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

• 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
• 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

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).

项目总结