Development Of An Eye Drop To Treat Presbyopia

描述(由申请者提供)：安可视觉已经确定了一种治疗老花眼的创新疗法。拟议的第一阶段研究的目的是开发我们的辅药的眼部局部配方，以达到兔房水中活性物质的治疗水平，而不会对角膜健康和晶状体新陈代谢产生不利影响。出现老花眼，导致40岁后进行性近视丧失，治疗选择有限，包括眼镜、隐形眼镜或激光手术。根据Encore Vision？S的工作假说，随着年龄的增长，形成蛋白质交联的蛋白质巯基氧化(PSH到PSSR和PSSP)增加，导致调节幅度丧失的晶状体弹性随年龄增加。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个月大的小鼠的眼睛时，它可以恢复晶状体的弹性。在兔的Draze试验中，该联合药物没有引起急性毒理学反应。这种辅药被细胞酯酶裂解，释放出一种促还原剂，当细胞氧化还原酶将其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晶状体的弹性。对该还原剂进行甲基化，以便在体内清除。依赖氧化还原酶的前体还原需要能量依赖地维持与NAD+、NADH和NADP+、NADPH的氧化还原平衡。清除过量还原剂的途径是以S-腺苷蛋氨酸为甲基供体。因此，使用促还原剂的局部治疗可能会潜在地导致能量消耗以及SAM水平的降低，这反过来可能会影响角膜和晶状体中的其他关键代谢过程。辅药的酯酶依赖的裂解也释放了一种中间产物来再生SAM。我们I期的具体目标是开发一种我们的辅助药物的配方，以确保角膜健康，同时防止晶状体中氧化还原平衡和SAM依赖的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对角膜屏障功能(荧光素)和角膜厚度(厚度)的影响。如果观察到角膜健康的永久性变化，将制备和测试较低剂量的制剂；任务2.确定我们的辅药、其代谢物、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，将使用角膜灌注和晶状体培养来确定角膜和晶状体的药代动力学，然后将其与兔眼局部给药后的房水水平进行比较。 公共卫生相关性：老花眼的发病，即40岁后近视的渐进性丧失，呈现出有限的治疗选择，包括眼镜、隐形眼镜或激光手术。Enore 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。

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.