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

重新利用小分子药物他法米迪 (CAP4349) 用于非手术治疗白内障

基本信息

批准号：
10202617
负责人：
Sambaiah Thota
金额：
$ 14.93万
依托单位：
PLEX PHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10202617
关键词：
3-Dimensional Address Adult Africa Aging Amyloid Amyloidosis Anatomy Area Back Bilateral Biological Availability Blindness Cardiomyopathies Cardiovascular system Caring Cataract Cataract Extraction Chemicals Clinical Treatment Clinical Trials Complex Cornea Corneal edema Crystalline Lens Crystallins Data Deposition Developed Countries Development Devices Diabetes Mellitus Disease Dose Drug Kinetics Endophthalmitis Enzymes Evaluation Exhibits Eye Eye Lens Protein FDA approved Far East Formulation Functional disorder Goals Half-Life Heart Heart failure Heat shock proteins Hospitalization Human Human Activities Inherited Intraocular lens implant device Keratoplasty Lasers Lead Lens Opacities Libraries Life Mediating Medical Medicare Metabolic Modality Modeling Molecular Chaperones Names New Zealand Operative Surgical Procedures Organ Culture Techniques Oryctolagus cuniculus Outcome Pathology Patients Pharmaceutical Preparations Pharmacology Phase Physiological Post-Translational Protein Processing Pre-Clinical Model Prealbumin Prevention Prodrugs Protein Family Proteins Public Health Reporting Restrictive Cardiomyopathy Retinal Detachment Risk Factors Route Safety Salts Screening Result Small Business Innovation Research Grant Smoking Solubility Source Time Tissue Model Topical application Trauma Ultraviolet Rays Uveitis Vision World Health Organization absorption acute toxicity aged alpha-Crystallins aqueous base blind cost effective cost effective intervention design disparity reduction drug candidate experimental study gamma-Crystallins improved in vivo indexing innovation lens lens capsule lens transparency light scattering low and middle-income countries member milligram misfolded protein mortality novel ophthalmic drug phase 1 study preclinical development prevent protein aggregation screening small molecule

项目摘要

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).

项目概要白内障，即眼睛晶状体混浊，导致世界上 51% 的失明。据世界世界卫生组织称，世界上有近 1800 万人因白内障而双眼失明。很容易得白内障通过手术治疗。然而，手术与严重的并发症相关：(i) 30-50% 的患者美国进行白内障手术两年内出现晶状体后囊混浊，需要激光治疗； (ii) 0.8%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% 出现眼内炎。此外，在许多偏远地区和在世界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，主要是由于缺乏眼部护理。因此，与白内障相关的失明率高达 50% 或世界贫困和偏远地区的这一比例更高，而发达国家仅为 5%。 α-晶状体蛋白 (AC)是三大眼晶状体蛋白之一，是小热休克的代表成员蛋白质家族。 AC 作为分子伴侣，保护受损或老化的晶状体蛋白质和酶避免聚集，否则会导致光散射和白内障形成。众所周知 AC 的类伴侣活性（CLA）对于晶状体透明度至关重要，并且假设维持最佳或增加的伴侣活性可能有助于预防或减缓白内障的发生。我们的理由该提案基于这样的观察：来自天然来源的小分子药物可以防止阿尔法晶状体蛋白 A 链 (AAC) 的 CLA 损失，并可以在临床前模型中延缓白内障的形成。据估计，延迟白内障形成10年可以减少医疗保险视力保健费用费用减少50%。我们的初步数据支持 FDA 批准的小分子药物的假设， tafamidis (CAP4349) 增加 AAC CLA 并维持器官培养中晶状体的透明度白内障模型实验。然而，tafamids及其盐的水溶性极差，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：优化 tafamids 通过使用前药概念来提高其溶解度，并展示其作为有前途的局部用药的潜力使用抗白内障剂的具体目的如下。目标 1a。 CAP4349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。配方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 人体器官模型评估化合物的角膜渗透和代谢转化角膜组织模型。目标 3a。新西兰白细胞 7 天重复局部剂量急性毒性和安全性兔子。目标 3b。体内眼药代动力学。项目里程碑：成功完成这些目标将确定至少两种具有可接受的体内功效和可接受的眼部效果的优化 tafamids 前药 PK 将进入非 GLP 临床前开发和 GLP 支持 IND 研究（第二阶段）。