Effect of diflunisal (IND68092) on familial amyloidosis

描述(申请人提供)：家族性淀粉样变性多发性神经病(FAP)是一种致死性常染色体显性疾病，由肝脏产生的转甲状腺蛋白错误折叠介导。在美国，只有不到20万名FAP患者，符合FAP孤儿疾病的条件。肝移植替代淀粉样变性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的四聚体，只有在解离为单体形式时才是淀粉样变性的。我们的数据表明，商业上可获得的非类固醇抗炎药二氟尼柳可以稳定跨甲状腺激素四聚体，防止错误折叠的跨甲状腺激素单体形成淀粉样原纤维。我们的I期人体研究表明，中等剂量的二氟尼柳稳定了转甲状腺素四聚体，没有明显的毒性。为了检验二氟尼柳对突变的转甲状腺素四聚体稳定性和FAP疾病进展的影响，我们建议进行一项国际性、多中心、随机、安慰剂对照的双盲试验，比较每天两次口服二氟尼柳250 mg与不服用药物治疗的效果。在拟议的研究中，我们将：目标1。确定二氟尼柳对FAP疾病进展的影响，为期两年。答：我们将使用经过验证的浸润性心肌病的综合神经病学评分和超声心动图测量，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。FAP患者每日服用二氟尼柳的耐受性将由每月的肾脏、肝脏和血液学指标来决定。目的2.检测FAP患者随机分为二氟尼沙组和安慰剂组的转甲状腺素四聚体稳定性。在随机接受二氟尼柳或安慰剂治疗的FAP患者的血清中，四聚体转甲状腺素(TTR)的稳定性将通过PAGE分析和免疫印迹进行评估。将确定二氟尼柳的药物水平以评估治疗依从性。我们将把FAP疾病的进展与TTR的稳定联系起来。

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.