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

开发一种新型疾病缓解聚糖疗法，用于镰状细胞病急性血管闭塞危象的早期家庭干预

• 批准号: 10603870
• 负责人: John Paderi
• 金额: $ 30.15万
• 依托单位: IHP THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-05 至 2023-09-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10603870
• 关键词: Absenteeism at work; Acute; Acute Lung Injury; Acute pain management; Address; Adhesions; Affect; Allergic Reaction; Antibodies; Anxiety; Area; Binding; Biological; Biological Assay; Biological Markers; Blood; Canis familiaris; Caring; Cause of Death; Cell Adhesion; Cells; Chemistry; Chronic; Clinical; Clinical Trials Design; Complement; Complement Activation; Complement Inactivators; Complex; Cytolysis; Detection; Development; Disease; Disease model; Dose; Early Intervention; Early treatment; Endothelium; Engineering; Event; Fatigue; Feedback; Feeling hopeless; Freedom; Glutamine; Healthcare Systems; Home; In Vitro; Infusion procedures; Intervention; Ischemia; Life; Life Expectancy; Measures; Mediating; Medical; Mental Depression; Microfluidics; Migraine; Modeling; Mus; Organ; Outcome; P-Selectin; Pain; Pathology; Patients; Performance; Persons; Pharmaceutical Preparations; Phase; Polysaccharides; Positioning Attribute; Productivity; Rattus; Reporting; Route; Schools; Selectins; Self Administration; Self Management; Serum; Sickle Cell; Sickle Cell Anemia; Subcutaneous Injections; Testing; Therapeutic; Tissues; Toxic effect; Vascular Cell Adhesion Molecule-1; Work; acute chest syndrome; clinical development; design; distrust; early onset; effective therapy; empowerment; experimental study; fluorescence imaging; health care service utilization; hydroxyurea; improved; in vivo; lung imaging; manufacture; medication compliance; mouse model; novel; novel therapeutics; pain self-management; pain symptom; potential biomarker; preclinical development; prophylactic; subcutaneous; success; therapeutically effective; vaso-occlusive crisis

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.

项目摘要/摘要 当前针对镰状细胞疾病的疗法在很大程度上无法满足患者的需求，尤其是为了管理 与这种毁灭性疾病有关的急性疼痛危机。医疗保健系统在很大程度上不足 在这些极度痛苦和威胁生命的事件中管理患者，使患者患有 医疗不信任，没有有效的治疗选择。因此，我们正在开发用于家庭自我的IHP-100 疼痛危机的管理，从而赋予患者能力并提供明显的疾病自由。 IHP-100 是一种新型的P-选择蛋白和补体抑制剂，在开始时通过皮下注射给药 疼痛危机的早期症状。这是我们最近对的护理范式转变 镰状细胞病理学并纳入直接患者的反馈，以提供真正有效的治疗方法。 IHP-100是一种新型基于聚糖的治疗性，旨在针对血管熟悉的关键病理学的关键 危机（VOC）。 VOC是多因素的，包括通过Selectins以及补充的细胞粘附 激活。鉴于其多效活性，聚糖是这种复杂病理的主要药物类别。我们 因此，已将IHP-100设计为单一试剂，可有效抑制P-选择素和补体。 因此，IHP-100在其生物学活性和最早的治疗范式中都有高度区分 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结合，抑制 补体介导的细胞裂解，并减少了城镇镰状细胞病小鼠模型中的血管c体 VOC。在拟议的工作中，我们将优化体内功效，转移制造和的剂量水平 分析对GMP设施的分析测试，并完成非临床IND启用剂量范围的发现。我们将 还进一步研究了缺乏p-选择蛋白的城镇镰状细胞小鼠模型中IHP-100的机制， 建立基于粘附的生物标志物临床开发策略。