Topical Eyedrop Therapy for Keratoconus

项目摘要 圆锥角膜是一种角膜病变，其角膜中央部分变薄并隆起 以锥形方式向前移动，导致近视、不规则散光，最终导致视力损害。 圆锥角膜的最早症状通常是视力模糊和频繁更换眼镜处方，或 不能用眼镜矫正的视力。圆锥角膜的症状一般开始在青少年后期 或者二十岁出头，但可以在任何时候开始。治疗选择是令人惊讶的有限，没有口服或局部 药物治疗大多数轻度的KCN可以用眼镜或软性隐形眼镜矫正，但通常情况下， 随着疾病的发展，患者将需要复曲面或硬接触。最终，五分之一的患者需要手术， 例如角膜移植或UV-A交联，这会带来疤痕、视觉模糊、波动 和痛苦. 我们的技术IVMED-80滴眼液是基于赖氨酰氧化酶（LOX）活性的辅助因子。LOX不足 角膜中的活性在遗传和生物化学上与圆锥角膜的发展有关。 利用第一阶段的资金支持，我们能够恢复人角膜成纤维细胞中赖氨酰氧化酶的活性， 圆锥角膜和增加的交联胶原水平，如通过兔眼中的赖氨酰正亮氨酸所测量的。 我们证明了局部治疗增加了人尸体角膜和兔角膜的生物力学强度， 通过离体拉伸测量法和体内波形变形分析测量的角膜。最后，Topical 铜治疗诱导的兔角膜扁平化与常规手术观察到的水平相当， 在人体内交联。这些数据导致iVeena被授予IVMED孤儿药认定- 80. 在这个2期SBIR项目中，我们提出了一些实验，使我们能够提交IND并开始美国临床试验。 审判我们建议分析治疗的最佳持续时间和不同持续时间后复发的潜在风险。 处理，根据ICH指导原则生产具有稳定性检测的GMP批次，并进行6个月 家兔GLP毒理学研究。

Project Summary Keratoconus (KCN) is a corneal disorder in which the central portion of the cornea becomes thinner and bulges forward in a cone-shaped fashion resulting in myopia, irregular astigmatism, and eventually visual impairment. The earliest signs of keratoconus are usually blurred vision and frequent changes in eye glass prescription, or vision that cannot be corrected with glasses. Symptoms of keratoconus generally begin in the late teenage years or early twenties, but can start at any time. Treatment options are surprisingly limited with no oral or topical pharmaceutical therapy. Most mild KCN can be corrected with glasses or soft contact lenses but very often patients will need toric or hard contacts as the disease progresses. Ultimately, 1 in 5 patients will require surgery, such as corneal transplant or UV-A crosslinking, which poses significant risks of scarring, visual haze, fluctuation, and pain. Our technology, IVMED-80 eye drops, is based on a co-factor for lysyl oxidase (LOX) activity. Deficient LOX activity in the cornea has been linked to the development of keratoconus both genetically and biochemically. Using Phase 1 funding support, we were able to restore lysyl oxidase activity in human corneal fibroblasts from keratoconic corneas and increase levels of crosslinked collagen as measured by lysylnorleucine in rabbit eyes. We demonstrated topical therapy increased biomechanical strength of human cadaver corneas and rabbit corneas as measured by both extensiometry ex vivo and waveform deformation analysis in vivo. Finally, topical copper therapy induced flattening of the rabbit cornea comparable to levels observed with conventional surgical crosslinking in humans. This body of data resulted in iVeena being granted orphan designation for IVMED- 80. In this Phase 2 SBIR project, we propose experiments that will enable us to submit an IND and start a US clinical trial. We propose to analyze optimal duration of therapy and potential risk of relapse after different durations of treatment, manufacture a GMP batch with stability testing according to ICH guidelines, and perform a 6-month GLP toxicology study in rabbits.