SynthoPlate: Intravenous Hemostatic Nanotechnology to Mitigate Bleeding in Thrombocytopenia

项目总结/摘要 人体血液中正常的血小板计数为150，000 - 400，000/μL，这些血小板负责高效的 止血监测和体内出血缓解。血小板减少症（TCP，低血小板计数）是一种 由血小板生成减少、血小板破坏或消耗增加引起的病症，或 脾隔离增加。免疫性血小板减少性紫癜（ITP）的年龄校正患病率为 据估计，在美国每100，000人中有3.3人，而药物引起的TCP影响每100，000人中有1-2人。 大多数（>95%）TCP病例由自身免疫性疾病引起或由化疗和化疗引起。 放射治疗以及其他药物。当血小板计数<50，000/μL时， 并发高出血风险，任何轻微损伤都可能导致出血过多。在计数<10，000/μL时， 自发性出血成为主要问题。因此，频繁的治疗性和预防性血小板减少 需要输血以增加血小板计数和减轻出血风险。然而， 天然血小板产品受到捐献者接近静态库和非常短的保质期（3-5天）的严重限制 因为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，我们认为， 对于能够减轻出血并发症的治疗剂存在显著的未满足的临床需求 在TCP患者中静脉注射，同时允许减少污染和长保质期，而不影响 功能为此，我们开发了一种合成止血纳米技术，称为SynthoPlateTM， 模拟血小板在体内损伤部位特异性粘附和聚集的能力。在第一阶段， SBIR，我们证明了血小板模拟止血功能，在体外以及在体内的概念验证TCP 出血的小鼠模型。在建议的第II期研究的基础上，我们的目的是： 用于监测血小板减少症（TCP）患者血液样品中SP功效的临床生物标志物，2）确定 家兔出血模型中SynthoPlateTM的有效药效学（PD）给药窗 血小板减少症，和3）建立SP在健康和血小板减少症患者中的药代动力学（PK）特征 (TCP)家兔总之，这些实验将建立PK并将其与离体功能测定相关联， 体内PD以指导临床评价。第二阶段提案的成功将用于生成目标产品 概况（TPP），将指导临床方案设计，并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使能Pharm/Tox研究的规定剂量指南， 提交IND申请进行临床评价的进展。

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.