Rho GTPase inhibitor for refrigerated platelet storage

摘要 自20世纪80年代以来，血小板输注的使用急剧增加，但一种安全、长期的血小板储存 方法仍然缺失。目前的做法是在准备后将血小板储存在20至24°C，这具有 将寿命限制在5天内，主要是因为担心细菌污染，因为冷藏 血小板导致可被宿主巨噬细胞和肝细胞识别的复杂分子损伤 对抗受体，导致输血时的吞噬和清除。在之前由NIH SBIR阶段1资助的 研究中，我们从功能上证明了小鼠、人类和恒河猴洗涤的血小板在储存时 在冷藏条件下，在存在可逆RhoA GTP酶抑制剂G04的情况下，7-14天可以完全 将功能维持到与常温保存的血小板相似的水平。我们假设这是可逆的 通过G04药物抑制剂抑制RhoA可以转化为一种新的治疗方案， 以及功能齐全的长期冷藏血小板。该项目将开发我们的产品RhoA G04的对映体S-G04，放在医用袋子里的血小板添加剂溶液中，用于 人血小板冷藏时间长达14天。基于之前与美国食品和药物管理局的讨论 ，我们的目标是评估S-G04在我们产品中的药代动力学和ADME，并 在FDA IND使能研究中确定S-G04的GLP稳定性和安全性。交付成果将包括 该产品在商业上可获得的血小板储存PAS/袋子中确定的安全性和有效性，以及 这项革命性的技术可用于所有需要输注PLT的血液中心/医院 库存，就像血浆和红细胞用品一样。

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.