GalT-KO Porcine Nerve Xenograft for Reconstruction of Large Nerve Gaps
Abstract
This study addresses the “Peripheral Nerve Injury” Peer Reviewed Orthopaedic Research Program focus area. Injuries to peripheral nerves can be a devastating component of a traumatic injury, resulting in pain, numbness, and paralysis of the target muscles. In high-energy trauma such as motor vehicle collision or ballistic trauma, there is often lost or devitalized tissue and a resulting nerve gap. There are several graft and conduit products that are effective for reconstruction of small nerve gaps, but ineffective in larger gaps (>3 cm). The gold standard for reconstructing large nerve gaps is autograft, or expendable nerves harvested from the patient’s own body. They contain viable schwann cells, which promote nerve regeneration. Other currently available products are either synthetic or lack cells, and they do not support regeneration to the same degree. The use of allograft, grafts harvested from human cadavers, has been investigated with some success, but availability and ethical concerns related to sourcing of human tissues discourage their use. Because no nerve reconstruction product provides efficacy comparable to autografting for long nerve defects and the amount of autologous nerve available for use as a graft material is often insufficient, functional outcomes for these injuries are generally poor. Unfortunately, injuries sustained by Soldiers at war are skewed toward the high-energy trauma mechanisms that result in large nerve gaps, often with multiple major nerves affected. In these cases, autografts are vastly inadequate in number, leaving members of the military disproportionately affected by poor outcomes from peripheral nerve injury and the currently available autograft alternatives. While development of improved nerve reconstruction options will benefit anyone with a major nerve injury, the severe nerve injuries in members of the military place them in a particular position to benefit. One possible solution lies in the field of xenotransplantation, using tissues from a nonhuman species. Nerve xenografts have previously been impossible beyond mouse studies because humans and nonhuman primates possess a preformed immune response to a molecule on the cells of other species resulting in hyperacute rejection when xenogeneic tissues are transplanted. We have developed a herd of genetically modified swine (GalT-knockout) whose tissues are able to avoid hyperacute rejection and are immunologically similar to allografts. Nerve allografts and xenografts both require some immunosuppressive therapy; however, this requirement is temporary as autologous cells migrate into the grafts over time, replacing donor cells. Conveniently, treatment with the immunosuppressant FK506 has been shown to independently promote nerve regeneration. Additionally, we have already completed proof-of-concept studies using skin from GalT-knockout swine for wound coverage in nonhuman primates, which performed equivalently to allogeneic skin grafts and for which we are preparing to begin a clinical trial. Based on this progress, this study will compare functional recovery after nerve gap reconstruction using xenograft vs. autograft with FK506 immunosuppression in a nonhuman primate model. It will also examine the effect of removing immunosuppression at the 6-month time point on recovery and graft survival. While graft rejection after withdrawal of immunosuppression is not anticipated based on small animal data, it is an important risk to characterize further. Pursuing this project will advance a promising new option for nerve reconstruction in a high-quality model of functional outcome and will result in a technology poised for subsequent clinical investigation. Following a clinical trial for GalT-KO skin grafts from this herd in 2017, along with successful completion of this and other final preclinical investigations in 2019, we plan for human clinical trials for xenogeneic nerve grafts to begin as soon as 2020.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710454
Entities
People
- Curtis L. Cetrulo, Jr
Organizations
- Massachusetts General Hospital
- United States Army