Multitargeted Therapy for Age-related Macular Degeneration

年龄相关性黄斑变性的多靶点治疗

• 批准号: 8057933
• 负责人: Danyang Chen
• 金额: $ 26.6万
• 依托单位: CHARLESSON, LLP
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-03-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8057933
• 关键词: Adrenal Cortex Hormones; Adverse effects; Affect; Age related macular degeneration; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Area; Attenuated; Blindness; Blood Vessels; Burn injury; Cell Cycle; Chickens; Choroid; Choroidal Neovascularization; Clinical; Clinical Research; Complex; Developed Countries; Development; Dexamethasone; Diabetic Retinopathy; Disease; Dose; Drug Carriers; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Elderly; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Exhibits; Extravasation; Eye; Eye Infections; FDA approved; Fibroblasts; Fluorescein Angiography; Genes; Glycolates; Growth; HIF1A gene; Health; Hypoxia Inducible Factor; Immunohistochemistry; Individual; Inflammation; Inflammatory; Injection of therapeutic agent; Intercellular adhesion molecule 1; Interleukin-1 beta; Interleukin-6; Intervention; Kenalog; Lasers; Low-Level Laser Therapy; Lung; Measures; Mediating; Methods; Modeling; Molecular; Monocyte Chemoattractant Protein-1; Normal Cell; Nuclear; Nuclear Translocation; Oxygen; Pathogenesis; Pathologic Processes; Pathway interactions; Patients; Pericytes; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Photochemotherapy; Physicians; Play; Prevention; Rattus; Retina; Retinal; Retinal Diseases; Retinal Neovascularization; Risk; Role; Route; Safety; Sclera; Screening procedure; Series; Small Business Innovation Research Grant; Solid; Structure of retinal pigment epithelium; TNF gene; Therapeutic; Therapeutic Agents; Therapeutic Studies; Toxic effect; Tube; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factors; Vascular Permeabilities; Vision; Visual Acuity; Visual impairment; Western Blotting; angiogenesis; biomaterial compatibility; cell growth; chorioallantoic membrane; copolymer; drug candidate; improved; in vivo; intravenous injection; laser photocoagulation; migration; nanoparticle; neovasculature; novel; nuclear factor 1; prevent; single molecule; small molecule; transcription factor

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is a sight-threatening disease which represents the leading cause of blindness and visual impairment in elderly individuals in developed countries. Recently, laser and photodynamic therapies with limited clinical benefit have been partially replaced by anti-vascular endothelial growth factor (VEGF) therapies. Clinical studies have demonstrated that anti-VEGF therapeutics can slow or reverse the progression of wet-AMD. However, these therapies, which target a single molecule only, do not benefit all patients with AMD. AMD is a complex disease involving numerous molecular pathways that are implicated in angiogenesis, inflammation and other pathological processes of AMD. Thus, there is a great demand for developing new drugs targeting multiple molecular pathways to improve the treatment of AMD. Through screening a series of a novel small molecule compounds to inhibit retinal neovascularization (NV) inflammation and vascular permeability, we have identified a novel compound, CLT-003, as a potential multi- targeted drug. The novel compound attenuated the activation of hypoxia-inducible factor-1alpha (HIF-11) and nuclear factor kappaB (NF B), and down-regulated the expression of VEGF in addition to the inflammatory intercellular adhesion molecule-1 (ICAM-1). These molecules are all pathogenic factors in AMD development. HIF-11 and NF B are the master transcription factors which regulate many genes associated with angiogenesis and inflammation, such as VEGF and ICAM-1. Therefore, HIF-11 and NF B likely are the main targets of CLT-003. Our studies demonstrated that CLT-003 inhibited the endothelial cell growth, migration and tube formation, arrested endothelial cell cycle and induced endothelial cell apoptosis; CLT-003, however, did not significantly affect the growth of normal cells (e.g. pericyte and lung fibroblast), suggesting endothelial cell-specific growth inhibition. CLT-003 inhibited angiogenesis in both chicken chorioallantoic membrane (CAM) and rat oxygen- induced retinopathy (OIR) models, and blocked retinal vascular leakage in both AMD and diabetic retinopathy animal models. CLT-003 had significantly higher potency to block vascular leakage as compared to Kenalog which is currently used clinically. Moreover, pharmacokinetic studies showed the CLT-003 was cleared rapidly following an intravenous injection in animals. Such pharmacokinetic profile of CLT-003 is appropriate as an ocular drug. Toxicity studies showed that high doses of CLT-003 were well tolerated in animals. These findings suggest that CLT-003 has potent anti-angiogenic, anti-inflammatory and anti-vascular permeability activities through targeting multiple molecular pathways, while exhibiting a highly favorable safety profile. Intravitreal administration is an efficient route for ocular drug delivery and offers high local concentrations in the vitreous and retina. However, frequent and repeated intraocular injections are undesirable in a clinical setting due to patient/physician burden, the increased risk of ocular infection and other side effects; thus, it is desirable to develop an ocular drug delivery system which mediates sustained release of ocular drugs. Nanoparticle-mediated drug delivery systems are widely considered a safe and efficient method for ocular drug delivery. Poly(lactic-co-glycolic acid) (PLGA) is a FDA-approved copolymer which is used as a carrier for drugs, owing to its biodegradability and biocompatibility. To overcome the short duration of the effects of the ocular drug after an intravitreal injection and maintain a sustained efficacious level of ocular drug in the eye, we have developed a PLGA CLT-003 nanoparticle (CLT-003NP) formulation. CLT-003NP mediated the sustained release of CLT-003 over 16 weeks, had a prolonged inhibitory effect on endothelial cell growth and significantly reduced retinal vascular leakage in diabetic retinopathy rats for at least 6 weeks. Taken together, CLT-003NP is a promising drug candidate for the long-term treatment of AMD as it targets multiple pathological factors in AMD development and can achieve prolonged efficacy. This phase I project including two specific aims will serve as a proof-of-concept study to evaluate the anti-angiogenic and anti-inflammatory efficacies of CLT-003NP in a rat choroidal neovascularization (CNV) model: 1) To evaluate the effect of CLT-003NP on angiogenesis. CNV is responsible for 75% of the severe vision loss attributable to AMD patients. Using a rat CNV model induced by laser, we will determine whether CLT-003 is capable of preventing CNV development and arresting CNV progression. 2) To determine the effect of CLT-003 on inflammation. Inflammation plays a crucial role in AMD pathogenesis. In the same animal model, we will explore whether CLT-003 has an anti-inflammatory effect. These studies will lay a solid ground for further studies in SBIR phase II toward developing CLT-003NP to become a novel and multi-targeted drug to improve the treatment of AMD.

