Sustained-release of novel neuroprotective agents for treatment of glaucoma

 青光眼是致盲的主要原因之一，影响全世界超过7000万人。青光眼是一种神经退行性视神经病变，由视网膜神经节细胞（RGC）缺失引起，导致视力丧失。目前的治疗都是针对降低眼内压（IOP），但尽管IOP降低，许多患者的RGC损失仍在继续。通过促进RGC存活来补充IOP降低的药物的鉴定将是改善青光眼患者视力结果的重大进展。使用原代RGC的培养物，我们筛选了10，000多种化合物，并确定了具有有效神经保护特性的候选物，包括FDA批准用于无关适应症的药物。我们进一步表征了这些化合物用于保护RGC的新途径，从而鉴定了用于神经保护的新药物/药物靶标组合。我们还开发了一种微粒眼部药物递送系统，其在玻璃体内给药后允许缓慢释放和持续局部递送至眼睛，而不会引起炎症。在这项应用中，我们将这些神经保护药物中的两种与我们的微粒递送系统相结合，以开发一种用于治疗青光眼的新疗法。在目标1中，我们将配制和表征连续释放神经保护药物长达6个月的微粒，以将所需的注射频率减少到每年2-3次注射。在目标2中，我们将测试药物释放微粒是否在小鼠视神经挤压和珠诱导的青光眼模型中促进RGC存活和功能。将进行药物剂量递增研究，并通过视动反应（OKR）评估视神经将视觉刺激从眼睛传递到大脑的功能。在目标3中，我们将评估兔眼6个月的眼内药代动力学，并在玻璃体内施用微粒后进行初步安全性分析。安全性评价将包括眼底检查、IOP和视网膜形态学分析，作为药物暴露对眼睛长期影响的初步评价。在啮齿动物神经变性模型中的功效证明，包括受保护的RGC的功能的验证，沿着长期药物释放并且在兔眼中没有明显毒性，将提供我们的神经保护性药物递送策略用于治疗青光眼的治疗潜力的证据。

 DESCRIPTION: Glaucoma is a major cause of blindness, affecting over 70 million people worldwide. Glaucoma is a neurodegenerative optic neuropathy caused by the loss of retinal ganglion cells (RGC), leading to loss of vision. Current therapies are all directed at lowering intraocular pressure (IOP), and yet RGC loss still continues in many patients despite IOP lowering. The identification of an agent that complements IOP lowering by promoting RGC survival would be a significant advance toward improving the visual outcomes of patients with glaucoma. Using cultures of primary RGC, we screened more than 10,000 compounds and identified candidates with potent neuroprotective properties, including a drug that is FDA-approved for an unrelated indication. We further characterized the novel pathway through which these compounds act to protect RGC, thus identifying a novel drug/drug target combination for neuroprotection. We have also developed a microparticle ocular drug delivery system that, following intravitreal administration, allows slow release and sustained localized delivery to the eye, without causing inflammation. In this application, we are combining two of these neuroprotective drugs with our microparticle delivery system to develop a new therapeutic for the treatment of glaucoma. In Aim 1, we will formulate and characterize microparticles that release the neuroprotective drugs continuously for up to 6 months to reduce the required injection frequency to 2-3 injections per year. In Aim 2, we will test whether the drug-releasing microparticles promote RGC survival and function in the mouse optic nerve crush and bead-induced glaucoma models. A drug dose escalation study will be performed and function of the optic nerve in transmitting visual stimulation from the eye to the brain will be assessed by optokinetic responses (OKR). In Aim 3, we will evaluate the intraocular pharmacokinetics in the rabbit eye for 6 months and perform preliminary safety analyses following intravitreal administration of microparticles. Safety evaluations will include fundus exams, IOP, and retinal morphology analyses as a preliminary evaluation of the long-term effects of drug exposure in the eye. The demonstration of efficacy in rodent models of neurodegeneration, including the verification of function of the protected RGCs, along with long-term drug release and no overt toxicity in the rabbit eye, would provide evidence of the therapeutic potential of our neuroprotective drug delivery strategy for the treatment of glaucoma.