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

项目概要/摘要 镰状细胞病的当前疗法在很大程度上不能满足患者的需求，特别是对于镰状细胞病的管理。 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装备不良， 在这些极其痛苦和危及生命的事件中管理患者， 医疗不信任和没有有效的治疗选择。因此，我们正在开发IHP-100，用于家庭自助， 管理疼痛危机，从而赋予患者权力，并使患者远离疾病。IHP-100 是一种新的P-选择素和补体抑制剂，在发病时皮下注射给药， 疼痛危象的早期症状这是一个重大的护理模式转变，建立在我们最近的理解， 镰状细胞病理学，并结合直接的患者反馈，以提供真正有效的治疗。 IHP-100是一种新型的基于聚糖的治疗剂，旨在靶向血管闭塞性疾病的关键基础病理学， 危机（VOC）。VOC是多因素的，包括通过选择素的细胞粘附以及补体 activation.鉴于其多效性活性，聚糖是用于此类复杂病理的主要药物类别。我们 因此，他们将IHP-100设计为有效抑制P-选择素以及补体的单一药剂。 因此，IHP-100在其生物活性和最早的治疗模式方面都是高度分化的 疼痛危机的症状。 我们已经表明，IHP-100抑制P-选择素介导的细胞与发炎的内皮细胞结合，抑制 补体介导的细胞溶解，并减少汤斯镰状细胞病小鼠模型中的血管闭塞 的VOC。在拟议的工作中，我们将优化剂量水平的体内疗效，转移制造和 GMP设施的分析测试，以及完成非临床IND剂量范围探索研究。我们将 还进一步研究了IHP-100在P-选择素缺陷型Townes镰状细胞小鼠模型中的机制， 为临床开发建立基于粘附的生物标志物策略。

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.