Novel Application of New PrC-210 Aminothiol to Reduce Ischemia Reperfusion Injury, Prolonging Preservation of Vascularized Composite Allografts
Abstract
The scientific objective of this proposal is to improve the preservation of vascularized composite allografts. These allografts are multiple tissues (skin, muscle, nerve, bone) transplanted as a single functional unit, such as a hand, foot, or part of the face. In the 1980s, development and commercialization of the University of Wisconsin organ preservation solution (called UW solution) transformed the field of solid organ transplantation (hearts, kidneys, livers, etc.) by preserving organs outside the body, extending their preservation time, and ultimately increasing the donor pool. The current gold standard for tissue preservation is cold (4oC/39oF), static storage in UW solution. Despite the success of this preservation solution, irreversible tissue damage due to overproduction of oxygen-free radicals in the grafted tissue remains a significant hurdle in transplantation. Thus, there is an unmet need in organ preservation for inclusion of a direct-acting (within seconds), oxygen-free radical scavenger that can detoxify in real time the oxygen-free radicals that are produced both during (1) the extended 4oC storage and (2) the warm reperfusion upon tissue implant. The rationale for this research is that real-time “scavenging” and detoxification of oxygen-free radicals will substantially improve both preservation time and ultimately the quality and success of vascular composite allografts, thereby substantially increasing the donor pool. This proposal addresses the FY19 Reconstructive Transplant Research Program focus area of advancing existing ex-vivo tissue preservation strategies to extend the timeline between procurement and transplantation, as well as the subtopic of developing novel approaches and models for perfused, hypothermic, high-subzero and low-subzero or static preservation techniques. We propose that addition of PrC-210, a newly invented oxygen-free radical scavenger, to UW solution will substantially reduce the incidence of irreversible tissue damage, both during (1) cold preservation and (2) warm reperfusion upon transplant of vascularized composite allografts. PrC-210 is the prototype of a new family of direct-acting oxygen-free radical scavengers (US Patent 9,458,100). It was tested against and significantly outperformed 13 of the most-studied scavengers or antioxidants in the published literature. Unlike traditional antioxidants that act indirectly over a period of hours to days at body temperature (37oC/98.6oF), PrC-210 directly removes oxygen-free radicals within seconds to confer 100% protection in both rodent survival and cell culture DNA protection tests. Our recently published studies showed that PrC-210 reduced oxygen-free radical damage to normal levels in mouse hearts and mouse kidneys during restricted blood flow (ischemia) and subsequent release of the restriction (reperfusion). These models are designed to imitate heart attack and post-transplant kidney failure. This proposal aims to substantially decrease irreversible tissue damage caused by oxygen-free radicals during vascular composite allograft preservation and transplant by combining PrC-210, currently the best oxygen-free radical scavenger, with UW solution. PrC-210 can be administered intravenously, orally, and topically and has been shown to have neither the side-effects of nausea and vomiting nor low blood pressure and fainting. Furthermore, PrC-210 can be sterilized, stored in injectable vials as a dried powder for over 4 years, rehydrated, and added to UW solution; or it can be administered intravenously in saline post-surgery/trauma. The anticipated clinical applications of PrC-210 are numerous, ranging from a protective agent against radiation injury (nuclear warfare, CT scan, cancer radiation therapy, space travel, etc.); heart attack; stroke; solid organ (heart, kidney, liver, etc.) and vascularized composite allograft preservation and subsequent transplantation. Results from this work will strengthen the appl
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010891
Entities
People
- Aaron M Dingle
Organizations
- United States Army
- University of Wisconsin–Madison