Translational development and clinical evaluation of a bioengineered human lung graft for clinical transplantation

Xylyx Bio, in collaboration with leading lung transplant physician-scientists at Vanderbilt University Medical Center (VUMC), is advancing the development of Inspirex® Lung – a bioengineered human lung graft – to address the critical shortage of donor lungs for transplant. This SBIR Direct-to-Phase II project aims to obtain Investigational New Drug (IND)-enabling safety and efficacy data for Inspirex® Lung, including first-in-human transplantation studies. The project builds on significant prior scientific achievements with our patented Xenogeneic Cross-circulation (XC) Platform and demonstrated feasibility to bioengineer lung grafts from damaged/discarded human donor lungs using a porcine bioreactor. We have demonstrated the ability to generate transplantable bioengineered lung grafts from discarded human donor lungs, and shown robust graft function despite presence of residual porcine immune components. The U.S. faces a dire shortage of donor lungs, with over 400,000 patients annually dying from end-stage lung disease, and only 1 in 5 donor lungs meeting transplant criteria. Current approaches to increase the availability of lungs for transplant include ex vivo lung perfusion (EVLP) devices, decellularized/recellularized lung scaffolds, 3D bioprinted lungs, and xenotransplantation of pig lungs into humans; however, none of these approaches have shown significant clinical impact on the number of lung transplants. Using swine in a novel role as a ‘bioreactor’ to bioengineer human lungs, Xylyx aims to double the utilization rate of donor lungs, potentially eliminating waitlist deaths and significantly expanding patient access to lung transplantation. The proposed research is organized into three specific aims: (1) Assess clinical quality and safety of bioengineered lung grafts in preparation for human use, including immune responses, pathogen surveillance, and graft health; (2) Establish specifications of the XC porcine bioreactor to support optimal lung graft bioengineering, including minimizing residual porcine cells and cross-species immune responses using pharmacologic, mechanical, and genetic approaches; (3) Evaluate safety and efficacy of bioengineered lung grafts after first-in-human clinical transplantation. Expected outcomes include comprehensive graft quality and safety assessments, with successful clinical transplantation as a project milestone and major value inflection point. Xylyx has made significant progress toward commercialization, securing intellectual property and a worldwide exclusive license, establishing a strategic partnership with VUMC and other transplant centers, and engaging key stakeholders (regulatory, reimbursement, surgeons, patients/advocates, bioethicists, public relations, et al.). Xylyx is poised to lead the clinical translation of this groundbreaking technology, with the goal of submitting an IND application, sponsoring additional clinical trials, and ultimately marketing Inspirex® Lung grafts as a breakthrough life-saving treatment for patients in need of new lungs. With a $5.5 billion U.S. organ transplant market, projected to grow to $11.2 billion by 2032, Inspirex® Lung has the potential to transform the field of lung transplantation and improve outcomes for patients with chronic lung disease. Project Number: 1R44HL182545-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: John O'Neill (+2 co-PIs) | Institution: XYLYX BIO, INC., BROOKLYN, NY | Award Amount: $1,266,937 | Activity Code: R44 | Study Section: Special Emphasis Panel[ZHL1 CSR-D (M1)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R44HL18254501