Graft-Targeted Gene Editing Strategies for Immunomodulation in VCA
Abstract
Rationale and Objectives of Research: Transplantation of hands, faces, and other “body parts” is the newest frontier of organ transplantation. Unlike organs like hearts, livers, or kidneys, these transplants do not “save lives” but rather can “improve quality of life” of patients including our wounded Service members and Veterans that suffer with devastating injuries that have no other treatment options. Also, unlike other organs, composite transplants like hand or face consist of different tissues such as skin, bone, and bone marrow among a host of other components. Since 1998, over 200 of these procedures, including over 100 hands and 30 face transplants have been performed around the world. Although there have been successes, there have been some patient deaths and, more importantly, there is the lifelong risk of immunosuppressive drugs needed by patients to prevent transplant rejection. Much of the research that has been funded by the military in these transplants has focused on new therapies such as those that use stem cells or bone marrow cells to eliminate the need for such drug treatment. Success has been scant and such therapies have yet to achieve wider feasibility. There is thus a need to investigate alternate, yet promising approaches that are safe, reliable, efficacious, and reproducible in achieving the goal of immunosuppression reduction or elimination after these transplants. Elimination of donor-recipient mismatches across these antigens in vascularized composite allotransplantation (VCA) will also result in decreased risk of graft rejection and lower overall need for immunosuppression. We propose a strategy of donor graft genomic manipulation prior to transplantation to inhibit expression of donor MHC antigens, reducing host adaptive immune responses to such antigens and consequently the need for an immunosuppression to sustain graft survival. Significance/Relevance: If it can be demonstrated that composite tissues can be genetically modified to essentially render them invisible to a recipient immune system, it would be an important advance in not just VCA, but potentially transplants as well. It would mean that the risk of immunosuppression and its attendant complications could be minimized, or eventually even eliminated altogether. This could in future radically favorably alter the risk/benefit ratio of transplantation, expand patient lifespans and well-being, and significantly expand the donor pool, as well as increase the number of patients that can be served with the existing donor pool, since graft rejection requiring re-transplantation would become increasingly rare. Applicability and Impact of Research: With the help of the current funding, we will be able to confirm for the first time in rat epigastric flap that pre-transplant genetic modification of the whole composite graft by arterial injection of Lentiviral Vector reduces immunogenicity of the graft, increases the survival of the transplanted flap, and decreases the need for immunosuppression. We believe that this strategy will reduce the adverse effects of immunosuppressive drugs in both VCA and solid organ transplantation. Our proposal is a major step in breakthrough strategies that modulate or tolerize the graft to the recipient rather than suppressing the recipient immune system towards the graft. If successful, this approach could facilitate long-term rejection-free graft acceptance/survival without lifelong immunosuppression and help benefit our wounded Service members and Veterans suffering from amputations, facial injuries, or genital injuries. This project is a partnership of civilian and military experts across multiple disciplines (transplant immunology, reconstructive surgery, and organ engineering) to bring to fruition a groundbreaking therapy that is safe, ethical, feasible, reproducible, and effective in our wounded Warriors.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910010
Entities
People
- Fatih Zor
Organizations
- United States Army
- Wake Forest University