Targeting integrin outside-in signaling for treating sepsis

靶向整合素由外向内信号传导治疗脓毒症

基本信息

批准号：
10625353
负责人：
Randal A Skidgel
金额：
$ 58.21万
依托单位：
DUPAGE MEDICAL TECHNOLOGY, INC.
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10625353
关键词：
Acute Respiratory Distress Syndrome Adult Affect Animal Model Antibiotics Bacterial Infections Binding Blood Blood Platelets Blood Vessels CD18 Antigens COVID-19 mortality Cause of Death Cells Clinical Treatment Clinical Trials Coagulation Process Cytoplasmic Tail Data Development Disseminated Intravascular Coagulation Drug Delivery Systems Drug Kinetics Drug Targeting Endotoxemia Extravasation FDA approved Functional disorder GTP-Binding Proteins Generations Hemorrhage Hemostatic Agents Hemostatic function Hypoxia ITGB3 gene Impairment Infection Inflammation Inflammatory Influenza Injury Integrin Signaling Pathway Integrin beta Chains Integrins Leucocytic infiltrate Leukocytes Life Ligand Binding Lipids Lung Marketing Medical Methods Modeling Multiple Organ Failure Mus Nature Neutrophil Infiltration Organ Patients Peptides Permeability Pharmaceutical Preparations Pharmacotherapy Phase Preparation Production Protein Subunits Protocols documentation Pulmonary Edema Reaction Recombinants Regimen Research Research Personnel Risk SARS-CoV-2 infection Safety Science Sepsis Shock Signal Transduction Small Business Innovation Research Grant Survival Rate Thrombin Thrombosis Toxic effect Virus Diseases Withdrawal activated Protein C cecal ligation puncture design drotrecogin alfa drug development efficacy evaluation fighting improved in vivo influenza epidemic inhibitor innovation manufacturing scale-up mortality mouse model myristoylation nanoparticle nanoparticle drug new therapeutic target novel novel therapeutics phase 1 study preservation prevent scale up sepsis induced ARDS septic standard care success systemic inflammatory response tissue injury

项目摘要

In severe sepsis, systemic inflammation induced by infection leads to vascular leakage, microvascular thrombosis, disseminated intravascular coagulation (DIC), multiple organ dysfunction, hemorrhage and circulatory collapse, resulting in high mortality. Antibiotics and standard care regimens are helpful, but ultimately ineffective for many patients. Despite years of intensive research, the only new drug FDA approved for treatment of sepsis is activated protein C (APC, Xigris®), which prevents thrombosis and reduces inflammation by inhibiting thrombin generation. However, Xigris also causes hemorrhage, which outweighed its benefits and resulted in withdrawal from the market. Thus, there is an urgent unmet need for new life-saving treatment of sepsis. Here, we propose to develop a new drug for sepsis treatment, which potently inhibits both thrombosis and inflammation without causing bleeding. This innovative drug targets a novel integrin signaling mechanism recently discovered in the lab of Xiaoping Du, co-investigator of this application (Gong et al Science 2010, Shen et al, Nature 2013, Shen MBoC 2015, Pang Blood 2018), who showed that integrin outside-in signaling requires direct interaction between the G protein subunit Galpha13 and an ExE motif conserved in the cytoplasmic domain of several integrin Beta subunits (including Beta3 in platelets and Beta2 in leukocytes). Disruption of Galpha13-integrin interaction abolishes outside-in signaling without affecting the ligand binding function of integrins important for hemostasis. We designed a selective peptide inhibitor of the Beta3 Galpha13 binding ExE motif that potently inhibited occlusive intravascular thrombosis without causing excessive bleeding (Shen et al, Nature, 2013). Because integrin outside-in signaling is critical not only in thrombosis but also in inflammation, we designed an ExE motif peptide, MB2mP6, that inhibits Galpha13 interaction with Beta3 integrins in platelets and also Beta2 integrins in leukocytes. In Phase I studies, we showed that treatment of mice with MB2mP6 immediately after or 6 h after sepsis onset potently inhibits inflammation and thrombosis in septic mice, significantly reducing mortality. This drug also protects lungs from vascular leakage and microthrombosis that can lead to ARDS, a severe consequence of sepsis and a major cause of mortality of SARS-coronavirus 2 infection (COVID19) as well as influenza. Importantly, this new drug did not exacerbate hemorrhage induced by either physical injury or inflammation. We further developed novel lipid-stabilized high-loading peptide nanoparticles (HLPN) for efficient in vivo drug delivery. In this Phase II application, we propose to (1) Evaluate the efficacy of MB2mP6 as an adjunct to antibiotics and standard care in treating sepsis and ARDS following bacterial and viral infection. (2) Evaluate the safety (absence of anti-hemostatic activity) and toxicity of MB2mP6 (3) Scale up production of a GMP-grade new drug and IND preparation and submission. This novel drug that targets thrombosis and excess inflammation, without impairing hemostasis and vascular integrity, holds promise for treating sepsis as well as ARDS arising from sepsis as well as viral infections.

