Sustained-Release of a Novel Neuroprotective Agent for Improved Glaucoma Therapy

持续释放新型神经保护剂以改善青光眼治疗

• 批准号: 8713791
• 负责人: Ming Yang
• 金额: $ 15.02万
• 依托单位: GRAYBUG, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8713791
• 关键词: Affect; Animals; Axon; Biodistribution; Biological; Biological Assay; Biological Preservation; Blindness; Brain; Cell Survival; Cell physiology; Chemicals; Clinical; Complement; Complete Blindness; Cytoprotection; Disease; Dose; Drug Delivery Systems; Drug Exposure; Drug Formulations; Drug Targeting; Electroretinography; Encapsulated; Evaluation; Exposure to; Eye; FDA approved; Fundus; Generations; Glaucoma; Goals; Human; In Vitro; Inflammation; Intellectual Property; Investigational New Drug Application; Kinetics; Lasers; Lead; Legal patent; Letters; Licensing; Long-Term Effects; Malignant Neoplasms; Measures; Mediating; Modeling; Monitor; Monkeys; Morphology; Mus; Nerve; Nerve Degeneration; Neuroprotective Agents; Optic Nerve; Optic Nerve Transections; Oryctolagus cuniculus; Outcome; Particle Size; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Photic Stimulation; Physiologic Intraocular Pressure; Physiological; Preparation; Process; Production; Rattus; Retinal; Retinal Ganglion Cells; Rodent; Safety; Sutent; System; Technology; Technology Transfer; Testing; Therapeutic; Time; Toxic effect; Training; Visual; Visual Fields; Visual evoked cortical potential; analog; base; drug biological activity; high throughput screening; improved; in vivo; intravitreal injection; novel; novel therapeutics; optic nerve disorder; particle; phase 2 study; prevent; public health relevance; research clinical testing; safety study; screening; therapeutic evaluation; tissue fixing; treatment strategy; visual stimulus

DESCRIPTION (provided by applicant): Glaucoma is a major cause of blindness, affecting over 70 million people worldwide. It is a neurodegenerative optic neuropathy in which vision loss results from the loss of retinal ganglion cells (RGC). Current therapies are all directed at lowering intraocular pressure (IOP), however, despite IOP lowering, RGC loss still continues in many patients. To improve the visual outcome of patients with glaucoma new treatment strategies are warranted. The identification of an agent that promotes RGC survival to complement IOP lowering would represent a significant treatment advance. Through the screening of over 10,000 compounds, and subsequent generation of structural analogs through medicinal chemistry, we have identified compounds that are highly neuroprotective of cultured primary RGCs. This surprising discovery represents the first description of neuroprotective activity for these agents, one of which is FDA-approved for an unrelated indication. GrayBug has developed a proprietary 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 one of the novel neuroprotective drugs with our microparticle delivery system to develop a new therapeutic for the treatment of glaucoma. In Aim 1, we will generate and characterize microparticles that release the neuroprotective drug continuously over a sustained period. Microparticles that encapsulate the neuroprotective agent(s) will be produced using the proprietary GrayBug technology exclusively licensed from Johns Hopkins. Similar microparticles produced using this technology were noninflammatory when delivered intracamerally to rabbits, an extremely sensitive evaluation model. The drug- releasing particles will be characterized fully and the duration of drug release in vitro will be evaluated. Finally, the biological activity of the drug released from the particles will be verifie in the primary murine RGC survival assay. In Aim 2, we will test whether the drug-releasing microparticles promote RGC survival and function in the laser-induced rat IOP glaucoma model. A drug dose escalation study will be performed and visual evoked potential (VEP), a clinical assay, will be used to verify and quantitate function of the optic nerve in transmitting visual stimulation from the eye to the brain. In Aim 3, we will evaluate the duration of drug release over a period of three months and perform preliminary safety analyses following intravitreal administration of microparticles to normal rats. Safety evaluations include fundus exams, IOP, ERG, and retinal morphology analyses, as a preliminary evaluation of the long-term effects of drug exposure to the eye. The demonstration of efficacy in the rodent glaucoma model, including the verification of function of the protected RGCs with long- term drug release and no overt toxicity in the eye, would provide evidence of the therapeutic potential of our neuroprotective drug delivery strategy for the treatment of glaucoma. Successful completion of these specific aims will lead us to Phase II and ultimately to human clinical evaluation.

描述（由申请人提供）：青光眼是致盲的主要原因，影响全球超过7000万人。它是一种神经退行性视神经病变，其中视力丧失是由视网膜神经节细胞（RGC）的丧失引起的。目前的治疗都是针对降低眼内压（IOP），然而，尽管IOP降低，但在许多患者中RGC损失仍然持续。为了改善青光眼患者的视力结果，新的治疗策略是必要的。鉴定促进RGC存活以补充IOP降低的药剂将代表显著的治疗进展。通过筛选超过10，000种化合物，以及随后通过药物化学产生的结构类似物，我们已经鉴定出对培养的原代RGC具有高度神经保护作用的化合物。这一令人惊讶的发现代表了这些药物的神经保护活性的首次描述，其中一种药物已被FDA批准用于不相关的适应症。GrayBug开发了一种专有的微粒眼部药物递送系统，在玻璃体内给药后，允许缓慢释放和持续局部递送到眼睛，而不会引起炎症。在这项应用中，我们将一种新型神经保护药物与我们的微粒递送系统相结合，以开发一种治疗青光眼的新疗法。在目标1中，我们将产生并表征在持续时间内连续释放神经保护药物的微粒。将使用由Johns霍普金斯独家许可的专有GrayBug技术生产包封神经保护剂的微粒。使用该技术生产的类似微粒在前房内给药至家兔时无炎症，这是一种非常敏感的评估模型。将充分表征药物释放颗粒，并评价体外药物释放持续时间。最后，将在原代鼠RGC存活测定中验证从颗粒释放的药物的生物活性。在目的2中，我们将测试药物释放微粒是否在激光诱导的大鼠IOP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，并将使用视觉诱发电位（VEP）（一种临床试验）验证和定量视神经在将视觉刺激从眼睛传递到大脑中的功能。在目标3中，我们将评估药物释放的持续时间， 三个月的时间，并在玻璃体内给予正常大鼠微粒后进行初步的安全性分析。安全性评价包括眼底检查、IOP、ERG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。在啮齿动物青光眼模型中的功效的证明，包括在眼睛中具有长期药物释放且无明显毒性的受保护的RGC的功能的验证，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。这些具体目标的成功完成将使我们进入第二阶段，并最终进入人体临床评估。