Effect of diflunisal (IND68092) on familial amyloidosis

描述（由申请方提供）：家族性淀粉样多发性神经病（FAP）是一种致死性常染色体显性疾病，由甲状腺素运载蛋白（一种由肝脏产生的转运蛋白）错误折叠介导。在美国，只有不到200，000名患有FAP的患者，符合FAP的孤儿病状态。肝移植替代甲状腺素运载蛋白基因是目前唯一有效的治疗方法。甲状腺素运载蛋白在其天然状态下是一种四聚体，仅在解离成其单体形式时才是淀粉样蛋白生成的。我们的数据表明，二氟尼柳，一种市售的非甾体抗炎药，稳定甲状腺素运载蛋白四聚体，防止错误折叠的甲状腺素运载蛋白单体形成淀粉样纤维。 我们的I期人体研究表明，中等剂量的二氟尼柳稳定甲状腺素运载蛋白四聚体，没有明显的毒性。为了检查二氟尼柳对突变的甲状腺素运载蛋白四聚体稳定性和FAP疾病进展的影响，我们建议进行一项国际、多中心、随机、安慰剂对照、双盲试验，比较每日两次口服二氟尼柳250 mg与无药物治疗。在这项研究中，我们将：目标1。确定2年内二氟尼柳对FAP疾病进展的影响。A.我们将采用经验证的浸润性心肌病的复合神经病学量表和超声心动图测量，采用随机、双盲、多中心设计，连续评估接受二氟尼柳或安慰剂治疗2年以上的FAP患者的终末器官疾病状态。B。FAP患者每日二氟尼柳的耐受性将通过每月的肾脏、肝脏和血液学指标来确定。目标二。检查甲状腺素运载蛋白四聚体在FAP患者中的稳定性，FAP患者被随机分配到二氟尼柳和安慰剂组。将通过PAGE分析，然后进行免疫印迹，评价随机分配至二氟尼柳或安慰剂治疗的FAP患者血清中四聚体甲状腺素运载蛋白（TTR）的稳定性。 将测定二氟尼柳药物水平以评估治疗依从性。我们将FAP疾病进展与TTR稳定相关联。

DESCRIPTION (provided by applicant): Familial amyloidotic polyneuropathy (FAP) is a lethal autosomal dominant disease mediated by misfolding of transthyretin, a transport protein produced by the liver. Less than 200,000 patients with FAP exist in the United States, qualifying FAP for Orphan Disease status. Replacing amyloidogenic transthyretin gene by liver transplantation is the only effective therapy at present. A tetramer in its native state, transthyretin is only amyloidogenic when dissociated to its monomeric form. Our data indicates that diflunisal, a commercially available non-steroidal anti-inflammatory agent, stabilizes transthyretin tetramers, preventing amyloid fibril formation by misfolded transthyretin monomers. Our phase I human study demonstrated that moderate doses of diflunisal stabilized transthyretin tetramers with no evident toxicities. To examine the effect of diflunisal on mutated transthyretin tetramer stability and FAP disease progression, we propose conducting an international, multi-center, randomized, placebo-controlled, double blind trial comparing diflunisal 250 mg taken orally twice daily to no drug treatment. In the proposed study we will: Aim 1. Define the effect of diflunisal on FAP disease progression over 2 years. A. We will employ validated composite neurologic scales and echocardiographic measures of infiltrative cardiomyopathy to serially assess end-organ disease state in patients with FAP receiving diflunisal or placebo over 2 years, using a randomized, double blind, multi-center design. B. The tolerability of daily diflunisal in FAP patients will be determined by monthly renal, liver, and hematologic indices. Aim 2. Examine transthyretin tetramer stability in FAP patients randomly assigned to the diflunisal and placebo groups. The stability of tetrameric transthyretin (TTR) in the sera of FAP patients randomized to diflunisal or placebo treatment will be evaluated by PAGE analysis followed by immunoblotting. poiuytrewq c Diflunisal drug levels will be determined to assess treatment compliance. We will correlate FAP disease progression with TTR stabilization.