描述（由申请人提供）： 年龄相关性黄斑变性（AMD）是一种威胁视力的疾病，是发达国家老年人失明和视力障碍的主要原因。最近，临床益处有限的激光和光动力疗法已部分被抗血管内皮生长因子（VEGF）疗法所取代。临床研究表明，抗 VEGF 疗法可以减缓或逆转湿性 AMD 的进展。然而，这些仅针对单个分子的疗法并不能使所有 AMD 患者受益。 AMD 是一种复杂的疾病，涉及众多分子途径，这些途径与血管生成、炎症和 AMD 的其他病理过程有关。因此，迫切需要开发针对多种分子途径的新药来改善AMD的治疗。通过筛选一系列抑制视网膜新生血管（NV）炎症和血管通透性的新型小分子化合物，我们发现了一种新型化合物CLT-003，作为一种潜在的多靶点药物。这种新型化合物可减弱缺氧诱导因子 1α (HIF-11) 和核因子 kappaB (NF B) 的激活，并下调 VEGF 以及炎症细胞间粘附分子 1 (ICAM-1) 的表达。 。这些分子都是AMD发展的致病因素。 HIF-11 和 NF B 是调节许多与血管生成和炎症相关的基因的主要转录因子，例如 VEGF 和 ICAM-1。因此，HIF-11和NF B可能是CLT-003的主要目标。我们的研究表明，CLT-003 抑制内皮细胞生长、迁移和管形成，阻滞内皮细胞周期并诱导内皮细胞凋亡；然而，CLT-003 并没有显着影响正常细胞（例如周细胞和肺成纤维细胞）的生长，表明内皮细胞特异性生长抑制。 CLT-003 抑制鸡绒毛尿囊膜 (CAM) 和大鼠氧诱导视网膜病变 (OIR) 模型中的血管生成，并阻止 AMD 和糖尿病视网膜病变动物模型中的视网膜血管渗漏。与目前临床上使用的 Kenalog 相比，CLT-003 具有显着更高的阻止血管渗漏的效力。此外，药代动力学研究表明，CLT-003 在动物静脉注射后迅速被清除。 CLT-003 的这种药代动力学特征适合作为眼部药物。毒性研究表明，高剂量的 CLT-003 在动物中具有良好的耐受性。这些发现表明，CLT-003 通过靶向多种分子途径具有有效的抗血管生成、抗炎和抗血管通透性活性，同时表现出非常有利的安全性。玻璃体内给药是眼部药物递送的有效途径，并在玻璃体和视网膜中提供高局部浓度。然而，由于患者/医生的负担、眼部感染风险增加和其他副作用，在临床环境中，频繁和重复的眼内注射是不可取的；因此，需要开发一种介导眼部药物持续释放的眼部药物递送系统。纳米颗粒介导的药物递送系统被广泛认为是一种安全有效的眼部药物递送方法。聚乳酸-乙醇酸 (PLGA) 是一种 FDA 批准的共聚物，由于其生物可降解性和生物相容性而被用作药物载体。为了克服玻璃体内注射后眼部药物作用持续时间短的问题，并维持眼部药物在眼内持续有效的水平，我们开发了PLGA CLT-003纳米颗粒（CLT-003NP）制剂。 CLT-003NP 介导 CLT-003 在 16 周内持续释放，对内皮细胞生长具有延长的抑制作用，并在糖尿病视网膜病变大鼠中显着减少视网膜血管渗漏至少 6 周。综上所述，CLT-003NP是一种有前途的长期治疗AMD的候选药物，因为它针对AMD发展中的多种病理因素，并且可以实现长期疗效。该一期项目包括两个具体目标，将作为概念验证研究，评估 CLT-003NP 在大鼠脉络膜新生血管 (CNV) 模型中的抗血管生成和抗炎功效： 1) 评估CLT-003NP 对血管生成的影响。 AMD 患者造成的严重视力丧失中有 75% 是由 CNV 造成的。使用激光诱导的大鼠 CNV 模型，我们将确定 CLT-003 是否能够预防 CNV 发展并阻止 CNV 进展。 2) 确定CLT-003对炎症的影响。炎症在 AMD 发病机制中起着至关重要的作用。在同一动物模型中，我们将探讨CLT-003是否具有抗炎作用。这些研究将为 SBIR II 期的进一步研究奠定坚实的基础，以开发 CLT-003NP，使其成为改善 AMD 治疗的新型多靶点药物。