Systemic AA Amyloidosis Inhibitors

描述(申请人提供)：系统性AA淀粉样变性的特征是含有AA淀粉样蛋白的不溶性纤维沉积在许多不同的器官(包括心、肾、脾、肺和/或胃肠道)中沉积和积聚，从而导致显著的器官功能障碍。系统性AA淀粉样变性与慢性炎症性疾病有关，包括类风湿性关节炎、骨髓炎、强直性脊柱炎、炎症性肠道疾病、结核病、麻风、霍奇金氏病、肾细胞癌和家族性地中海热。全身器官中纤维状AA淀粉样蛋白沉积的后果对患者是有害的，大多数患者在发病后3-7年内死于肾脏或心力衰竭。目前，AA淀粉样变性尚无有效的治疗方法，迫切需要新的治疗方法。利用各种体外筛选技术和AA淀粉样变性的实验小鼠模型，我们发现了一类新的小化合物，它们在小鼠模型中显著阻止纤维状AA淀粉样蛋白的形成和沉积。在这个第一阶段的SBIR项目中，我们将在我们重要的初步观察的基础上，使用体外筛选方法(Aim 1)和细胞培养(Aim 2)来鉴定具有特定结构特征的小分子无毒化合物，这些化合物对于抑制组织中纤维状AA淀粉样蛋白的形成和沉积非常重要。要测试的化合物类型包括商业上可用的化合物和特定的合成类似物(代表物质的新成分)，它们将产生与观察到的疗效的结构-活性关系有关的有价值的信息。使用体外筛选技术确定的最活跃的无毒化合物将在口服后利用相关的系统性AA淀粉样变性小鼠模型进一步测试有效性。这项第一阶段的SBIR建议预计将导致新的治疗化合物，用于治疗在各种慢性炎症性疾病患者中发现的系统性AA淀粉样变性。

DESCRIPTION (provided by applicant): Systemic AA amyloidosis is characterized by the deposition and accumulation of insoluble fibrillar deposits containing the AA amyloid protein in a number of different organs (including heart, kidney, spleen, lungs and/or gastrointestinal tract), whereby such amyloid accumulation leads to marked organ dysfunction. Systemic AA amyloidosis is associated with chronic inflammatory disorders and includes patients with rheumatoid arthritis, osteomyelitis, ankylosing spondylitis, inflammatory bowel diseases, tuberculosis, leprosy, Hodgkin's disease, renal cell carcinoma, and Familial Mediterranean Fever. The consequences of fibrillar AA amyloid deposition in systemic organs are detrimental to the patient, with most patients dying within 3-7 years from disease onset, due to kidney or heart failure. Currently, there is no effective cure or treatment for AA amyloidosis, and new therapeutics are desperately needed. Using various in vitro screening technologies, and an experimental mouse model of AA amyloidosis, we have discovered a new class of small compounds that demonstrate efficacy in significantly arresting fibrillar AA amyloid formation and deposition in systemic organs in a mouse model. In this Phase I SBIR project, we will build on our important initial observations and use in vitro screening methodologies (aim 1) and cell culture (aim 2) to identify small non-toxic compounds with specific structural features important for the inhibition of formation and deposition of fibrillar AA amyloid in tissues. The types of compounds to be tested include both commercially available compounds and specific synthetic analoqs (representing new compositions of matter) that will yield valuable information pertaining to structure-activity relationships for the observed efficacy. The most active non-toxic compounds identified using in vitro screening techniques will then be further tested for efficacy following oral administration utilizing a relevant mouse model of systemic AA amyloidosis. This Phase I SBIR proposal is anticipated to lead to new therapeutic compounds for the treatment of systemic AA amyloidosis found in patients with a variety of chronic inflammatory disorders.