Novel Application of PrC-210 Aminothiol Free Radical Scavenger for the Protection of Vascularized Allotransplants
Abstract
Objective: This proposal addresses most of the FY21 RTRP-ATDA Focus Areas to support the development of a novel tissue protector, which reduces tissue damage and short- and long-term immunogenicity, as well as significantly prolongs the preservation time. It might also lead for new biomarkers for acute and chronic rejection. The primary objective of this proposal is to demonstrate the capacity of PrC-210 as a limb protector during all stages of vascularized allotransplantation in a clinically translatable large animal model for ischemia reperfusion injury (IRI). Rationale: Despite immunosuppressive therapy, the major hurdle of vascularized allotransplants (VCAs) is still acute rejection, which is reported to exceed 80% within the first year after transplantation. Oxidative stress and ischemic reperfusion injury (IRI) caused by free radicals is one of the key underlying reasons for the induction of acute and chronic immune response in vascularized allotransplant and solid organ transplant (SOT) and for both acute rejection and reduced long-term graft survival. The current gold standard for tissue preservation (static cold storage in organ preservation solution) is insufficient for maintaining large, complex VCAs for more than 4-6 hours. Obvia Pharmaceuticals previously developed the world’s best oxygen free radical scavenger, named the PrC210, a prototype of a new family of direct-acting oxygen free radical scavengers (US Patent 9,458,100). When tested against one another, it significantly out-performed 13 of the most-studied oxygen free radical scavengers, including major antioxidants in the published literature. Unlike traditional antioxidants that act indirectly over a period of hours to days at body temperature (37°C/98.6°F), PrC-210 directly removes oxygen free radicals within seconds, to confer 100% protection in both rodent survival and cell culture DNA protection tests. In recent, published, peer-reviewed studies, we showed that PrC-210 reduced oxygen free radical damage to normal levels in mouse hearts and mouse kidneys following IRI. It also protected kidneys and limbs during ischemic time in UW preservation solution and thereby prolonged their preservation time. PrC-210 can be used to protect injured or amputated hands or extremities during longer transportations by extending the current preservation time from a battlefield to hospitals from 4-6 hours to 8 and more hours and increases the probability of successful salvage or replantation to restore full function. It will also reduce the risk of an acute or chronic rejection in case of a transplantation and thereby increases the likelihood of successful reconstructive transplantations for amputated Service Members. The anticipated clinical uses 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 transplant (heart, kidney, liver, etc.), and limb preservation and protection. Successful completion of the proposed research will become a significant part of the necessary documentation for submission to the Food and Drug Administration (FDA) as an Investigational New Drug (IND). Following IND approval by the FDA, completion of Phase I in humans and the transplantation study of this grant, we will then be ready to pursue phase 2 clinical trials in humans.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210886
Entities
People
- William Fahl
Organizations
- United States Army