A new drug to treat transplant-associated renal ischemia-reperfusion injury

PROJECT SUMMARY/ABSTRACT Renal replacement therapy is a worldwide problem. Kidney transplantation (KTx) provides significant advantages over dialysis in terms of health outcomes and quality of life. However, there is a shortage of organs given this growing population. Centers have lowered standards for acceptable transplant organs. Thus, transplantation (Tx) of kidneys that have undergone longer periods of ischemia or are from older or deceased donors is on the rise. Due to the extended hypoxia endured by these “less ideal” organs, ischemia-reperfusion injury (IRI) results upon Tx. IRI is caused by complex oxidative and inflammatory assaults on damaged ischemic cells following the reintroduction of blood flow after a period of oxygen deprivation. Tissue becomes swollen due to inflammation and vascular leakage. Microvascular thrombosis causes vascular occlusion, depriving blood supply to tissues in the newly transplanted organ. IRI leads to cell death and renal impairment, including delayed graft function (DGF) and rejection. There is a need for a therapy that reduces inflammation and thrombosis, without increasing vascular leakage and postoperative bleeding. Most drugs with potential to treat IRI induce bleeding and should not be taken in conjunction with surgery. Our overall objective is to develop a new drug for treatment of IRI associated with organ Tx, which potently inhibits both thrombosis and inflammation without causing vascular leakage and bleeding. Based on our new concept (Gong et al. Science 2010, Shen et al, Nature 2013) that Gα13-dependent outside-in signaling of the platelet integrin αIIbβ3 (GPIIb-IIIa) is selectively important in occlusive thrombosis but not hemostasis, we designed a peptide inhibitor of the Gα13- integrin interaction, M3mP6, and a novel high-loading peptide nanoparticle (HLPN) formulation for in vivo intracellular peptide delivery. In proof-of-concept studies, we have demonstrated that M3mP6 HLPN potently inhibits renal IRI caused by a pedicle clamping without causing bleeding. Importantly, M3mP6 also has anti- inflammatory effects mediated by inhibition of β2-Gα13 binding in leukocytes, thereby reducing neutrophil function. Pilot toxicology studies carried out with M3mP6 HLPN showed no toxicity. Based on these exciting new data, we propose in this Phase I SBIR application to further develop this novel drug from the proof-of-concept stage to IND for the treatment of renal IRI associated with KTx. Our specific aims are (1) Evaluate the effect of M3mP6 HLPN on KIRI-associated renal thrombosis, inflammation, and vascular leakage. (2) Characterize therapeutic efficacy of M3mP6 HLPN in an KTx IRI mouse model. (3) Scale-up method development for M3mP6 HLPN formulation. If successful, this new drug should have a major impact in further improving outcomes following renal IRI associated with KTx.