Development Of An Eye Drop To Treat Presbyopia

开发治疗老花眼的滴眼剂

• 批准号: 8393414
• 负责人: MARGARET H GARNER
• 金额: $ 15万
• 依托单位: ENCORE VISION, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8393414
• 关键词: Acids; Acute; Affect; Age; Aqueous Humor; Betaine; Choline; Cleaved cell; Contact Lenses; Cornea; Development; Dose; Drops; Drug Formulations; Drug Kinetics; Elasticity; Ensure; Equilibrium; Eye; Eyedrops; Eyeglasses; Fluorescein; Goals; Health; Maintenance; Metabolism; Methionine; Methylation; Mus; Myopia; NADH; NADP; Natural regeneration; Operative Surgical Procedures; Oryctolagus cuniculus; Oxidation-Reduction; Oxidoreductase; Perfusion; Pharmaceutical Preparations; Phase; Presbyopia; Proteins; Reducing Agents; Route; S-Adenosylmethionine; Sulfhydryl Compounds; Testing; Therapeutic; Thick; Thioctic Acid; Tissues; Topical application; Toxicology; Vision; Work; age related; crosslink; dihydrolipoic acid; disulfide bond; esterase; in vivo; innovation; lens; oxidation; phase 1 study; prevent

DESCRIPTION (provided by applicant): Encore Vision has identified an innovative treatment for Presbyopia. The aim of the proposed phase I studies is to develop a topical ocular formulation of our co-drug to achieve therapeutic levels of active agent in the rabbit aqueous humor without adversely affecting cornea health and lens metabolism. Onset of Presbyopia leading to progressive loss of near vision after age of 40 presents with limited treatment options including eyeglasses, contact lenses, or Lasik surgery. According to Encore Vision¿s working hypothesis, the age-dependent increase in protein sulfhydryl group oxidation (PSH to PSSR and PSSP) to form protein cross-links contributes to the age-dependent decrease in lens elasticity underlying the loss of accommodative amplitude. We have identified a proprietary amphipathic co-drug that restores the elasticity of the lens when applied topically to the eyes of 8-month-old mice. The co-drug elicits no acute toxicology in Draize testing in rabbits. The co-drug is cleaved by cellular esterases to release a pro-reductant, that when converted to active reducing agent by cellular oxidoreductases, increases mouse lens elasticity by decreasing the number of protein-disulfide bonds. The reducing agent is methylated for clearance in vivo. Oxidoreductase-dependent reduction of the pro-reducing agent requires energy-dependent maintenance of the redox balance with NAD+, NADH and NADP+, NADPH. The route for clearance of excess reducing agent uses S-adenosylmethionine (SAM) as the methyl donor. Therefore topical treatment with pro-reductant could potentially cause an energy drain as well as a reduction in SAM levels that in turn could affect other critical metabolic processes in the cornea and lens. The esterase-dependent cleavage of the co-drug also releases an intermediate to regenerate SAM. Our phase-I Specific Aim is to develop a formulation of our co-drug that ensures cornea health while preventing adverse changes in redox balance and SAM-dependent methylation potential in the lens. To achieve our aim we will complete the following tasks: Task 1. Using rabbits, determine, the effects topical ocular doses of our co-drug formulation on cornea barrier function (Fluorescein) and cornea thickness (pachymetry). If permanent changes in cornea health are observed, lower dose formulations will be prepared and tested; Task 2. Determine the ocular pharmacokinetics of our co-drug, its metabolites, SAM-cycle intermediates and redox balance. For task 2, cornea perfusion and lens culture will be used to define corneal and lenticular pharmacokinetics that will then be compared to aqueous humor levels after topical ocular dosing of rabbits. PUBLIC HEALTH RELEVANCE: Onset of Presbyopia, the progressive loss of near vision after age of 40, presents with limited treatment options including eyeglasses, contact lenses, or Lasik surgery. Encore Vision's goal is to develop a safe topical ocular drop as an option for the treatment of presbyopia.

描述（由申请人提供）：Encore Vision已经确定了一种治疗老视的创新疗法。拟定I期研究的目的是开发我们的联合药物的局部眼部制剂，以在兔眼房水中达到治疗水平的活性剂，而不会对角膜健康和透镜代谢产生不良影响。40岁以后老视发作导致近视力逐渐丧失，治疗选择有限，包括眼镜、隐形眼镜或Lasik手术。根据Encore Vision的工作假设，蛋白质巯基氧化（PSH到PSSR和PSSP）形成蛋白质交联的年龄依赖性增加有助于透镜弹性的年龄依赖性降低，这是晶状体振幅损失的基础。我们已经确定了一种专有的两亲性联合药物，当局部应用于8个月大的小鼠眼睛时，可以恢复透镜的弹性。在兔Draize试验中，联合药物未表现出急性毒性。联合药物被细胞酯酶裂解以释放前还原剂，当其被细胞氧化还原酶转化为活性还原剂时，通过减少蛋白质-二硫键的数量来增加小鼠透镜弹性。还原剂被甲基化用于体内清除。前还原剂的氧化还原酶依赖性还原需要与NAD+、NADH和NADP+、NADPH的氧化还原平衡的能量依赖性维持。清除过量还原剂的途径使用S-腺苷甲硫氨酸（SAM）作为甲基供体。因此，用还原剂前体进行局部治疗可能会导致能量消耗以及SAM水平的降低，这反过来可能会影响角膜和透镜中的其他关键代谢过程。共药物的酯酶依赖性裂解也释放中间体以再生SAM。我们的I期具体目标是开发我们的联合药物的配方，确保角膜健康，同时防止透镜中氧化还原平衡和SAM依赖性甲基化潜力的不利变化。为了实现我们的目标，我们将完成以下任务：任务1.使用兔，确定我们的联合药物制剂的局部眼部剂量对角膜屏障功能（黄绿素）和角膜厚度（角膜厚度测量）的影响。如果观察到角膜健康的永久性变化，则将制备并检测较低剂量制剂;任务2。确定我们的联合药物，其代谢产物，SAM循环中间体和氧化还原平衡的眼部药代动力学。对于任务2，角膜灌注和透镜培养将用于定义角膜和晶状体药代动力学，然后将其与兔眼部局部给药后的房水水平进行比较。 公共卫生关系：老花眼的发病，即40岁以后近视力的逐渐丧失，治疗选择有限，包括眼镜，隐形眼镜或LASIK手术。Encore Vision的目标是开发一种安全的局部滴眼液，作为治疗老花眼的一种选择。