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

基本信息

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
项目类别：
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

项目摘要

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.

概括眼移植物抗宿主病（OGVHD）是一种严重的眼表面炎症性疾病（OSID），发生接受同种异体造血干细胞移植（HSCT）的患者的特点是。干眼、睑板腺功能障碍、结膜疤痕、眼睑边缘疤痕、角膜病和角膜溃疡，导致受影响患者显着的眼部发病率和视力丧失。 OGVHD 的有效疾病缓解疗法本次 SBIR II 期拨款申请的目的是开发新的有效疗法来治疗 OGVHD 和潜在的其他 OSID。 Pulsar Life Sciences 的提案重点是开发钙/钙调蛋白依赖性蛋白激酶针对眼部疾病的激酶 2 (CaMKK2) 靶向疗法。 Eyedesis Biosciences（母公司）的 1 STTR 证明小鼠 OGVHD 与 T 细胞和 MФ 结膜浸润，这两种细胞类型之前已被证明 CaMKK2 是其中的一种局部应用工具化合物 SMIC STO-609，显着调节炎症细胞功能；降低小鼠 OGVHD 体内严重程度；并且许多化合物来自新型 SMIC 专有库 Eyedesis 发明的体外抑制 CaMKK2 活性的研究结果支持了新颖的假设。 CaMKK2 抑制剂可用于治疗 OGVHD，Eyedesis 已成功完成第一阶段目标。证明许多新型 SMIC 在体外是 CaMKK2 的有效抑制剂，大多数新型 SMIC 都表现良好局部应用于眼部时具有耐受性，两种新型 SMIC 局部给药在以下方面有效：治疗小鼠 OGVHD 在后续 2 期 SBIR 应用中，Pulsar 将完成先导化合物优化和我们提交 IND 申请所需的 IND 支持研究目标 1 将完成先导化合物优化并选择。主要候选者，Aim 2 将向合同 GMP 药品制造商和合同进行技术转让 GMP药物配方，建立CMC特性，并表征配方稳定性，目标3将执行最终成果是向 IND 提交药理学和毒理学研究。 FDA 并用这种局部滴眼液治疗 OGVHD 进行了首次人体临床研究。