疾病，最终导致认知和运动障碍。这些疾病在美国影响着500多万人，到2010年，全球预计将有2000万人患有某种形式的新城疫。尽管有这么大的数字，ND仍然是一个未得到满足的医疗需求，相对较少受到制药业的关注。显然，发现新城疫的疾病修正药物将需要实施一种不那么依赖于工业的新研究模式。一个这样的模型已经在神经变性药物发现实验室(LDDN)投入使用。LDDN成立于2001年底，目的是与哈佛医学院神经科学界合作，发现可能成为开发治疗ND的新一代药物的起点的化学物质。在最初的两年里，LDDN已经开展了不少于20个项目，并启动了六个药物化学项目。LDDN现在已经到了其药物发现模式发展的关键阶段，必须扩大其合作互动，将全国各地的实验室包括在内，并创建一个国家神经变性药物发现中心(NCDDN)。该提案概述了该中心的创建，并将建立组织基础设施的关键要素(例如，指导委员会、里程碑、知识产权共享和出版政策)以及详细的研究计划作为其具体目标，该计划将在五年内每年应用于五个新药发现项目。这项提议的药物发现研究是由国家疾病控制和预防网络的长期工作人员和来自合作实验室的一名研究人员之间的密切互动推动的。他们将共同扩展合作研究员(CI)从“家庭”实验室带到NCDDN的基础神经科学发现，并(I)开发适用于高通量筛选的精确分析，(Ii)筛选组成LDDN不断增长的化合物文库的数万个类似药物的分子，(Iii)鉴定和验证筛选“HITS”，以及(Iv)实施探索性药物化学的有限计划，以优化化合物的效力。对于成功的项目，研究计划规定了在CI在NCDDN的一年任期之后继续进行的额外研究，并包括更广泛的以药物化学为主导的化合物系列优化计划，以及在动物疾病模型中对这些化合物的有效性测试。这项工作的最后阶段，以及LDDN和NCDDN的总体目标，将超越本申请所要求的支持，但将包括与业界建立伙伴关系，为新城疫患者带来疾病修正药物。在这一修订申请中，我们：(I)特别澄清了指导委员会的性质和运作原则；(Ii)修订和扩大了与追求知识产权和分配研究衍生材料有关的政策；(Iii)更清楚地概述了项目的里程碑和GO/NOGO决策点；(Iv)扩大了药物化学的资源；以及(Iv)描述了AMMA模型中的疗效研究以及我们将如何完成这些研究。

DESCRIPTION (provided by applicant): Neurodegenerative diseases (ND) are CNS disorders characterized by progressive cell death of neurons that ultimately leads to cognitive and motor deficits. These diseases effect more than 5 million people in the U.S. and by 2010, 20 million people worldwide are projected to suffer from some form of ND. Despite these large numbers, ND remains an unmet medical need, receiving relatively little attention from the pharmaceutical industry. It is clear that the discovery of disease-modifying drugs for ND will require the implementation of a new research model that is not so dependent on industry. One such model has been put into operation in the Laboratory for Drug Discovery in Neurodegeneration (LDDN). The LDDN was established in late 2001 to collaborate with the Harvard Medical School neuroscience community to discover chemical entities that could become the starting points for development into a new generation of drugs to treat ND. During its first two years, the LDDN has worked on no less than twenty projects and launched half-a-dozen medicinal chemistry projects. The LDDN has now reached a critical stage in the development of its drug discovery model where it has become essential to expand its collaborative interactions to include laboratories from around the country and to create a NATIONAL CENTER FOR DRUG DISCOVERY IN NEURODEGENERATION (NCDDN). This proposal outlines the creation of this center and has as its specific aims the establishment of key elements of organizational infrastructure (e.g., steering committee, milestones, sharing of intellectual property, and publication policy) as well as a detailed research plan that will be applied to five new drug discovery projects each year for five years. The drug discovery research of this proposal is driven by close interaction between permanent staff members of the NCDDN and an investigator that comes from the collaborating laboratory. Together, they will extend the discoveries in basic neuroscience that the collaboration investigator (CI) brings to the NCDDN from the "home" lab and (i) develop a precise assay suitable for high-throughput screening, (ii) screen tens of thousands of drug-like molecules that comprise LDDN's growing compound library, (iii) identity and validate screening "hits", and (iv) conduct a limited program of exploratory medicinal chemistry to optimize compound potency. For successful programs, the research plan provides for additional studies that will continue beyond the CI's one year tenure in the NCDDN and include a more extensive program of medicinal chemistry-driven optimization of the lead series of compounds as well as efficacy testing of these compounds in animal models of disease. The final phase of this work, and the over-arching goals of the LDDN and NCDDN, will go beyond the support requested in this application, but will include the crafting of partnerships with industry to bring disease-modifying drugs to patients suffering from ND. In this revised application, we have: (i) specially clarified the nature and operating principles of the Steering Committee, (ii) revised and expanded on the policies relating to the pursuit of intellectual property and the distribution of research-derived materials, (iii) outline more clearly milestones and GO/NOGO decision points for projects, (iv) expanded the resources for medicinal chemistry, and, (iv) described efficacy studies in ammal models and how we will get them done.