A Biocompatible Therapeutic Platform for Precise Regulation of Vascularized Composite Allotransplant Rejection via Enhanced Costimulation Blockage
Abstract
Close to 40% of combat injuries sustained in the last 15 years by Service members involved severe extremity and craniofacial trauma. Despite the best reconstructive efforts using native tissue, these injuries frequently result in need of amputations. Eighty percent of amputees are then permanently retired while experiencing amputation-related disabilities that include poor professional and social interactions. Vascularized composite allotransplantation (VCA) has become a viable approach for functional restoration and enables patients to return to a higher quality of life than that afforded by any currently available prosthesis. However, the toxic and debilitating side effects (e.g., infections, nephrotoxicity, cardiovascular disease, diabetes, and cancer) of the multi-drug immunosuppressive therapy necessary to preserve the transplanted limb from the rejection mediated by the patient immune system counterbalances its benefits and prevents widespread use. In particular, the use of calcineurin inhibitors (CNIs; tacrolimus), representing the current mainstay therapy in VCA, is associated with substantial morbidity and is relatively ineffective in preventing rejection long term. Minimizing the need for immunosuppression, or even altering the recipient’s immune system to tolerate the transplant (by replacing calcineurin inhibitors with tolerance sparing/promoting drugs), will impact the life of a multitude of Service members by pushing the benefit/risks ratio toward making VCA safer and more broadly applicable. Biologic agents such as the co-stimulation blocking Belatacept (which blocks the activation of lymphocytes) have been developed to overcome this limitation. Despite a significant reduction in side effects, clinical studies have shown that Belatacept is not as effective as an immunosuppressant. Our own studies, however, indicate that the capacity of Belatacept to regulate the immune response against a transplant can be amplified by the co-administration of the Jak-inhibitor, Tofacitinib. This combination limits the activation of the destructive arms of the immune system while promoting the function of the regulatory ones. The only limiting factors in the translation of this approach to a clinical application are the difficulties in maintaining the proper concentration of Tofacitinib in the body and the possible toxic effect associated with spikes in its concentration. To solve this problem, we propose to embrace cutting-edge advances in biomaterial design via a collaboration between three Principal Investigators with complementary expertise. The goal of our study is to optimize and demonstrate the efficacy of a novel drug delivery platform designed to suppress the rejection response in a localized and tunable fashion via a regimen that is permissive of immunomodulatory mechanisms. We propose to use a “Russian dolls” approach, where one material, lipid nanoparticles carrying Tofacitinib, is enclosed into a second biomaterial, a peptide hydrogel that can be injected in any tissue. The hydrogel is also designed to be degradable by the effector mechanisms of the rejection response. By injecting this bio-construct subcutaneously in the vascularized composite allograft, lipid nanoparticles will be released in response to the intensity of the rejection response and will deliver Tofacitinib locally and selectively to immune cells where the rejection response is initiated. Combining this with the systemic administration of the biologic, CTLA4-Ig, will render a regulated and localized synergism that our experimental data indicate is feasible and very effective in modulating the rejection response. Thanks to the manufacturing scalability of the biomaterials investigated (capable to meet the demand of clinical use), our proposal is designed to move from efficacy and optimization studies in a small animal model to a pilot study in a preclinical large animal model. All of these studies, independently from the outco
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810789
Entities
People
- Giorgio Raimondi
Organizations
- Johns Hopkins University
- United States Army