Sustained-release of novel neuroprotective agents for treatment of glaucoma

用于治疗青光眼的新型神经保护剂的缓释

基本信息

批准号：
9233122
负责人：
Laura Ensign
金额：
$ 40.5万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-01 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9233122
关键词：
Adverse effects Affect Biological Biological Assay Biological Preservation Blindness Brain Cell Culture Techniques Cell Survival Cell physiology Cells Chemicals Chronic Clinical Treatment Complement Data Dose Drug Controls Drug Delivery Systems Drug Exposure Drug Kinetics Drug Targeting Electroretinography Evaluation Eye FDA approved Formulation Frequencies Fundus Glaucoma Glycolates In Vitro Inflammation Inflammatory Response Injection of therapeutic agent Intraperitoneal Injections Kinetics Lactic acid Lasers Leucine Zippers Long-Term Effects Malignant Neoplasms Measurement Mediating Modeling Molecular Weight Morphology Mus Nerve Crush Nerve Degeneration Neuropathy Neuroprotective Agents Optic Nerve Oral Oryctolagus cuniculus Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Chemistry Pharmaceutical Preparations Phosphotransferases Photic Stimulation Physiologic Intraocular Pressure Polyethylene Glycols Polymers Property Rattus Retinal Retinal Degeneration Retinal Ganglion Cells Rodent Model Safety Signal Transduction Site Sutent System Testing Therapeutic Toxic effect Treatment Efficacy Visual Visual Fields Visual Pathways analog base copolymer drug candidate high throughput screening improved in vivo intravitreal injection neuroprotection new therapeutic target novel novel therapeutics optic nerve disorder particle pressure prevent public health relevance response treatment strategy

项目摘要

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.

描述：青光眼是失明的主要原因，影响了全球超过7000万人。青光眼是残留神经节细胞（RGC）引起的一种神经退行性神经病，导致视力丧失。当前的疗法均针对降低人眼压（IOP），但在许多患者目的地IOP降低的患者中，RGC损失仍在继续。通过促进RGC存活来降低IOP的鉴定将是改善青光眼患者的视觉结局的重大进步。使用原发性RGC培养物，我们筛选了10,000多种化合物，并确定了具有潜在神经保护特性的候选物，其中包括通过FDA批准的药物以获得无关的指示。我们进一步表征了这些化合物来保护RGC的新型途径，从而确定了一种新型的药物/药物靶标组合神经保护作用。我们还开发了一个微粒眼药物输送系统，在玻璃体内给药后，允许缓慢释放并持续向眼睛局部递送，而不会引起炎症。在此应用中，我们将其中两种神经保护药物与微粒递送系统相结合，以开发一种用于治疗青光眼的新理论。在AIM 1中，我们将制定和表征微粒，这些微粒连续释放神经保护药物长达6个月，以将所需的注射频率降低至每年2-3注射。在AIM 2中，我们将测试释放药物的微粒是否促进RGC的存活率和小鼠视神经压抑和珠子诱导的青光眼模型的功能。将进行一项药物剂量升级研究，并通过光动力学反应（OKR）评估视神经在将视觉刺激从眼睛传输到大脑中的功能。在AIM 3中，我们将评估兔眼中的眼内药代动力学6个月，并在玻璃体内给药后进行初步安全分析。安全评估将包括眼底检查，IOP和视网膜形态分析，作为对眼睛中药物暴露的长期影响的初步评估。神经退行性模型中有效性的证明，包括受保护RGC的功能以及长期药物释放的验证，并且在兔眼中没有明显的毒性，这将提供证据证明我们神经保护药物递送策略的治疗潜力的证据。