Development of a novel disease-modifying glycan therapeutic for early at-home intervention of acute vaso-occlusive crisis in sickle cell disease

项目摘要/摘要 目前治疗镰状细胞病的方法很大程度上不能满足患者的需要，特别是在治疗镰状细胞病方面。 与这种毁灭性疾病相关的急性疼痛危机。医疗保健系统在很大程度上没有为 在这些极其痛苦和危及生命的事件中管理患者，让患者 医疗不信任，没有有效的治疗选择。因此，我们正在开发适用于家庭自助的IHP-100 管理疼痛危机，从而增强患者的能力，并提供显著的疾病自由。IHP-100 是一种新型的P-选择素和补体抑制剂，在发病时皮下注射 疼痛危象的早期症状。这是一个重大的护理范式转变，建立在我们最近对 镰状细胞病理学，并结合直接的患者反馈，提供真正有效的治疗。 IHP-100是一种基于葡聚糖的新型治疗药物，旨在针对血管闭塞的关键潜在病理 危机(VOC)。VOC是多因素的，包括通过选择素和补体的细胞黏附 激活。葡聚糖具有多效性，是治疗这种复杂病理的主要药物类别。我们 因此，他们设计了IHP-100作为单一药物，有效地抑制P-选择素和补体。 因此，IHP-100在其生物活性和最早的治疗范例方面都具有很高的差异性 疼痛危机的症状。 我们已经证明，IHP-100抑制P-选择素介导的细胞与炎症的内皮细胞结合，抑制 补体介导的细胞溶解和减少汤斯镰状细胞病小鼠模型中的血管闭塞 挥发性有机化合物。在拟议的工作中，我们将优化体内疗效、转移制造和 分析测试到GMP设施，并完成非临床IND使剂量范围发现研究。我们会 还进一步研究了IHP-100在P-选择素缺乏的汤斯镰状细胞小鼠模型中的作用机制，以及 建立以黏附为基础的临床发展生物标记物策略。

PROJECT SUMMARY/ABSTRACT Current therapies for sickle cell disease largely fail to meet patient needs, particularly for the management of acute pain crisis associated with this devastating disease. Healthcare systems are largely ill-equipped for managing patients in the midst of these extremely painful and life-threatening events, leaving patients with medical distrust and no effective treatment option. We are therefore developing IHP-100 for at-home self- management of pain crisis, thus empowering patients and providing significant freedom from disease. IHP-100 is a novel P-selectin and complement inhibitor that is administered by subcutaneous injection at the onset of early symptoms of pain crisis. This is a major paradigm shift in care that builds on our recent understanding of sickle cell pathology and incorporates direct patient feedback to provide a truly effective treatment. IHP-100 is a novel glycan-based therapeutic, designed to target the key underlying pathology of vaso-occlusive crisis (VOC). VOC is multi-factorial and includes both cellular adhesion via selectins as well as complement activation. Glycans are a prime drug class for such complex pathologies given their pleiotropic activities. We have therefore engineered IHP-100 as a single agent that potently inhibits P-selectin as well as complement. IHP-100 is therefore highly differentiated both in its biological activity and in its treatment paradigm at the earliest symptom of pain crisis. We have shown that IHP-100 inhibits P-selectin mediated cell binding to inflamed endothelium, inhibits complement-mediated cell lysis, and reduces vaso-occlusions in the Townes sickle cell disease mouse model of VOC. In the proposed work, we will optimize the dose level for in vivo efficacy, transfer manufacturing and analytical testing to a GMP facility, and complete non-clinical IND enabling dose-range finding studies. We will also further investigate mechanisms of IHP-100 in a P-selectin-deficient Townes sickle cell mouse model, and establish an adhesion-based biomarker strategy for clinical development.