TARGETING ENDOGENOUS SIGNALING PATHWAYS TO AMELIORATE SYSTEMIC AMYLOIDOSES

描述(申请人提供)：全身性淀粉样病，如转甲状腺素(Ttr)淀粉样变性是一类破坏性的疾病，由特定的失稳蛋白病理性聚集和沉积在远端组织上。 蛋白质的合成。目前，还没有非侵入性治疗方法来治疗这些疾病中的大多数，这使得系统性淀粉样变性成为一个巨大的未得到满足的医疗需求。定义病理性胞外蛋白聚集的一个主要因素是从效应组织(如肝脏)分泌不稳定的淀粉样蛋白。这些蛋白的有效分泌增加了血清淀粉样蛋白的浓度，可用于病理性的、浓度依赖的聚集，直接影响患者的疾病发病机制。肝移植受者的临床结果表明，降低血清淀粉样蛋白浓度可以减少病理性蛋白聚集，减轻外周蛋白毒性，并改善各种不同的系统性淀粉样变性患者的预后。我们假设，激活调节效应组织蛋白质分泌的内源未折叠蛋白反应(UPR)信号通路是一种非侵入性策略，类似地减少分泌和减少可用于病理性细胞外聚集的淀粉样蛋白的细胞外浓度。与这一预测一致，我们表明激活UPR相关的转录因子ATF6减少了不稳定的、导致淀粉样变的TTR突变体的分泌，但不影响野生型TTR的分泌或内源性分泌的蛋白质组。在这里，我们使用TTR作为淀粉样变性蛋白的模型，利用一种新的患者来源的、多系统诱导的TTR淀粉样病多能干细胞模型来证明ATF6激活具有治疗潜力，可以减少淀粉样变性TTR突变体的病理性细胞外聚集和蛋白毒性。该模型概括了患者观察到的TTR淀粉样病病理的几乎所有方面。此外，我们正在扩展这项分析，以表明ATF6激活类似地减少了其他系统性淀粉样疾病中涉及的淀粉样蛋白的分泌和蛋白毒性，包括轻链淀粉样变性-一种影响全球100万人的获得性系统性淀粉样病。通过这些努力，我们将表明，UPR相关信号通路(如ATF6调控的信号通路)的应激非依赖性激活是一种广泛适用的治疗策略，可以减少与多发性系统性淀粉样蛋白疾病相关的淀粉样蛋白的分泌和病理性细胞外聚集。这些结果将进一步推动我们正在进行的高通量筛选工作，以确定ATF6激活剂，因为单个小分子ATF6激活剂具有治疗多个系统性淀粉样变性(即一种药物：多个疾病的治疗范式)的潜力，极大地提高了将选择性ATF6激活剂转化到临床以改善与这些疾病相关的病理性细胞外聚集的经济性。

DESCRIPTION (provided by applicant): Systemic amyloid diseases such as the transthyretin (TTR) amyloidoses are a class of devastating disorders caused by the pathologic aggregation and deposition of specific destabilized proteins as amyloid fibrils on tissues distal from the site of protein synthesis. Currently, no non-invasive therapies exist to treat the majority of these diseases, making systemic amyloidoses a large unmet medical need. A primary factor defining the pathologic extracellular protein aggregation central to these disorders is the secretion of destabilized, amyloidogenic proteins from effector tissues such as the liver. The efficient secretion of these proteins increases serum concentrations of amyloidogenic protein available for pathologic, concentration-dependent aggregation, directly impacting disease pathogenesis in patients. Clinical results from liver transplant recipients show that reducing serum concentrations of amyloidogenic proteins can decrease pathologic protein aggregation, attenuate peripheral proteotoxicity and improve prognosis for patients presenting with a variety of distinct systemic amyloidoses. We hypothesize that activating the endogenous Unfolded Protein Response (UPR) signaling pathways that regulate protein secretion from effector tissues is a non-invasive strategy to similarly decrease secretion and reduce extracellular concentrations of amyloidogenic proteins available for pathologic extracellular aggregation. Consistent with this prediction, we show that activating the UPR- associated transcription factor ATF6 reduces secretion of destabilized, amyloidogenic TTR mutants, but does not affect the secretion of wild-type TTR or the endogenous secreted proteome. Here, we employ TTR as a model amyloidogenic protein to show that ATF6 activation has therapeutic potential to reduce pathologic extracellular aggregation and proteotoxicity of amyloidogenic TTR mutants using a novel patient-derived, multi- system induced pluripotent stem cell model of TTR amyloid disease that recapitulates nearly all aspects of TTR amyloid disease pathology observed in patients. Furthermore, we are extending this analysis to show that ATF6 activation similarly reduces the secretion and proteotoxicity of amyloidogenic proteins involved in other systemic amyloid diseases including Light Chain Amyloidosis - an acquired systemic amyloid disease that affects >1 million individuals worldwide. Through these efforts, we will show that the stress-independent activation of UPR-associated signaling pathways such as that regulated by ATF6 is a broadly-applicable therapeutic strategy to reduce the secretion and pathologic extracellular aggregation of amyloidogenic proteins associated with multiple systemic amyloid diseases. These results will further motivate our ongoing high- throughput screening efforts to identify ATF6 activators, as a single small molecule ATF6 activator has the potential to treat multiple systemic amyloidoses (i.e. a one-drug:multiple-disease therapeutic paradigm) dramatically improving the economics of translating selective ATF6 activators into the clinic to ameliorate pathologic extracellular aggregation associated with these diseases.