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.

在严重的败血症中，感染引起的全身性炎症会导致血管泄漏，微血管血栓形成，散布的血管内凝血（DIC），多器官功能障碍，出血和回路塌陷，导致高死亡率。抗生素和标准护理方案很有帮助，但最终对许多患者无效。尽管经过多年的深入研究，但唯一批准用于治疗败血症的新药是激活的蛋白C（APC，XIGRIS®），可通过抑制凝血酶产生来防止血栓形成和减少感染。但是，Xigris还会引起出血，这超过了其益处，并导致从市场上退出。这是急需对败血症挽救生命的新疗法的未满足的需求。在这里，我们建议开发一种用于败血症治疗的新药，该药物可能会抑制血栓形成和炎症而不会引起出血。 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 configured in the cytoplasmic domain of several integrin β亚基（包括血小板中的beta3和白细胞中的beta2）。 galpha13-整合素相互作用的破坏会消除外部信号传导，而不会影响整联蛋白对止血重要的配体结合功能。我们设计了beta3 galpha13结合基序的选择性肽抑制剂，该基序有可能抑制闭塞性血管内血栓形成而不会导致过多的出血（Shen等，Nature，Nature，2013）。由于整联蛋白外部信号传导不仅在血栓形成中，而且在炎症中至关重要，因此我们设计了EXE基序肽MB2MP6，它抑制了galpha13在血小板中与Beta3整合素的相互作用，在白细胞中也抑制了beta2整合蛋白。在第一阶段的研究中，我们表明败血症发作后或6小时后用MB2MP6治疗小鼠可能会抑制化粪池小鼠的感染和血栓形成，从而大大降低死亡率。该药物还可以保护肺免受可导致ARDS的血管渗漏和微栓塞性，这是败血症的严重后果，也是SARS-核负病毒2感染（COVID19）以及影响力的主要原因。重要的是，这种新药不会加剧由于身体损伤或感染引起的出血。我们进一步开发了新型的脂质稳定的高加载肽纳米颗粒（HLPN），以有效地体内药物递送。在此II阶段应用中，我们建议（1）评估MB2MP6作为抗生素和标准护理的效率，以治疗细菌和病毒感染后治疗败血症和ARDS的效率。（2）评估MB2MP6的安全性（缺乏抗震荡活性）（3）扩大了GMP级新药的产生以及IND的准备和提交。靶向血栓形成和过量炎症的这种新型药物，而不会损害止血和血管完整性，这有望治疗败血症以及由败血症以及病毒感染引起的疾病。