Establishing Strategies to Ameliorate Amyloid Pathology in Light Chain Amyloidosis

轻链淀粉样变性（AL）是由浆细胞的克隆扩增引起的破坏性疾病， 分泌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LC聚集 转化为毒性低聚物和淀粉样纤维，其存款在外周靶组织如肾脏和心脏中 导致器官功能障碍最终死亡目前的AL治疗使用化疗和自体干细胞 细胞移植以消融潜在的患病浆细胞群，通过以下方式减少AL淀粉样病变： 除去分泌不稳定的、易于聚集的LC的细胞。虽然这一策略对70%的人有效， AL患者，其余30%的患者因LC对心脏或肾脏的毒性而病情严重，无法耐受 化疗这就需要开发新的策略来减少AL淀粉样蛋白病理学， 允许化疗药物进入该患者群体中的患病浆细胞。在此前的融资中， 在此期间，我们发现，未折叠蛋白反应（UPR）相关的激活 转录因子ATF 6通过两种不同的途径降低AL相关的LC毒性， 机制等我们发现，应激非依赖性ATF 6激活选择性地减少了分泌和毒性。 不稳定的淀粉样蛋白生成LC的聚集。此外，AL相关靶组织中的ATF 6活化 包括肾脏和心脏诱导抗氧化基因的表达， 氧化应激类型-LC在这些组织中诱导毒性的相同机制。这些结果 提示使用小分子激活ATF 6可以减轻AL淀粉样病变的可能性 通过两种互补的组织特异性机制：1）减少分泌和随后的毒性 AL浆细胞中淀粉样蛋白生成LC的聚集和2）外周靶组织的抵抗力增加 LC相关的氧化应激。为了解决这一潜力，我们正在使用一流的化合物， 在上一个供资期间，有选择地和有力地激活ATF 6。在这里，我们测试假设 我们的ATF 6激活化合物可以通过两种不同的组织特异性的， 机制等我们正在使用这些化合物来确定它们减轻LC相关毒性的潜力 通过浆细胞和外周靶组织中的互补的多组织机制， 肾脏和心脏我们将证明我们的ATF 6激活剂在AL患者中诱导ER蛋白稳态重构， 浆细胞选择性地减少淀粉样蛋白生成LC的分泌和毒性聚集。而且我们 将显示在原代心脏或肾脏细胞中的药理学ATF 6活化减弱LC相关毒性 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ATF 6 激活剂提供了显著的翻译潜力，通过不同的，多组织， 机制，并允许化疗药物进入目前的基础AL相关浆细胞， 患有严重肾脏或心脏受累的不可治疗的AL患者群体。

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.