Tissue and organ transplantation procedures save and/or improve the lives of hundred of thousands of patients annually in the US. The goal of this research is to develop a local anti-complement therapy for donor organ ex vivo application that will reduce complement-induced injury to the vascular endothelium. An unavoidable consequence of transplantation (allografts or autografts) is ischemia/reperfusion (IR) injury. Studies have shown that IR-induced complement activation leads to the formation of several key inflammatory mediators that alter vascular homeostasis and stimulate leukocyte activation and chemotaxis. After decades of neglect, complement has been rediscovered as a potent mediator of inflammation and rejection in organ transplants. In Phase I of this proposal, we successfully provided proof-of-concept that our novel therapy reduced complement deposition in vitro after activation of the classical pathway. Our therapy is based on a platform technology that allows the rapid display of protective exogenous proteins on the surface of cells during organ harvest. The goal in Phase II is to prepare the technology for clinical use. This will be accomplished by developing safe and stable lyophilized components, which upon reconstitution, are perfused into organs ex vivo to effectively reduce locally complement mediated injury in vivo. The technical objectives are: 1) Reduce cost of therapeutic formulations by using the most economical components without compromising anti-complement efficacy. 2) Determine potential toxicity of therapy and demonstrate its efficacy in a kidney rat model of IR. 3) Develop stable lyophilized therapeutic components for storage and demonstrate in vitro that reconstituted components are just as effective as freshly prepared components. 4) Demonstrate in kidney rat models of IR and transplantation that lyophilized products are effective in reducing antigen-independent and antigent-dependent IR injury. If successful these studies will demonstrate the potential clinical value of our therapy in enhancing natural anti-complement defenses in allografts. Our therapy will be applied during routine flushes of donor organs and will achieve therapeutic levels of drug locally without systemic adverse effects. Application of our therapy may extend the donor pool by allowing organ harvest from non-beating heart donors. Our approach is a faster alternative to gene therapy, in that proteins can be displayed on the cell membranes in less than 1 hour. The economic implications for this novel therapeutic approach in transplantation are vast, not only in terms of the potential benefits to patients but also in reducing health care costs associated with re-operations and complications arising from failed procedures. ? ? Public Health Relevance: The goal of this project is to develop a new targeted therapy that prevents damage to transplanted organs. An unavoidable inherent problem of transplantation is that blood flow during organ harvest must be cutoff and later reestablished during implantation. This process causes the activation of the immune component called the complement system, which causes unintended tissue injury that ultimately leads to organ malfunction and failure. Anti-complement agents that are administered systemically have been developed but their use leaves transplant recipients vulnerable to viral and bacterial infections. EndoProtech, Inc. is proposing to develop a novel safer anti-complement therapeutic agent that binds to cells of transplanted organs and eliminates systemic circulation of the agent. The therapy is applied during harvest while organs are outside the body before implantation. The objective is to protect tissues from complement-related injury with minimal side effects. ? ? ?
| Fensterer, Tathyana F; Miller, Cynthia J; Perez-Abadia, Gustavo et al. (2014) Novel cuff design to facilitate anastomosis of small vessels during cervical heterotopic heart transplantation in rats. Comp Med 64:293-9 |
| Fensterer, Tathyana F; Keeling, W Brent; Patibandla, Phani K et al. (2013) Stabilizing endothelium of donor hearts with fusogenic liposomes reduces myocardial injury and dysfunction. J Surg Res 182:331-8 |
| Pushpakumar, Sathnur B; Perez-Abadia, Gustavo; Soni, Chirag et al. (2011) Enhancing complement control on endothelial barrier reduces renal post-ischemia dysfunction. J Surg Res 170:e263-70 |
