Establishing Strategies to Ameliorate Amyloid Pathology in Light Chain Amyloidosis

 描述(申请人提供)：轻链淀粉样变性(AL)是一种由恶性浆细胞克隆性扩张引起的破坏性疾病，该细胞分泌不稳定的淀粉样免疫球蛋白轻链(LC)。导致淀粉样变性的LC会发生错误折叠和浓度依赖的聚集，形成有毒的低聚物和淀粉样纤维，沉积在心脏等远端组织上。因此，AL患者同时患有浆细胞恶性肿瘤和系统性淀粉样变性疾病。目前的AL治疗使用化疗和自体干细胞替代来减少克隆性浆细胞数量，仅间接影响AL淀粉样变的病理。虽然这种方法对70%的患者有效，但其余30%的患者因LC蛋白毒性而无法忍受这种治疗。为了治疗这些患者，必须开发新的治疗方法来治疗AL病理中的LC蛋白毒性。开发这种策略的一个挑战是AL相关的淀粉样变性LC序列的异质性。因此，任何改善AL淀粉样蛋白病理的策略都必须针对一个基本的生物机制，该机制介导了异质性淀粉样变性LC的毒性，但不会在全球范围内损害机体免疫或内源性分泌蛋白质组的分泌。我们假设内质网(ER)蛋白稳定通路的活性是中毒性LC聚集的关键决定因素，可用于改善AL淀粉样蛋白的病理。内质网蛋白平衡途径可以促进不稳定的淀粉样蛋白的分泌，增加其可用于毒性错误折叠和聚集的血清浓度。因此，调节ER蛋白平衡通路的活性提供了一个独特的机会来降低失稳的、淀粉样变性LC的血清浓度，从而减少蛋白毒性LC的聚集。我们发现，通过选择未折叠蛋白反应(UPR)相关转录因子的应激无关激活来适应ER蛋白稳定途径，可以减少不稳定的淀粉样变性LC的分泌和细胞外聚集，而不影响非淀粉样变性LC、IGGS或全球内源性分泌蛋白质组的分泌。在这里，我们通过确定优先参与淀粉样变性LC的分泌、细胞外聚集和随后的毒性的途径，来定义ER蛋白平衡通路在毒性LC聚集中的作用。此外，我们将证明小分子ER蛋白平衡调节剂改变这些ER蛋白平衡途径的活性，减少AL患者来源的浆细胞中不稳定的淀粉样变性LC的分泌和毒性聚集。通过这些努力，我们将证明内质网蛋白平衡通路的活性是决定AL淀粉样蛋白病理的基本决定因素。此外，我们将确定一流的小分子内质网蛋白平衡调节剂，针对这些途径来减弱淀粉样变性LC的分泌和毒性聚集。我们的结果将建立ER蛋白抑制调节作为改善AL淀粉样蛋白病变的第一策略，然后可以与化疗药物联合用于治疗患有严重LC蛋白毒性的AL患者队列。

 DESCRIPTION (provided by applicant): Light chain amyloidosis (AL) is a devastating disease caused by the clonal expansion of a malignant plasma cell that secretes a destabilized, amyloidogenic immunoglobulin light chain (LC). Amyloidogenic LCs undergo misfolding and concentration-dependent aggregation into toxic oligomers and amyloid fibrils that deposit on distal tissues such as the heart. Thus, AL patients suffer from both a plasma cell malignancy and a systemic amyloid disease. Current AL treatments use chemotherapy and autologous stem cell replacement to decrease the clonal plasma cell population, only indirectly affecting AL amyloid pathology. While this approach is efficient for 70% of patients, the remaining 30% of patients are too sick from LC proteotoxicity to tolerate this treatment. In order to treat these patients, new therapies must be developed to treat the LC proteotoxicity in AL pathology. A challenge in developing such strategies is the heterogeneity of AL-associated, amyloidogenic LC sequences. Thus, any strategy to ameliorate AL amyloid pathology must target a fundamental biologic mechanism that mediates toxicity of heterogeneous amyloidogenic LCs, but does not globally compromise organismal immunity or secretion of the endogenous secreted proteome. We hypothesize that the activity of endoplasmic reticulum (ER) proteostasis pathways is a critical determinant in toxic LC aggregation that can be targeted to ameliorate AL amyloid pathology. ER proteostasis pathways can facilitate secretion of destabilized, amyloidogenic proteins, increasing their serum concentrations available for toxic misfolding and aggregation. Thus, modulating the activity of ER proteostasis pathways offers a unique opportunity to reduce serum concentrations of destabilized, amyloidogenic LCs and thus decrease proteotoxic LC aggregation. We show that adapting ER proteostasis pathways through stress-independent activation of select Unfolded Protein Response (UPR)-associated transcription factors reduces the secretion and extracellular aggregation of a destabilized, amyloidogenic LC, without affecting secretion of a non-amyloidogenic LC, IgGs or the global endogenous secreted proteome. Here, we define the contribution of ER proteostasis pathways in toxic LC aggregation by identifying pathways preferentially involved in the secretion, extracellular aggregation and subsequent toxicity of amyloidogenic LCs. Furthermore, we will demonstrate that small molecule ER proteostasis regulators that alter the activity of these ER proteostasis pathways reduce secretion and toxic aggregation of destabilized, amyloidogenic LCs in AL patient-derived plasma cells. Through these efforts, we will show that the activity of ER proteostasis pathways is a fundamental determinant in dictating AL amyloid pathology. Furthermore, we will identify first-in-class small molecule ER proteostasis regulators that target these pathways to attenuate secretion and toxic aggregation of amyloidogenic LCs. Our results will establish ER proteostasis regulation as the first strategy to ameliorate AL amyloid pathology that can then be used in combination with chemotherapeutics to treat the AL patient cohort suffering from severe LC proteotoxicity.