在严重脓毒症中，感染引起的全身炎症导致血管渗漏、微血管血栓形成、弥散性血管内凝血（DIC）、多器官功能障碍、出血和循环衰竭，导致高死亡率。抗生素和标准护理方案虽然有帮助，但最终无效。尽管经过多年的深入研究，FDA 批准用于治疗脓毒症的唯一新药是活化蛋白 C（APC、Xigris®），它通过抑制来预防血栓形成和炎症。然而，Xigris 也会导致出血，这超过了其益处并导致其退出市场。因此，迫切需要开发一种治疗脓毒症的新药。这种创新药物可有效抑制血栓形成和炎症，且不会引起出血。 2010, Shen et al, Nature 2013, Shen MBoC 2015, Pang Blood 2018），他们表明整合素由外向内信号传导需要 G 蛋白亚基 Galpha13 和几个整合素 Beta 亚基胞质域中保守的 ExE 基序之间的直接相互作用（包括血小板中的 Beta3 和白细胞中的 Beta2）。消除由外向内的信号传导，而不影响对止血重要的整合素的配体结合功能。我们设计了一种 Beta3 Galpha13 结合 ExE 基序的选择性肽抑制剂，可有效抑制闭塞性血管内血栓形成，而不会导致过度出血（Shen 等人，Nature，2013）。由于整合素由外而内的信号传导不仅在血栓形成中至关重要，而且在炎症中也至关重要，因此我们设计了一种 ExE 基序肽 MB2mP6，它可以抑制Galpha13 与血小板中的 Beta3 整合素以及白细胞中的 Beta2 整合素相互作用。在 I 期研究中，我们表明在脓毒症发作后立即或 6 小时后用 MB2mP6 治疗小鼠可有效抑制脓毒症小鼠的炎症和血栓形成，从而显着降低死亡率。还可以保护肺部免受血管渗漏和微血栓形成的影响，这些血管渗漏和微血栓可能导致急性呼吸窘迫综合征（ARDS），这是脓毒症的严重后果，也是导致患者死亡的主要原因重要的是，这种新药不会加剧由身体损伤或炎症引起的出血。我们进一步开发了新型脂质稳定的高负载肽纳米颗粒（HLPN），用于有效的体内药物。在此 II 期应用中，我们建议 (1) 评估 MB2mP6 作为抗生素和标准护理的辅助治疗细菌和病毒感染后败血症和 ARDS 的疗效。（2）评估MB2mP6的安全性（无抗止血活性）和毒性。（3）扩大GMP级新药的生产和IND准备和提交，该新药针对血栓和过度炎症，且不损害止血。和血管完整性，有望治疗脓毒症以及脓毒症和病毒感染引起的急性呼吸窘迫综合征。