TARGETING ENDOGENOUS SIGNALING PATHWAYS TO AMELIORATE SYSTEMIC AMYLOIDOSES

描述（由申请人提供）：系统性淀粉样蛋白疾病，如甲状腺素运载蛋白（TTR）淀粉样变性是一类破坏性疾病，由特定不稳定蛋白质在远离该部位的组织上病理性聚集和沉积为淀粉样纤维引起 蛋白质的合成。目前，没有非侵入性疗法来治疗大多数这些疾病，使得系统性淀粉样变性成为一个巨大的未满足的医疗需求。定义这些疾病的核心病理性细胞外蛋白质聚集的主要因素是从效应组织如肝脏分泌不稳定的淀粉样蛋白。这些蛋白质的有效分泌增加了可用于病理性、浓度依赖性聚集的淀粉样蛋白的血清浓度，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，减弱外周蛋白毒性，改善各种不同的全身性淀粉样变性患者的预后。我们假设，激活内源性未折叠蛋白反应（UPR）信号通路，调节效应组织的蛋白质分泌是一种非侵入性的策略，以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减少不稳定的，淀粉样蛋白TTR突变体的分泌，但不影响野生型TTR或内源性分泌蛋白质组的分泌。在此，我们使用TTR作为模型淀粉样蛋白来显示ATF 6活化具有治疗潜力以减少淀粉样蛋白TTR突变体的病理性细胞外聚集和蛋白毒性，其使用TTR淀粉样蛋白疾病的新型患者来源的多系统诱导多能干细胞模型，其概括了在患者中观察到的TTR淀粉样蛋白疾病病理学的几乎所有方面。此外，我们正在扩展这项分析，以表明ATF 6激活类似地减少了与其他系统性淀粉样蛋白疾病（包括轻链淀粉样变性-一种影响全球超过100万人的获得性系统性淀粉样蛋白疾病）有关的淀粉样蛋白生成蛋白的分泌和蛋白毒性。通过这些努力，我们将证明，UPR相关信号通路（例如ATF 6调节的信号通路）的应激非依赖性激活是一种广泛适用的治疗策略，可减少与多种系统性淀粉样蛋白相关的淀粉样蛋白的分泌和病理性细胞外聚集疾病。这些结果将进一步激发我们正在进行的高通量筛选努力以鉴定ATF 6激活剂，因为单个小分子ATF 6激活剂具有治疗多种全身性淀粉样变性的潜力（即，一种药物：多种疾病的治疗范例），显著改善了将选择性ATF 6激活剂转化到临床中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.