A Novel Enzyme Replacement Therapy for Robust Hypoxia Tolerance and Mitigation of Reperfusion Injury in Vascularized Composite Allotransplantation
Abstract
Organ transplantation is a definitive intervention for the management of solid organ failure, most notably heart, kidney, liver, and lung. The success of solid organ transplantation has led several clinical teams to apply this technology to patients with unreconstructable injuries such as severe burns or limb amputation and is now known as a vascularized composite allotransplantation (VCA). Currently, most reconstructive procedures for major tissue defects due to trauma, tumor removal, or congenital anomalies are performed with autologous (the patients own) tissue. However, there are severe defects that cannot be reconstructed this way. In complex injuries or defects not amenable to conventional reconstruction, VCA could potentially achieve near-normal tissue restoration and improved functional and esthetic outcomes. VCA refers to the transplantation of multiple tissues such as muscle, bone, nerve, and skin as a functional unit (e.g., a hand or face) from a deceased donor to a recipient with a severe injury. These grafts serve as potential replacements for traumatic tissue losses such as limb loss from explosive devices, accidents with farm machinery, burns, or other major injuries. VCAs tolerate limited hypoxia without blood supply and require rapid reestablishment of blood flow and donor-recipient matching. VCAs are thus identical to transplanted organs (governed by UNOS regulations) rather than tissue (for which none of these stipulations apply) and have unique characteristics for regulatory purposes. During the past decade, over 200 patients have received a VCA worldwide. However, in VCA, unlike organs, matching the skin color, tone, gender, and size of the graft, in addition to blood type between donor and recipient, further limits suitable donors. Also, subsequent efforts to streamline allocation and improve recipient matching may indeed mandate donor VCA sharing across wider geographic distances, increasing ischemia times. Thus, any measures to increase the donor pool will significantly impact not only solid organs but also, more importantly, VCA. Novel strategies such as induction of specific fructose metabolic pathways in VCA muscle tissue by enzyme replacement therapy (ERT) with KHK-C can promote utilization of fructose as the preferred energy substrate during ex vivo preservation and effectively prolong the procurement-to-transplant window of VCA up to 24 hours.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910643
Entities
People
- Fatih Zor
Organizations
- United States Army
- Wake Forest University