Reengineering Fibroblast Growth Factor 2 to Address Allograft Vasculopathy

About This Grant

PROJECT SUMMARY The success of solid organ transplantation (Tx) is limited by immune-mediated rejection, with allograft vasculopathy (AV) being a significant cause of long-term graft loss. Endothelial cell (EC) barrier damage inevitably occurring during Tx triggers a cascade of immunological responses culminating in AV. Re- transplantation is the only potential treatment for graft failure from AV. This represents an unmet need for innovative strategies to protect ECs and prevent AV. To address this, we prepared bioactive supramolecular peptide amphiphile nanofibers displaying a fibroblast growth factor-2 mimetic signal (FGF-2 PA). FGF-2 is a therapeutic agent regulating EC barrier function, and PAs are supramolecular nanostructures emerging as promising drug delivery platforms for regenerative medicine. We previously demonstrated the bioactivity of FGF-2 PAs in inducing EC proliferation and migration. Using the murine allogeneic aortic Tx model as a surrogate for studying AV in solid organs, our data demonstrated that ex vivo pre-treatment of donor aortas with FGF-2 PA reduced AV but did not eliminate it. Given the therapeutic potential of FGF-2 PAs, we propose engineering novel supramolecular polymers that display both the FGF-2 mimetic and collagen-binding sequences (cFGF-2 PA). Collagen is the dominant structural component of the EC extracellular matrix and is exposed and immunogenic when the EC barrier is damaged during organ Tx. By targeting the supramolecular nanostructures to exposed collagen in the damaged EC barrier, localized and enhanced bioactivity of FGF-2 can be achieved. Collectively, our data led us to hypothesize that ex vivo pre-treatment of donor allografts with cFGF-2 PAs will protect the EC barrier, thereby mitigating early injury and preventing AV. We propose utilizing an ex vivo pre-treatment strategy, as inevitable damage to the EC barrier in donor allografts occurs during organ procurement and preservation. In Aim 1, the biodistribution, mechanism, and therapeutic efficacy of cFGF-2 PAs in ex vivo pre-treated donor aortas will be investigated to enhance the EC barrier and mitigate early allograft ischemic injury in the murine aortic Tx model. In Aim 2, the therapeutic efficacy of ex vivo pre-treated donor organs will be investigated to prevent AV in murine aortic and heart Tx models. Additionally, its synergistic effect with the recipient sub-therapeutic immunosuppression regimen will be tested to abrogate AV further. Damage to the donor EC barrier is inevitable during Tx, and donor organ pre-treatment regimens are not currently used clinically. Treating the allograft before implantation could minimize the maintenance immunosuppression regimen for the recipient, leading to improved overall graft and patient longevity. Therefore, this study will provide proof of concept and the clinical feasibility of pre-treating donor allografts prior to Tx as a therapeutic strategy to abrogate AV. This study will also support R01-level funding to demonstrate the therapeutic feasibility of maintaining the EC barrier in Tx during organ preservation, leading to a paradigm shift in the current standard of donor organ preservation in Tx.