Establishing Strategies to Ameliorate Amyloid Pathology in Light Chain Amyloidosis

制定改善轻链淀粉样变性淀粉样蛋白病理学的策略

• 批准号: 10057800
• 负责人: Rockland Luke Wiseman
• 金额: $ 54.98万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-05 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10057800
• 关键词: ATF6 gene; Address; Amyloid; Amyloid Fibrils; Amyloidosis; Antioxidants; Attenuated; Autologous Stem Cell Transplantation; Award; Cardiac; Cardiac Myocytes; Cell secretion; Cells; Cessation of life; Clonal Expansion; Complex; Deposition; Development; Disease; Endoplasmic Reticulum; Epithelial Cells; Funding; Genes; Genetic Transcription; Goals; Heart; In Vitro; Injury; Kidney; Light; Light-Chain Immunoglobulins; Modeling; Molecular; Monitor; Organ; Oxidative Stress; Pathogenesis; Patients; Peripheral; Peripheral Resistance; Pharmacology; Phototherapy; Plasma Cells; Population; Primary Cell Cultures; Proteins; Regulation; Serum; Stress; Testing; Tissues; Toxic effect; amyloid pathology; analog; arm; chemotherapy; heart cell; improved; in vivo; kidney cell; mouse model; next generation; patient population; primary amyloidosis of light chain type; proteostasis; renal epithelium; response; small molecule; transcription factor

Light chain amyloidosis (AL) is a devastating disease caused by the clonal expansion of a plasma cell that secretes a destabilized, amyloidogenic immunoglobulin light chain (LC). In the serum, these LCs aggregate into toxic oligomers and amyloid fibrils that deposit in peripheral target tissues such as the kidneys and heart causing organ malfunction and eventual death. Current AL treatments use chemotherapy and autologous stem cell transplantation to ablate the underlying diseased plasma cell population, reducing AL amyloid pathology by removing the cells secreting the destabilized, aggregation-prone LC. While this strategy is effective for 70% of AL patients, the remaining 30% of patients are too sick from LC toxicity on the heart or kidney to tolerate chemotherapy. This necessitates the development of new strategies to decrease AL amyloid pathology and allow chemotherapeutic access to the diseased plasma cells in this patient population. In the previous funding period of this award, we showed that activation of the unfolded protein response (UPR)-associated transcription factor ATF6 has significant potential to reduce AL-relevant LC toxicity through two distinct mechanisms. We found that stress-independent ATF6 activation selectively reduces the secretion and toxic aggregation of destabilized, amyloidogenic LCs. Furthermore, ATF6 activation in AL-relevant target tissues including the kidney and heart induces expression of anti-oxidant genes that protect these tissues from diverse types of oxidative stress – the same mechanism by which LCs induce toxicity in these tissues. These results suggested the possibility that activating ATF6 using small molecules could mitigate AL amyloid pathology through two complementary, tissue-specific mechanisms: 1) reducing the secretion and subsequent toxic aggregation of amyloidogenic LCs in AL plasma cells and 2) increasing resistance of peripheral target tissues to LC-associated oxidative stress. To address this potential, we are using first-in-class compounds established during the previous funding period that selectively and robustly activate ATF6. Here, we test the hypothesis that our ATF6 activating compounds can mitigate AL amyloid pathology through two distinct, tissue-specific mechanisms. We are using these compounds to define their potential to mitigate LC-associated toxicity through complementary, multi-tissue mechanisms in both plasma cells and peripheral target tissues such as the kidney and heart. We will show that our ATF6 activators induce ER proteostasis remodeling in AL patient plasma cells to selectively reduce the secretion and toxic aggregation of amyloidogenic LCs. Furthermore, we will show that pharmacologic ATF6 activation in primary heart or kidney cells attenuates LC-associated toxicity through increased expression of anti-oxidant genes. Through these efforts, we will show that our ATF6 activators offer significant translational potential to reduce AL amyloid pathology through distinct, multi-tissue mechanisms and allow chemotherapeutic access to the underlying AL-associated plasma cells in the currently untreatable population of AL patients suffering from severe kidney or cardiac involvement.

轻链淀粉样变性（AL）是一种由血浆细胞的克隆扩张引起的毁灭性疾病 分泌一个不稳定的淀粉样蛋白生成免疫球蛋白轻链（LC）。在血清中，这些LCS聚集 进入有毒的低聚物和淀粉样蛋白原纤维，这些原纤维沉积在外围目标时机（例如孩子和心脏） 导致器官故障和最终死亡。当前的Al治疗方法使用化学疗法和自体茎 细胞移植向根本的解散的浆细胞群，从而减少AL淀粉样蛋白病理学 去除分泌不稳定的，容易产生的LC的细胞。虽然该策略可有效70％ Al患者，其余30％的患者因心脏或肾脏的LC毒性而患病，无法忍受 化学疗法。这需要制定新策略来减少淀粉样蛋白病理学和 允许该患者人群中的化学治疗访问渗透的浆细胞。在以前的资金中 奖励期间，我们表明展开的蛋白质反应（UPR）相关的激活 转录因子ATF6具有降低与AL相关的LC毒性的显着潜力 机制。我们发现，与压力无关的ATF6激活有选择地减少分泌和有毒 不稳定的淀粉样蛋白生成LCS的聚集。此外，与AL相关的目标组织中的ATF6激活 包括肾脏和心脏影响抗氧化基因的表达，这些基因保护这些时机免受潜水员的侵害 氧化应激的类型 - LCS影响这些组织中毒性的相同机制。这些结果 建议使用小分子激活ATF6可以减轻淀粉样蛋白病理的可能性 通过两个完整的组织特异性机制：1）减少分泌并随后的有毒 Al浆细胞中淀粉样蛋白生成LC的聚集和2）增加外周靶向时间的抗性 与LC相关的氧化应激。为了解决这一潜力，我们正在使用建立的第一类化合物 在上一个资金期间，可以选择性地激活ATF6。在这里，我们检验假设 我们的ATF6激活化合物可以通过两个不同的组织特异性来减轻淀粉样蛋白病理 机制。我们正在使用这些化合物来定义它们的潜力，以减轻LC相关的毒性 通过完成，浆细胞和外围目标时机的多组织机制，例如 肾脏和心脏。我们将证明我们的ATF6激活剂会诱导Al患者进行ER蛋白抑制作用。 血浆细胞有选择地减少淀粉样蛋白生成LC的分泌和毒性聚集。此外，我们 将表明原发性心脏或肾细胞中的药理学ATF6激活减弱与LC相关的毒性 通过增加抗氧化基因的表达。通过这些努力，我们将证明我们的ATF6 激活剂具有巨大的翻译潜力，可通过不同的多组织来减少淀粉样蛋白病理 机理并允许化学治疗访问目前的基础AL相关浆细胞 患有严重肾脏或心脏受累的AL患者的不可治疗人群。