Novel Small Molecule Anti-Inflammatory Eye Drops for Ocular Graft Versus Host Disease

新型小分子抗炎滴眼液治疗眼移植物抗宿主病

• 批准号: 10334520
• 负责人: Jindong Ding
• 金额: $ 75万
• 依托单位: PULSAR LIFE SCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10334520
• 关键词: Accounting; Affect; Allogenic; Anti-Inflammatory Agents; Applications Grants; Artificial Tears; Biological Sciences; Blindness; Bone Marrow Transplantation; Ca(2+)-Calmodulin Dependent Protein Kinase; Canis familiaris; Cell physiology; Cells; Chemistry; Cicatrix; Clinical; Clinical Research; Collaborations; Contact Lenses; Contracts; Corneal Ulcer; Cyclosporine; Data; Development; Disease; Dose; Drug Formulations; Excretory function; Eye; Eye Development; Eyedrops; FDA approved; Feasibility Studies; Formulation; Gland; Goals; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Histopathology; Immune; Immunosuppressive Agents; In Vitro; Infiltration; Inflammatory; Intellectual Property; Keratopathy; Label; Lead; Libraries; Lung; Manufacturer Name; Mass Spectrum Analysis; Metabolism; Methods; Morbidity - disease rate; Mus; Organ; Orphan; Oryctolagus cuniculus; Pain; Parents; Patients; Perforation; Persons; Pharmaceutical Preparations; Pharmacology and Toxicology; Phase; Phosphotransferases; Property; Pulsar; Rattus; Scanning; Severity of illness; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Solubility; Specificity; Steroids; Structure; T-Lymphocyte; Tissues; Topical Corticosteroids; Topical application; Toxicology; Tumor-infiltrating immune cells; Universities; Visual impairment; absorption; analog; base; cell motility; cell type; design; drug metabolism; drug production; effective therapy; eye dryness; first-in-human; graft vs host disease; in vitro activity; in vivo; inhibitor; lead candidate; lead optimization; macrophage; meibomian gland dysfunction; novel; novel drug class; novel therapeutics; ocular surface; rational design; small molecule; small molecule inhibitor; standard of care; targeted treatment; tool

SUMMARY Ocular graft versus host disease (OGVHD) is a severe ocular surface inflammatory disease (OSID), occurring in patients undergoing allogenic hematopoietic stem cell transplantation (HSCT). OGVHD is characterized by dry eye, meibomian gland dysfunction, conjunctival scarring, lid margin scarring, keratopathy, and corneal ulceration, causing significant ocular morbidity and vision loss for affected patients. Presently, there are no effective disease-modifying therapies for OGVHD. The purpose of this SBIR Phase II grant application is to develop novel and effective therapies for the treatment of OGVHD and potentially other OSIDs. The current proposal from Pulsar Life Sciences is focused on developing calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2)-targeted therapies for ocular diseases. Our preliminary studies and the results from a Phase 1 STTR to Eyedesis Biosciences (parent company) demonstrate that murine OGVHD is associated with conjunctival infiltration by T cells and MФ, two cell types in which CaMKK2 has been previously shown to be a regulator of inflammatory cell function; topical application of the tool compound SMIC, STO-609, significantly reduced murine OGVHD severity in vivo; and many compounds from a proprietary library of novel SMICs invented by Eyedesis inhibited CaMKK2 activity in vitro. These findings support the hypothesis that novel inhibitors of CaMKK2 can be developed to treat OGVHD. Eyedesis has successfully completed Phase 1 aims to demonstrate that many novel SMICs were potent inhibitors of CaMKK2 in vitro, most novel SMICs were well tolerated when applied topically to the eye, and two novel SMICs administered topically were efficacious in treating murine OGVHD. In this follow-on Phase 2 SBIR application, Pulsar will complete lead optimization and IND-enabling studies required for our filing of an IND application. Aim 1 will finalize lead optimization and select the lead candidate, Aim 2 will perform the technical transfer to contract GMP drug manufacturer and contract GMP drug formulation, establish CMC properties, and characterize formulation stability, and Aim 3 will perform IND-enabling pharmacology and toxicology studies. The end deliverable will be to submit an IND application to the FDA and perform the first-in-human clinical studies with this topical eyedrop for OGVHD.

总结 眼移植物抗宿主病（OGVHD）是一种严重的眼表炎症性疾病（OSID），发生于 异基因造血干细胞移植（HSCT）患者。OGVHD的特征在于 干眼症、睑板腺功能障碍、结膜瘢痕形成、睑缘瘢痕形成、角膜病变和角膜 溃疡，对受影响的患者造成显著的眼部发病率和视力丧失。目前，没有 有效的OGVHD疾病缓解疗法。此SBIR第二阶段拨款申请的目的是 开发新的和有效的治疗OGVHD和潜在的其他OSID的疗法。当前 Pulsar Life Sciences的一项提案专注于开发钙/钙调素依赖性蛋白激酶 激酶2（CaMKK 2）靶向治疗眼部疾病。我们的初步研究和一个阶段的结果 Eyedesis Biosciences（母公司）的1份STTR证明了鼠OGVHD与 T细胞和M细胞的结膜浸润，这两种细胞类型中，CaMKK 2先前已被证明是一种免疫抑制剂。 炎症细胞功能的调节剂;局部应用工具化合物SMIC，STO-609， 降低小鼠体内OGVHD严重程度;以及来自新型SMIC专有库的许多化合物 本发明在体外抑制CaMKK 2活性。这些发现支持了一个假设， 可以开发CaMKK 2的抑制剂来治疗OGVHD。Eyedesis已成功完成第一阶段的目标， 表明许多新的SMIC在体外是CaMKK 2的有效抑制剂，大多数新的SMIC在体外表现良好， 局部应用于眼睛时耐受，两种新型SMIC局部给药有效， 治疗鼠OGVHD。在后续的第2阶段SBIR应用中，Pulsar将完成电极导线优化， 我们提交IND申请所需的IND使能研究。Aim 1将最终确定潜在客户优化并选择 主要候选人Aim 2将向合同GMP药品生产商和合同进行技术转让 GMP药物制剂，确定CMC特性，并表征制剂稳定性，Aim 3将执行 IND使能药理学和毒理学研究。最终可交付成果将是提交IND申请， FDA和执行第一次在人类临床研究与这种局部滴眼液的OGVHD。