Reactive (AA)Amyloidosis

描述(由申请人提供)： AA淀粉样变性(反应性，继发性)是由细胞外蛋白质纤维沉积引起的，这种沉积扰乱了正常的器官功能，通常会导致死于肾、肝或心脏衰竭。它是许多慢性炎症性疾病的严重并发症，包括类风湿性关节炎、强直性脊柱炎、区域性肠炎(克罗恩病)，以及遗传性反复发热性疾病，如常染色体隐性遗传性家族性地中海热(FMF)，以及一组常染色体显性综合征，包括肿瘤坏死因子-α受体相关周期综合征(Traps)、Muckle-Wells综合征、家族性寒冷性荨麻疹(FCAS)和高免疫球蛋白D综合征。它也是慢性传染病的致命并发症，如截瘫或四肢瘫痪患者的骨髓炎。所有这些疾病，无论是后天的还是遗传性的，都会引起反复的炎症，导致血清淀粉样蛋白A(SAA)家族急性期蛋白的表达增加。SAA是血浆高密度脂蛋白的载脂蛋白，是淀粉样原纤维亚单位AA的前体。目前对AA淀粉样变性发病机制的认识是，SAA是一种由104个氨基酸残基组成的单一多肽，在慢性炎症过程中过度产生，部分蛋白降解，氨基末端1-76个残基聚集形成不溶性纤维。这些纤维沉积会损害正常的组织功能，并导致进行性器官衰竭。虽然在理解AA淀粉样蛋白形成的致病机制方面已经取得了相当大的进展，但还没有针对这种疾病的特效治疗方法。在患有慢性炎症性疾病的AA患者中，抗炎药物的治疗一直是治疗原发病的主要手段，预计SAA水平的降低将减少AA淀粉样蛋白沉积的形成。大量的临床证据表明，降低炎症标志物，包括血清淀粉样蛋白A，可以预防或减缓AA淀粉样变性的进展；然而，许多患者对包括免疫抑制和抗肿瘤坏死因子生物制剂在内的抗炎药没有完全反应。这是一组患有淀粉样变性的慢性病患者。虽然控制炎症可以防止AA淀粉样变性的发展，但一旦这个过程开始，改变进展的有效方法就不得而知了。这项建议的总体目标是开发特定的治疗策略来改变AA淀粉样变性的进展。这将从两个方面进行探索：目的1)使用AA淀粉样纤维形成的细胞培养模型来确定抗肿瘤坏死因子药物抑制AA淀粉样蛋白沉积的机制。坊间报道表明，抗肿瘤坏死因子制剂可能通过抑制炎症反应以外的其他方式抑制AA淀粉样蛋白的进展。目的2)利用AA淀粉样变性小鼠模型，验证特异性反义寡核苷酸(ASO)减少肝脏SAA合成，通过限制AA纤维前体的可获得性来减少SAA，阻止淀粉样原纤维形成的假说。这些目标的成功实现将为开发治疗这种致命疾病的特定疗法提供基础。

DESCRIPTION (provided by applicant): AA amyloidosis (reactive, secondary) is caused by the extracellular deposition of protein fibrils which disrupts normal organ function and usually leads to death from renal, hepatic or cardiac failure. It is a serious complication of many chronic inflammatory diseases including rheumatoid arthritis, ankylosing spondylitis, regional enteritis (Crohn's disease), and inherited recurrent febrile diseases such as the autosomal recessive familial Mediterranean fever (FMF), and a group of autosomal dominant syndromes including TNF-alpha receptor associated periodic syndrome (TRAPS), Muckle-Wells syndrome, familial cold urticaria (FCAS), and hyper- immunoglobulin D syndrome. It is also a fatal complication of chronic infectious diseases such as osteomyelitis in patients with paraplegia or quadriplegia. All of these diseases, whether acquired or genetic, cause recurrent inflammation resulting in elevated expression of the acute phase proteins of the serum amyloid A (SAA) family. SAA, an apolipoprotein of plasma HDL, is the precursor of the amyloid fibril subunit AA. The current understanding of the pathogenesis of AA amyloidosis is that SAA, a single polypeptide of 104 amino acid residues, which is overproduced during chronic inflammation, is partially proteolyzed, and the amino-terminal 1- 76 residues aggregate to form insoluble fibrils. These fibril deposits then compromise normal tissue function and lead to progressive organ failure. While considerable progress has been made in understanding the pathogenic mechanisms involved in AA amyloid formation, no specific therapy for this disease has been developed. In AA patients with chronic inflammatory diseases treatment with agents to decrease inflammation have been the mainstay for treating the primary disease with the projection that reduction in SAA blood levels will curtail the formation of AA amyloid deposition. Considerable clinical evidence suggests that reduction in inflammatory markers, including serum amyloid A, may prevent or slow the progression of AA amyloidosis; however, many patients do not have complete response to anti-inflammatory agents including immunosuppressive and anti-TNF biologic agents. This is a group of chronic disease patients that develop amyloidosis. While control of inflammation may prevent the development of AA amyloidosis, once the process has started effective means of altering progression are not known. The overall objective of this proposal is to develop specific therapeutic strategies to alter progression of AA amyloidosis. This will be explored in two lines of investigation: Aim 1) Use a cell culture model of AA amyloid fibril formation to define the mechanisms by which anti-TNF agents may inhibit AA amyloid deposition. Anecdotal reports suggest that anti-TNF agents may inhibit AA amyloid progression in ways other than just their ability to suppress the inflammatory response. Aim 2) Use a murine model of AA amyloidosis to test the hypothesis that reduction of hepatic synthesis of SAA by specific antisense oligonucleotides (ASO) can reduce SAA and stop progression of amyloid fibril formation by limiting availability of AA fibril precursor. Successful completion of these aims will offer a basis for development of specific therapeutics to treat this fatal disease.