SynthoPlate: Intravenous Hemostatic Nanotechnology to Mitigate Bleeding in Thrombocytopenia

项目摘要/摘要 人体血液中正常的血小板计数为150,000-400,000/μL，这些血小板负责有效地 监测止血和减轻体内出血。血小板减少症(TCP，低血小板计数)是一种 由于血小板生成减少、血小板破坏或消耗增加而引起的疾病，或 脾隔离症增多。年龄调整后的免疫性血小板减少性紫癜(ITP)患病率为 据估计，在美国，每100,000人中有3.3人感染，而药物引起的TCP影响每100,000人中有1-2人。 大多数(&gt；95%)的tcp病例是由自身免疫紊乱引起的或由化疗和化疗引起的。 放射疗法以及其他药物。在血小板计数50,000/μL，外科手术是 合并高出血风险和任何轻微损伤都可能导致大量出血。在Counts&lt；10,000/μL， 自发性出血成为一个主要问题。因此，频繁的治疗和预防血小板 需要输血以增加血小板数量并降低出血风险。然而，可用 天然血小板产品严重受限于近乎静止的捐献者和非常短的保质期(3-5天)。 由于细菌污染和储存相关的血小板活化和脱颗粒的高风险。因此， 临床上对一种能够减少出血并发症的治疗剂的需求还远远没有得到满足。 在减少污染和延长货架期的同时，不影响TCP患者的静脉注射 功能。为此，我们开发了一种名为SynthoPlateTM的合成止血纳米技术， 模仿血小板在体内损伤部位的黏附和聚集能力。在这个项目的第一阶段 SBIR，我们在体外和体内的概念验证TCP中展示了类似于血小板的止血功能 出血的小鼠模型。在拟议第二阶段研究的基础上，我们的目标是：1)建立适当的 监测血小板减少症患者血液中SP疗效的临床生物标志物，2)确定 SynthoPlateTM在兔出血模型中的有效药效给药窗 血小板减少，以及3)建立SP在健康人和血小板减少患者中的药代动力学(PK)谱 (Tcp)兔。总之，这些实验将建立和关联PK与体外功能分析和 体内帕金森病指导临床评价。此阶段第二阶段计划的成功将用于生成目标产品 简介(TPP)，它将指导临床方案设计，以及帮助筹集后续资金和伙伴关系 从多个潜在来源进行产品开发。在这些成果的基础上，第三阶段将实施 使用GMP生产的SP进行IND药物/毒性研究的定义剂量指南，从而 提交IND申请进行临床评估的进展情况。

Project Summary/Abstract The normal platelet count in human blood is 150,000-400,000/μL, and these platelets are responsible for efficient hemostatic surveillance and bleeding mitigation in the body. Thrombocytopenia (TCP, low platelet count) is a condition caused by a decrease in platelet production, increase in platelet destruction or consumption, or increase in splenic sequestration. The age-adjusted prevalence of immune thrombocytopenic purpura (ITP) is estimated to be 3.3 per 100,000 persons in the USA, while drug-induced TCP affects 1-2 per 100,000 persons. The majority (>95%) of TCP cases result from autoimmune disorders or are induced by chemo- and radiotherapies as well as other pharmaceuticals. At platelet counts <50,000/μL, surgical procedures are complicated by high bleeding risks and any minor injury may lead to excessive bleeding. At counts <10,000/μL, spontaneous bleeding becomes a major concern. Therefore, frequent therapeutic and prophylactic platelet transfusions are required to increase platelet counts and mitigate bleeding risks. However, the availability of natural platelet products is severely limited by a near-static pool of donors and a very short shelf-life (3-5 days) due to high risks of bacterial contamination and storage-related platelet activation and degranulation. Therefore, there exists a significant unmet clinical need for a therapeutic agent that can mitigate bleeding complications intravenously in TCP patients, while allowing reduced contamination and long shelf-life without compromising function. To this end, we have developed a synthetic hemostatic nanotechnology, called SynthoPlateTM, that mimics platelet’s ability to adhere and aggregate specifically at a site of injury in the body. In Phase I of this SBIR, we demonstrated platelet-mimetic hemostatic functions in vitro as well as in vivo in proof-of-concept TCP murine models of bleeding. Building on this in the proposed Phase II studies, we aim to: 1) Establish appropriate clinical biomarkers for monitoring SP efficacy in thrombocytopenic (TCP) patient blood samples, 2) determine the effective pharmacodynamic (PD) dosing window of SynthoPlateTM in a rabbit bleeding model of thrombocytopenia, and 3) establish the pharmacokinetic (PK) profile of SP in healthy and thrombocytopenic (TCP) rabbits. Altogether, these experiments will establish and correlate PK with ex vivo functional assays and in vivo PD to guide clinical evaluation. Success in this Phase II proposal will be used to generate a Target Product Profile (TPP), which will guide clinical protocol design, as well as aid in raising follow-on-funding and partnerships for product development from multiple potential sources. Building on these results, Phase III will implement defined dosage guidelines for IND-enabling Pharm/Tox studies with GMP-manufactured SP and thereby progress towards submitting an IND application for clinical evaluation.