Development of a LystaMab coated pericardial adhesion barrier

LystaMab 涂层心包粘连屏障的开发

• 批准号: 10009583
• 负责人: Cameron Austin Best
• 金额: $ 30.89万
• 依托单位: LYST THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-22 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10009583
• 关键词: Adhesions; Adverse effects; Anesthetics; Antibodies; Area; Attenuated; Binding; Blood Platelets; Bone Marrow; Businesses; CHS1 gene; Cardiac; Cardiac Surgery procedures; Cardiac development; Cause of Death; Cells; Child; Childhood; Cicatrix; Clinical; Collaborations; Common Ventricle; Congenital Abnormality; Congenital Heart Defects; Defect; Development; Dissection; Dose; Ensure; FDA approved; Fibrin; Genes; Health Expenditures; Hearing; Heart; Heart Ventricle; Heart failure; Hemorrhage; Hospitalization; Immunoglobulin G; Immunologics; Immunomodulators; Impairment; Implant; Incidence; Industry Standard; Inflammation; Medical; Mesothelial Cell; Methods; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Mus; Mutant Strains Mice; Mutation; Natural Killer Cells; Newborn Infant; Ohio; Operative Surgical Procedures; Outcome; Patients; Pediatric Hospitals; Pericardial body location; Pericarditis; Pericardotomy; Perioperative; Pilot Projects; Point Mutation; Population; Postoperative Complications; Postoperative Period; Proteins; Reconstructive Surgical Procedures; Repeat Surgery; Reporting; Research Institute; Risk; Safety; Series; Site; Source; Sternotomy; Techniques; Testing; Therapeutic; Time; Tissues; Translations; Trauma; base; bench to bedside; commercialization; congenital heart disorder; cost; design; head-to-head comparison; iatrogenic injury; immunoregulation; improved; improved outcome; infant outcome; macrophage; mortality; mutant; mutant mouse model; novel; novel therapeutics; operation; prevent; prophylactic; protein function; response; success; surgery outcome; wound healing

SUMMARY Despite significant advances in the surgical and medical management of congenital heart disease, congenital cardiac anomalies remain a leading cause of death in the newborn period. Most severe forms of congenital heart disease require multiple, staged surgical interventions. A significant source of the heightened morbidity and mortality associated with these operations is the development of cardiac adhesions. Adhesions are fibrous bands of scar tissue that connect two areas of the body not normally connected and arise due to unavoidable surgical trauma. Adhesions are exacerbated by excessive inflammation in the post-operative period. Dissection of adhesions significantly complicate reoperation by increasing operative and anesthetic time and amplifying the risks of perioperative bleeding and iatrogenic injury to the heart and great vessels, which are all associated with worse outcomes and increased cost. Currently there are no FDA approved products that reduce the incidence of the complications associated with reoperation in congenital heart surgery. We recently discovered that the LYST protein underlies the development of dense adhesions after cardiothoracic surgery and hypothesize that rational inhibition of LYST will attenuate excessive inflammation following surgery, thereby preventing adhesions formation. A top priority for the LYST Therapeutics is to derisk the use of anti-LYST therapy to inhibit the formation of adhesions after cardiac surgery. In this proposal, we will investigate the use of local delivery of LystaMab (a monoclonal anti-Lyst antibody) to optimize its safety and efficacy for preventing pericardial adhesions. The successful development of anti-LYST therapy to mitigate the development of cardiac adhesions would represent a novel form of rationally designed immunomodulation that could significantly improve outcomes in the pediatric congenital hear population. Development of safe and effective strategy to prevent the formation of cardiac adhesions would significantly benefit children born with congenital heart defects requiring multiple surgeries and would overcome a major barrier to progress in the field of congenital heart surgery.

总结 尽管在先天性心脏病的外科和医学管理方面取得了重大进展，但先天性心脏病仍然是一种严重的疾病。 心脏异常仍然是新生儿死亡的主要原因。最严重的先天性 心脏病需要多次、分阶段的外科手术干预。发病率升高的一个重要原因 与这些手术相关的死亡率是心脏粘连的发展。粘连是 疤痕组织的纤维带，连接身体两个通常不连接的区域，由于 不可避免的手术创伤术后过度炎症会加剧粘连 期粘连的剥离显著增加了再次手术的复杂性， 增加围手术期出血和心脏及大血管医源性损伤的风险， 这些都与更糟糕的结果和更高的成本有关。目前FDA还没有批准 降低先天性心脏病手术中再次手术相关并发症发生率的产品。 我们最近发现，LYST蛋白是高密度粘连形成的基础， 并假设合理抑制LYST将减轻过度炎症 手术后，从而防止粘连形成。LYST Therapeutics的首要任务是降低风险 使用抗LYST疗法抑制心脏手术后粘连的形成。在本提案中，我们 将研究LystaMab（单克隆抗Lyst抗体）局部给药的使用，以优化其安全性 和预防心包粘连的功效。成功开发抗LYST疗法以缓解 心脏粘连的发展将代表一种合理设计的免疫调节的新形式 这可以显著改善儿童先天性耳聋人群的预后。发展安全和 预防心脏粘连形成的有效策略将使出生时患有 先天性心脏缺陷需要多次手术，并将克服一个主要障碍，以取得进展， 先天性心脏病手术领域。