Novel Small Molecule Macrophage Inhibitors for the Treatment of Retinal Diseases

用于治疗视网膜疾病的新型小分子巨噬细胞抑制剂

• 批准号: 9200221
• 负责人: Scott William Cousins
• 金额: $ 22.5万
• 依托单位: EYEDESIS BIOSCIENCES, LLC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9200221
• 关键词: Achievement; Applications Grants; Attenuated; Biological Assay; Biological Sciences; Biotechnology; Blindness; Blood; Blood capillaries; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium/calmodulin-dependent protein kinase; Cells; Clinic; Clinical; Collaborations; Data; Development; Disease; Dose; Elderly; Experimental Models; Extravasation; Exudative age-related macular degeneration; Eye; Feasibility Studies; Fibrosis; Formulation; Funding; Genetic; Goals; Grant; Growth; Growth Factor; In Vitro; Inflammatory; Injectable; Injection of therapeutic agent; Intellectual Property; Lead; Lesion; Macular degeneration; Mediating; Modeling; Mus; Muscle Cells; Myofibroblast; Outcome; Pathologic; Patients; Performance; Perivascular Fibrosis; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Phosphorylation; Phosphotransferases; Plasma; Production; Program Development; Protein Kinase; Recruitment Activity; Research Institute; Research Personnel; Retinal Diseases; Risk; Scientist; Seeds; Series; Signal Transduction; Small Business Technology Transfer Research; Specificity; Toxic effect; Toxicology; Translational Research; Universities; Vascular Endothelial Growth Factors; Vascular Smooth Muscle; Vascularization; Vision; Wild Type Mouse; Work; analog; arteriole; base; capillary; design; drug candidate; drug development; effective therapy; eye pharmacology; improved; in vitro activity; in vivo; inhibitor/antagonist; innovation; intravitreal injection; macrophage; macula; medical schools; mouse model; neovascular; novel; novel drug class; novel therapeutics; osteopontin; pre-clinical; prevent; small molecule; small molecule inhibitor; systemic toxicity; therapeutic target; tumor; tumor growth

PROJECT SUMMARY / ABSTRACT Persistent disease activity (PDA) in spite of anti-vascular endothelial growth factor (VEGF) therapy remains a significant clinical unmet need for patients with neovascular age-related macular degeneration (NVAMD). The purpose of this STTR Phase I grant application is to develop novel therapies that will be effective for the treatment of PDA associated with NVAMD. The current proposal represents a collaboration between Eyedesis Biosciences, LLC, a spinout biotechnology company focused on retinal diseases, and a Collaborative Team of investigators from Eye, Pharmacology, and Medicinal Chemistry at Duke University School of Medicine. This team has established that the primary cause of PDA in the clinic is neovascular remodeling (NVR), and that NVR appears to be mediated by blood-derived macrophages in experimental models of NVAMD. The Pharmacology Team has identified calcium / calmodulin-dependent protein kinase kinase 2 (CaMKK2) as a key regulatory kinase that amplifies macrophage effector function. A collaborative effort of Eye and Pharmacology has demonstrated that both genetic deletion and local pharmacologic inhibition of CaMKK2 prevents the development of NVR in experimental NVAMD. The Medicinal Chemistry team has designed and initiated the synthesis of novel small molecule inhibitors of CaMKK2 for the treatment of NVAMD and other retinal diseases with macrophage-mediated pathobiology. Funded by an internal Duke Translational Research Institute seed-fund grant, this Collaborative Team of investigators has performed critical work to establish 1) CaMKK2 as a potential therapeutic target for NVAMD, and 2) a viable drug development initiative with Duke- owned novel intellectual property (IP). Eyedesis Biosciences was founded to formalize this initiative as a commercial drug development program following IP outlicense. The proposed STTR Phase I project will attempt to achieve four key milestones: (1) Novel small molecules are potent inhibitors of macrophage CaMKK2 and effector function in vitro; (2) These small molecules are more selective for CaMKK2 than STO-609 with less off-target activity; (3) The small molecules are well tolerated when injected around the eye (i.e. subconjunctivally); and (4) Subconjunctival ocular administration of these compounds is effective in preventing NVR. The key deliverable will be the identification of at least one small molecule that meets these goals. Successful realization of the Phase I milestones will justify additional development in Phase II, including: (1) nomination of lead candidate(s) for intravitreal therapy; (2) clinical formulation for intravitreal injection of candidate drugs; (3) performance of IND-enabling studies (i.e. GLP toxicology and PK) for injectable therapies.

项目总结/摘要 尽管抗血管内皮生长因子（VEGF）治疗，但持续性疾病活动（PDA）仍然是一个危险因素。 新生血管性年龄相关性黄斑变性（NVAMD）患者的显著临床未满足需求。的 这项STTR第一阶段赠款申请的目的是开发新的疗法，将有效的 治疗与NVAMD相关的PDA。目前的提案代表了Eyedesis Biosciences，LLC是一家专注于视网膜疾病的衍生生物技术公司， 来自杜克大学医学院眼科、药理学和药物化学的研究人员。 该研究小组已经确定，临床上PDA的主要原因是新生血管重塑（NVR）， 在NVAMD的实验模型中，NVR似乎是由血液来源的巨噬细胞介导的。的 药理学团队已经确定钙/钙调蛋白依赖性蛋白激酶激酶2（CaMKK 2）是一种 放大巨噬细胞效应子功能的关键调节激酶。Eye和 药理学已经证明，CaMKK 2的基因缺失和局部药理学抑制都是通过抑制CaMKK 2的表达来实现的。 防止实验性NVAMD中NVR的发展。药物化学团队设计并 启动了新型CaMKK 2小分子抑制剂的合成，用于治疗NVAMD和其他 视网膜疾病与巨噬细胞介导的病理生物学。由内部杜克转化研究资助 研究所种子基金赠款，这个研究人员合作小组进行了关键的工作，以建立1） CaMKK 2作为NVAMD的潜在治疗靶点，以及2）与杜克合作的可行药物开发计划- 拥有新颖的知识产权（IP）。 Eyedesis Biosciences的成立是为了将这一倡议正式确定为商业药物开发计划 IP outlicense之后。拟议的STTR第一阶段项目将试图实现四个关键里程碑： (1)新型小分子是巨噬细胞CaMKK 2和效应器功能的有效抑制剂; (2)这些小分子比STO-609对CaMKK 2更具选择性，脱靶活性更低; (3)小分子在眼周注射（即结膜下）时耐受性良好;以及 (4)这些化合物的结膜下眼部给药在预防NVR中是有效的。 关键的可交付成果将是确定至少一种满足这些目标的小分子。成功 第一阶段里程碑的实现将证明第二阶段的额外发展是合理的，包括： (1)提名玻璃体内治疗的主要候选人; (2)用于玻璃体内注射候选药物的临床制剂; (3)注射治疗IND使能研究（即GLP毒理学和PK）的性能。