Reversing the ocular impact of NM and SM through novel therapies

通过新疗法扭转 NM 和 SM 对眼部的影响

• 批准号: 10490420
• 负责人: ROBERT M LAVKER
• 金额: $ 49.33万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10490420
• 关键词: Acute; Adverse effects; Affect; Aftercare; Anterior; Anti-Inflammatory Agents; Attenuated; Autophagocytosis; Binding; Biological; Cells; Characteristics; Chemical Burns; Chemical Warfare Agents; Cholecalciferol; Clinical; Collagen; Complex; Cornea; Corneal Injury; Corneal Neovascularization; Data; Defect; Deterioration; Development; Dyes; Epithelial; Evaluation; Exclusion; Exposure to; Eye; Eye Injuries; Eyedrops; Film; Fluorescein; Funding; Glycolates; High Density Lipoproteins; Immune; Immunologics; Inflammation; Inflammatory; Injury; Ischemia; Knowledge; Laboratories; Light; Lipids; Mechlorethamine; MicroRNAs; Modality; Morphology; Mus; Mustard Gas; Non-Steroidal Anti-Inflammatory Agents; Oryctolagus cuniculus; Patients; Penetration; Peripheral; Phase; Phenotype; Protocols documentation; Regimen; Signal Transduction; Stains; Steroids; Stress; Surface; System; Testing; Therapeutic; Thinness; Tissues; Topical application; Universities; Variant; Vision; acute symptom; analog; angiogenesis; base; corneal epithelium; cytokine; delivery vehicle; efficacy evaluation; healing; improved; inflammatory marker; innovation; limbal; nano; nanoparticle; neovascularization; novel; novel therapeutics; ocular surface; particle; patient subsets; preservation; prevent; response; scaffold; screening program; side effect; stem cells; translational potential; wound healing

PROJECT SUMMARY/ABSTRACT The ocular anterior surface in conjunction with the tear film provide the first line of defense against penetration of noxious agents, which can adversely affect vision. Once this two-component system is breached, the anterior surface is capable of mounting a vigorous response, which involves a relatively rapid re- epithelialization along with a brisk inflammatory episode. A variant on the response of the anterior segment to perturbation occurs to patients following exposure to the chemical warfare agent, sulfur mustard (SM). The acute symptoms usually resolve completely without further inflammation after 2-6 weeks. However, in a subset of patients, corneal epithelial erosions, limbal ischemia, and, occasionally, peripheral corneal thinning and neovascularization may slowly progress. With respect to treatment modalities, either steroidal or non-steroidal anti-inflammatory drugs are the accepted treatment for the acute and prolonged phases. However, long-term use of topical steroids in SM ocular injuries is not ideal. Thus, additional therapies to prevent the ocular deterioration of SM victims is a major unmet need. We have recently demonstrated that topical application of synthetic, functional high-density lipoprotein nanoparticles (HDL NPs) inherently enhance re-epithelialization following corneal wounding and can act as anti-inflammatory agents following a chemical burn to the cornea. Furthermore, HDL NPs are effective vehicles for the delivery of miRNAs to the cornea. Therefore, HDL NPs will be complexed with miR-184, a highly angiostatic miRNA in the cornea, to treat the delayed phase of NM- induced corneal injury. We also have evidence that Vitamin D3 (Vit D3) and poly(lactic-co-glycolicacid) immune modifying nanoparticles (PLGA-IMPs) systemically or HDL NPs topically, administered to mice that were exposed to topical nitrogen mustard (NM), an analogue of SM, significantly reduce pro-inflammatory and angiogenic signaling. Collectively, these observations on HDLs, Vit D3, miR-184 and PLGA-IMPs have vast translational potential as novel treatment modalities for SM-induced injury to the eye. To test this idea, we will develop and assess these topical ocular therapeutics for the acute and delayed phases of NM injury to mice. We will evaluate the efficacy and mechanisms underlying these treatments with a combination of clinical, morphological, cell biological and immunological approaches. Additionally, we will evaluate a new class of HDL NPs that replace the inorganic Au core with an organic, transparent lipid-conjugated core scaffold, which will not inhibit the passage of light. We will also appraise the utility of systemic administration of Vit D3 or PLGA- IMPs to treat the delayed phase of NM-induced ocular injury. These results will establish the most effective topical and systemic regimens to treat the acute and delayed phases of NM injury. Finally, we will apply this knowledge to evaluate the efficacy of our chosen treatments for SM injury in rabbit eyes using the approaches described for NM injury. Ultimately, our studies will yield innovative treatments for SM-induced injury that will have anti-inflammatory, anti-angiogenic, pro-resolving, capabilities with minimal side effects.

项目概要/摘要 眼前表面与泪膜结合提供了防止渗透的第一道防线 有毒物质，会对视力产生不利影响。一旦这个两部分系统被破坏， 前表面能够产生强烈的反应，这涉及相对快速的重新反应 上皮化伴随着快速的炎症发作。前段反应的变体 接触化学战剂硫芥（SM）后，患者会出现紊乱。这 急性症状通常会在 2-6 周后完全消退，不会出现进一步的炎症。然而，在一个子集中 患者的角膜上皮糜烂、角膜缘缺血，偶尔还会出现周边角膜变薄和 新血管形成可能会缓慢进展。关于治疗方式，无论是类固醇还是非类固醇 抗炎药物是急性期和长期期公认的治疗方法。然而，长期来看 在 SM 眼损伤中使用局部类固醇并不理想。因此，需要额外的治疗来预防眼部疾病 SM 受害者的病情恶化是一个未得到满足的重大需求。我们最近证明了局部应用 合成的功能性高密度脂蛋白纳米颗粒 (HDL NP) 本质上增强了上皮再形成 角膜受伤后可用作角膜化学烧伤后的抗炎剂。 此外，HDL NP 是将 miRNA 递送至角膜的有效载体。因此，HDL NP 将与 miR-184（角膜中高度血管抑制的 miRNA）复合，以治疗 NM- 的延迟期 诱发角膜损伤。我们还有证据表明维生素 D3 (Vit D3) 和聚（乳酸-乙醇酸）免疫 全身修饰纳米颗粒 (PLGA-IMP) 或局部 HDL 纳米颗粒，给予小鼠 接触局部氮芥 (NM)（SM 的类似物）可显着减少促炎和 血管生成信号传导。总的来说，这些关于 HDL、Vit D3、miR-184 和 PLGA-IMP 的观察具有广泛的意义。 作为 SM 引起的眼损伤的新型治疗方式的转化潜力。为了测试这个想法，我们将 开发和评估这些针对小鼠 NM 损伤急性期和迟发期的局部眼部治疗方法。 我们将结合临床、 形态学、细胞生物学和免疫学方法。此外，我们将评估一类新的 HDL 用有机、透明的脂质共轭核心支架取代无机金核心的纳米颗粒，这将 不抑制光的通过。我们还将评估 Vit D3 或 PLGA 系统给药的效用 IMP 用于治疗 NM 引起的眼损伤的延迟期。这些结果将建立最有效的 治疗 NM 损伤急性期和迟发期的局部和全身方案。最后，我们将应用这个 使用这些方法评估我们选择的治疗兔眼 SM 损伤的疗效的知识 描述了 NM 损伤。最终，我们的研究将为 SM 引起的损伤提供创新的治疗方法，这将 具有抗炎、抗血管生成、促消退的能力，且副作用最小。