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

项目摘要 白内障，眼睛透镜的混浊是造成世界失明的51%的原因。根据世界 世界上有近1800万人因白内障而双目失明。白内障很容易 通过手术治疗。然而，手术与显著的并发症相关：（i）30-50%的患者在外科手术中， 美国白内障手术后两年内出现后透镜囊混浊，需要 激光治疗;（ii）0.8%患有视网膜脱离;（iii）0.6-1.3%因角膜水肿住院或需要 角膜移植和（iv）约1%的眼内炎。此外，在许多偏远地区， 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， 主要原因是缺乏眼部护理。因此，与白内障相关的失明率高达50%， 在世界上贫穷和偏远地区，这一比例高于发达国家的5%。晶体蛋白 (AC)是三大眼透镜晶体蛋白之一，是小热休克的代表成员 蛋白质家族AC作为分子伴侣，保护受损或老化的透镜蛋白和酶 避免聚集，否则会导致光散射和白内障形成。已充分证实 AC的分子伴侣样活性（CLA）对于透镜的透明度是关键的，并且假设维持AC的分子伴侣样活性（CLA）对于透镜的透明性是关键的。 最佳的或增加的伴侣蛋白活性可能有助于预防或减缓白内障。我们的基本原理 该提议基于这样的观察，即来自天然来源的小分子药理学试剂可以 防止α晶体蛋白A链（AAC）的CLA损失，并可在临床前模型中延迟白内障形成。 据估计，将白内障的形成推迟10年可以减少医疗保险视力护理 50%的费用。我们的初步数据支持这样的假设，即FDA批准的小分子药物， 他伐他汀（CAP 4349）增加AAC CLA并在器官培养中保持眼透镜的透明度 白内障模型实验。然而，tafamids及其盐表现出极差的水溶性， 限制了其作为眼科药物的潜力。因此，我们建议的基本目标是： tafamids通过使用前药概念来改善其溶解度，并证明其作为有前途的局部药物的潜力。 抗白内障剂，具有以下特定目的。目标1a。CAP 4349前药的设计和合成。 目标1b。前药转化为活性代谢物的酶促评价。目标2a。制定 用于局部递送途径的前药，以实现增强的角膜渗透和代谢转化。目的 2b.使用3D人体器官型评估用于角膜渗透和代谢转化的化合物 角膜组织模型目标3a。新西兰白色动物7天重复局部给药的急性毒性和安全性 家兔目标3b。体内眼部药代动力学。项目里程碑：成功完成这些目标将 鉴定最少两种优化的tafamid前药，其具有可接受的体内功效和可接受的眼部功效， PK将进入非GLP临床前开发和GLP支持IND研究（II期）。

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).