Establishing Strategies to Ameliorate Amyloid Pathology in Light Chain Amyloidosis

轻链淀粉样变性(AL)是一种由浆细胞克隆性扩张引起的破坏性疾病 分泌一种不稳定的淀粉样免疫球蛋白轻链(LC)。在血清中，这些LC聚集在一起 转化为有毒的寡聚体和淀粉样纤维，沉积在肾脏和心脏等周围靶组织中 导致器官功能障碍并最终死亡。目前AL的治疗方法是化疗和自体干细胞。 细胞移植去除潜在的病变浆细胞群，通过以下方式减少AL淀粉样蛋白病理 去除分泌不稳定、易聚集的LC的细胞。虽然这一策略对70%的 AL患者，其余30%的患者因LC对心脏或肾脏的毒性太重而无法忍受 化疗。这就需要开发新的策略来减少AL淀粉样变性和 允许对该患者群体中的患病浆细胞进行化疗。在之前的资助中 在本奖项期间，我们发现激活的未折叠蛋白反应(UPR)与 转录因子ATF6通过两种不同的方式显著降低AL相关的LC毒性 机械装置。我们发现，非应激依赖的ATF6的激活选择性地减少了分泌和毒性 不稳定的淀粉样变性LC的聚集。此外，AL相关靶组织中ATF6的激活 包括肾脏和心脏在内，诱导抗氧化基因的表达，保护这些组织免受不同 氧化应激的类型--LCS在这些组织中引起毒性的相同机制。这些结果 提示使用小分子激活ATF6可以减轻AL淀粉样变的可能性 通过两种互补的、组织特有的机制：1)减少分泌和随后的毒性 淀粉样变性LCs在AL浆细胞中的聚集和2)周围靶组织抵抗力的增加 与LC相关的氧化应激有关。为了应对这一潜力，我们正在使用一流的化合物 在上一次筹资期间，有选择地有力地激活了ATF6。在这里，我们检验这个假设 我们的ATF6激活化合物可以通过两种不同的、组织特异性的方式减轻AL淀粉样病变 机械装置。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 通过浆细胞和周围靶组织中的互补、多组织机制，如 肾脏和心脏。我们将展示我们的ATF6激活剂诱导AL患者ER蛋白平衡重塑 浆细胞选择性地减少淀粉样变性LCS的分泌和毒性聚集。此外，我们 将显示原代心脏或肾脏细胞中药物ATF6的激活可减轻LC相关的毒性 通过增加抗氧化基因的表达。通过这些努力，我们将展示我们的ATF6 激活剂具有显著的翻译潜力，可通过不同的多组织减少AL淀粉样蛋白的病理改变 机制，并允许化疗进入潜在的AL相关浆细胞在目前 无法治疗的AL患者，患有严重的肾脏或心脏受累。

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.