Rho GTPase inhibitor for refrigerated platelet storage

用于冷藏血小板储存的 Rho GTPase 抑制剂

• 批准号: 10758680
• 负责人: Jose A Cancelas
• 金额: $ 85.87万
• 依托单位: OGB4 INC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10758680
• 关键词: Animals; Authorization documentation; Biochemistry; Birth; Blood; Blood Banks; Blood Platelets; Blood Transfusion; Blood Vessels; Canis familiaris; Clinical Trials; Coagulation Process; Complex; Cryopreservation; Data; Development; Dose; Dreams; Drug Kinetics; Equipment and supply inventories; Erythrocytes; Evaluation; Excretory function; Funding; Generations; Genes; Genetic; Guanosine Triphosphate Phosphohydrolases; HIV; Hematological Disease; Hematology; Hemorrhage; Hemostatic Agents; Hemostatic function; Hepatocyte; Hospitals; Hour; Human; In Vitro; Investigation; Kidney; Kinetics; Lesion; Life; Macaca mulatta; Macrophage; Malignant Neoplasms; Marketing; Measures; Medical; Medical center; Metabolic; Metabolic Pathway; Methods; Microsomes; Modeling; Molecular; Monkeys; Mus; Oncology; Operative Surgical Procedures; Patients; Pediatric Hospitals; Phagocytosis; Phagocytosis Inhibition; Phase; Phenotype; Plasma; Platelet Count measurement; Platelet Transfusion; Pregnancy; Preparation; Prevention; RHOA gene; Rattus; Reaction; Recovery; Refrigeration; Regimen; Reporting; Resuscitation; Risk; Rodent; Route; Safety; Small Business Innovation Research Grant; Survival Rate; System; Technology; Temperature; Toxic effect; Toxicology; Transfusion; Translating; Transplantation; Trauma; Trauma patient; United States Food and Drug Administration; United States National Institutes of Health; Work; authority; burn therapy; clinical development; commercialization; cost efficient; enantiomer; exposed human population; improved; in silico; in vivo; inhibitor; metabolic profile; nonhuman primate; novel; novel therapeutics; pathogen; pharmacologic; platelet storage; pre-clinical; preclinical safety; preservation; prevent; receptor; repaired; rho GTP-Binding Proteins; safety assessment

SUMMARY The use of platelet transfusions has increased dramatically since 1980s, but a safe, long-term platelet storage method remains missing. Current practice has platelets stored at 20 to 24°C after preparation, which has a limited lifetime up to 5 days primarily due to concerns about bacterial contamination, because cold storage of platelets results in complex molecular lesions that are recognized by host macrophages and hepatocyte counterreceptors, leading to phagocytosis and clearance upon transfusion. In prior NIH SBIR phase 1 funded studies, we demonstrate functionally that murine, human and Rhesus-macaque washed platelets, when stored in refrigerated conditions for 7-14 days in the presence of a reversible RhoA GTPase inhibitor, G04, can fully maintain function to a level like that of room-temperature stored platelets. We hypothesize that reversible inhibition of RhoA via the G04 pharmacologic inhibitor can be translated to a new regimen for safe, cost-efficient, and fully functional long-term storage of platelets in refrigeration. This project will develop our product, the RhoA inhibitor S-G04, an enantiomer of G04, in a Platelet Additive Solution contained in a medically available bag, for human platelet cold storage up to 14 days. Based on a previous discussion with the US Food and Drug Administration (FDA), we aim to assess the pharmacokinetics and ADME of S-G04 in our product and to determine the GLP stability and safety of S-G04 in FDA IND-enabling studies. The deliverables will include an established safety and efficacy of this product in a commercially available platelet storage PAS/bag, and that this revolutionary technology can be available to all blood centers/hospitals needing PLT transfusion as a single inventory, like that for plasma and red blood cell supplies.

概括 自 20 世纪 80 年代以来，血小板输注的使用急剧增加，但安全、长期的血小板储存 方法仍然缺失。目前的做法是将血小板制备后保存在 20 至 24°C 下，其具有 使用寿命有限，最多 5 天，主要是由于担心细菌污染，因为冷藏 血小板导致复杂的分子病变，并被宿主巨噬细胞和肝细胞识别 反受体，导致输血时的吞噬作用和清除作用。在之前的 NIH SBIR 第一阶段资助中 研究中，我们从功能上证明了鼠类、人类和恒河猴在储存时可以洗涤血小板 在可逆 RhoA GTPase 抑制剂 G04 存在的情况下，在冷藏条件下保存 7-14 天，可以完全 将功能维持在与室温储存的血小板相似的水平。我们假设可逆 通过 G04 药物抑制剂抑制 RhoA 可以转化为一种新的治疗方案，以实现安全、经济高效、 以及功能齐全的血小板冷藏长期储存。该项目将开发我们的产品 RhoA 抑制剂 S-G04，G04 的对映体，存在于医用袋中的血小板添加剂溶液中，用于 人血小板冷藏长达 14 天。基于之前与美国食品药品监督管理局的讨论 管理（FDA），我们的目标是评估我们产品中 S-G04 的药代动力学和 ADME，并 确定 S-G04 在 FDA IND 支持研究中的 GLP 稳定性和安全性。可交付成果将包括 已确定该产品在市售血小板储存 PAS/袋中的安全性和有效性，并且 这项革命性的技术可用于所有需要 PLT 输血的血液中心/医院 库存，例如血浆和红细胞供应品的库存。