Re-purposing the small-molecule drug, tafamidis (CAP4349) for the non-surgical treatment of cataracts

项目摘要 白内障，眼睛晶状体的混浊是导致世界失明的51%。《世界报》 世界卫生组织有近1800万人因白内障而双眼失明。白内障很容易 通过手术治疗的。然而，手术与严重的并发症有关：(I)30%-50%的患者在 接受白内障手术的美国人在两年内出现晶状体后囊膜混浊，并要求 激光治疗；(Ii)0.8%的人有视网膜脱离；(Iii)0.6%-1.3%的人因角膜水肿或需要 角膜移植和(Iv)约1%的患者出现眼内炎。此外，在许多偏远和 在世界上发展中和欠发达地区的贫困地区，人们仍然因白内障而失明， 主要原因是无法获得眼部护理。因此，与白内障相关的失明高达50%或 世界上贫穷和偏远地区的这一比例更高，而发达国家仅为5%。α-结晶蛋白 (Ac)是眼晶状体三大晶状体蛋白之一，是小热休克的代表性成员 蛋白质家族。AC作为分子伴侣，保护受损或老化的晶状体蛋白质和酶 从聚集，否则将导致光散射和白内障的形成。众所周知， AC的伴侣样活性(CLA)是晶状体透明度的关键，并假设维持 最佳或增加伴侣活动可能有助于预防或减缓白内障。我们的理念是 这一建议是基于观察到的来自自然来源的小分子药理物质可以 在临床前模型中，可防止α-晶状体蛋白A链(AAC)共轭亚油酸的丢失，并可延缓白内障的形成。 据估计，将白内障的形成推迟10年可能会减少医疗保险的视力护理 费用减少50%。我们的初步数据支持FDA批准的小分子药物的假设， 他法米司(CAP4349)在器官培养中增加AAC CLA并保持眼晶状体的透明度 白内障模型实验。然而，他法米德及其盐类在水中的溶解性极差， 限制了它作为眼科药物的潜力。因此，我们建议的基本目标是：优化 利用前药概念改善他法胺的溶解性并展示其作为一种有前途的局部用药的潜力 抗白内障药剂的使用有以下具体目的。目标1a。CAP4349前体药物的设计与合成。 目标1b。前药转化为活性代谢物的酶学评价。目标2a。提法 用于局部给药途径的前药，以实现增强角膜渗透和代谢转化。目标 2B。应用3D人体器官模型评价用于角膜渗透和代谢转化的化合物 角膜组织模型。目标3a。新西兰白鼠七天重复局部用药的急性毒性和安全性 兔子。目标3b。眼内药代动力学研究。项目里程碑：成功完成这些目标将 确定至少两种优化的、具有可接受的体内疗效和可接受的眼部效果的他法米德前体药物 PK将进入非GLP临床前开发和GLP使能IND研究(第二阶段)。

Project Summary Cataract, the clouding of the eye lens is responsible for 51% of world blindness. According to World Health Organization nearly 18 million people are bilaterally blind from cataracts in the world. Cataract is easily treated by surgery. However, surgery is associated with significant complications: (i) 30-50% of patients in the US having cataract surgery develop opacification of the posterior lens capsule within two years and require laser treatment; (ii) 0.8% have retinal detachments; (iii) 0.6-1.3% are hospitalized for corneal edema or require corneal transplantation and (iv) about 1% are presented with endophthalmitis. In addition, in many remote and poor areas of the developing and under-developed regions of the world, people still remain blind from cataracts, primarily due to lack of access to eye care. As a result of which, cataract related blindness is as high as 50% or more in poor and remote regions of the world compared to only 5% in developed countries. Alpha-crystallin (AC) is one of the three major eye lens crystallins and is a representative member of the small heat shock protein family. AC serves as molecular chaperone, protecting damaged or aged lens proteins and enzymes from aggregation that would otherwise lead to light scattering and cataract formation. It is well established that chaperone-like activity (CLA) of AC is critical for lens transparency and it is hypothesized that maintaining optimal or increasing chaperone activity might aid in the prevention or slowing of cataracts. The rationale of our proposal is based on the observation that small molecule pharmacological agents from natural sources can prevent the loss of CLA of Alpha crystallin A-chain (AAC) and can delay cataract formation in preclinical models. It has been estimated that delaying cataracts formation by 10 years can reduce the Medicare vision care expense by 50%. Our preliminary data supports the hypothesis that an FDA approved small-molecule drug, tafamidis (CAP4349) increases AAC CLA and maintains transparency of the eye lens in organ culture experiments of cataract model. However, tafamids and its salts exhibit extremely poor aqueous solubility, limiting its potential as an ophthalmic drug. Therefore, the basic goal of our proposal is: optimization of tafamids to improve its solubility by using prodrug concept and demonstrate its potential as a promising topical anti-cataract agent using the following specific aims. Aim 1a. Design and synthesis of prodrugs of CAP4349. Aim 1b. Enzymatic evaluation of conversion of prodrugs into active metabolite. Aim 2a. Formulation of prodrugs for topical route of delivery to achieve enhanced corneal permeation and metabolic conversion. Aim 2b. Evaluation of compounds for corneal permeation and metabolic conversion using 3D human organotypic corneal tissue model. Aim 3a. Seven day repeat topical dose acute toxicity and safety in New Zealand white rabbits. Aim 3b. In-vivo ocular pharmacokinetics. Project milestone: Successful completion of these aims will identify a minimum of two optimized tafamids prodrugs with acceptable in-vivo efficacy and acceptable ocular PK to be advanced into non-GLP preclinical development and GLP enabling IND studies (Phase II).