Effect of diflunisal (IND68092) on familial amyloidosis

描述（由申请人提供）：家族性淀粉样变性多神经病变（FAP）是一种致命的常染色体显性遗传病，由肝脏产生的转运蛋白转甲状腺素错误折叠介导。在美国，FAP患者不到20万，符合孤儿病的资格。肝移植替代淀粉样蛋白转甲状腺素基因是目前唯一有效的治疗方法。转甲状腺素是天然状态下的四聚体，只有当解离成单体形式时才会产生淀粉样蛋白。我们的数据表明，二氟尼柳，一种市售的非甾体抗炎剂，稳定转甲状腺素四聚体，防止由错误折叠的转甲状腺素单体形成淀粉样蛋白纤维。我们的I期人体研究表明，中等剂量的双氟尼拉稳定甲状腺转甲素四聚体没有明显的毒性。为了研究双氟尼拉对突变甲状腺素四聚体稳定性和FAP疾病进展的影响，我们建议开展一项国际、多中心、随机、安慰剂对照、双盲试验，比较口服双氟尼拉250 mg、每日两次与不用药治疗。在拟议的研究中，我们将：目标1。确定双氟尼柳对2年内FAP疾病进展的影响。a .我们将采用一项随机、双盲、多中心设计，采用经过验证的复合神经系统量表和超声心动图测量浸润性心肌病，连续评估接受双氟尼拉或安慰剂治疗2年以上FAP患者的终末器官疾病状态。FAP患者每日使用双氟尼松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2。检查随机分配到双氟尼拉组和安慰剂组的FAP患者甲状腺素四聚体的稳定性。随机分配到双氟尼拉或安慰剂治疗的FAP患者血清中四聚体甲状腺素（TTR）的稳定性将通过PAGE分析和免疫印迹进行评估。将确定双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稳定联系起来。

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.