University of Pittsburgh researchers have discovered that inhibition of heparanase (HPSE) in high-risk donor organs can improve the quality of organ grafts after transplantation. Using small molecules administered to organs before implantation in the recipient, HPSE can be inhibited, preventing degradation of endothelial glycocalyx (eGC) associated with post-transplant graft dysfunction. This novel ex vivo lung perfusion (EVLP) treatment could improve the quality and quantity of organs available for transplant, reduce transplant waiting lists, and dramatically improve the lives of patients with end-stage organ failure in desperate need of transplants.
Description
The number of people requiring organ transplants is increasing. However, there is a global shortage of organs suitable for transplantation. Many patients develop complications or reject organs post-transplant and require further treatment. There exists an urgent clinical need to develop methods to improve the quality and quantity of transplantable organs. Degradation of eGC in organs leads to microvascular damage and dysfunction, resulting in complications post-transplant, suggesting that preservation of eGC is a therapeutic target to improve organ quality. This novel treatment approach inhibits HPSE activity, known to promote eGC degradation, preserve eGC integrity, maintain organ quality, and improve post-transplantation outcomes.
Applications
- Lung transplant
- Other solid organ or graft transplants
Advantages
After lungs are removed from a donor, they undergo EVLP to both preserve the lungs and assess their suitability for transplant. However, EVLP can activate HPSE, which in turn induces eGC degradation.
In this novel approach, therapeutic compounds can be added to the perfusate during EVLP to inhibit HPSE and preserve organ quality, increasing the number of organs suitable for transplant. Given that EVLP is routinely performed during the transplant process, healthcare settings can readily include therapeutics into the perfusate as part of workflows.
Invention Readiness
Several HPSE inhibitors are regularly used in cancer research. In vitro studies demonstrated the potential of heparastatin (SF4) to inhibit HPSE activity with low cellular toxicity in human lung microvascular endothelial cells. In animal models, administration of SF4 via the perfusate during EVLP for 4 hours reduced HPSE activity and graft inflammation. This intervention led to improved endothelial barrier function and better oxygen exchange function following transplantation compared to heparin treatment or control animals. These results demonstrate the potential to improve organ quality as well as patient outcomes. Work is now required to optimize this approach, including conducting clinical trials and exploring the benefits of treating transplant patients with HPSE inhibitor post-surgery to reduce the risk of organ rejection.
IP Status
https://patents.google.com/patent/WO2023175581A1
