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 Lyst Therapeutics is to de-risk the use of anti-LYST therapy to inhibit the formation of adhesions after cardiac surgery. In this proposal, we will investigate the use of cell- targeting and 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 heart 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.
Public Health Relevance Statement: NARRATIVE Congenital cardiac anomalies are the most common birth defect and a leading cause of death in the newborn period. Severe forms of congenital cardiac anomalies require multiple reconstructive surgeries. Unfortunately, complications arising from the development of adhesions are a significant cause of postoperative morbidity and mortality. The development and translation of a safe and effective strategy to prevent the development of cardiac adhesions without adversely effecting wound healing holds great promise for advancing the field of congenital heart surgery and improving outcomes of infants requiring repeat surgical intervention.
Project Terms: Adhesions; Adverse effects; Anesthetics; Antibodies; Area; Attenuated; base; bench to bedside; Binding; Blood Platelets; Bone Marrow; Businesses; Cardiac; Cardiac development; Cardiac Surgery procedures; Cause of Death; Cells; Child; Childhood; CHS protein; CHS1 gene; Cicatrix; Clinical; Collaborations; commercialization; Common Ventricle; comparative efficacy; Congenital Abnormality; Congenital Heart Defects; congenital heart disorder; cost; Coupled; Defect; design; Development; Dissection; Drug Delivery Systems; Ensure; FDA approved; Fibrin; Genes; head-to-head comparison; Health Expenditures; Heart; Heart failure; Heart Ventricle; Hemorrhage; Hospitalization; Iatrogenesis; Immunoglobulin G; Immunologics; Immunomodulators; immunoregulation; Immunotherapy; Impairment; improved; improved outcome; Incidence; Industry Standard; infant outcome; Inflammation; Injury; Liposomes; macrophage; Medical; Mesothelial Cell; Methods; Modeling; Monoclonal Antibodies; Morbidity - disease rate; mortality; Mus; mutant; mutant mouse model; Mutation; Natural Killer Cells; Newborn Infant; novel; novel therapeutics; Ohio; operation; Operative Surgical Procedures; Outcome; Patients; Pediatric Hospitals; Performance; Pericardial body location; Pericarditis; Pericardotomy; Perioperative; Phase; Pilot Projects; Point Mutation; Population; Postoperative Complications; Postoperative Period; prevent; prophylactic; protein function; Proteins; Reconstructive Surgical Procedures; Repeat Surgery; Reporting; response; Risk; Safety; Series; Source; Sternotomy; success; surgery outcome; Systemic Therapy; Techniques; Therapeutic; Time; Tissues; Translations; Trauma; Universities; Wound Healing
