Efficacy and pharmacokinetic assessment of renal-targeted therapy in a pig model of cisplatin induced acute kidney injury.

PROJECT SUMMARY Acute kidney injury (AKI) is a common clinical condition associated with increased morbidity and mortality. AKI accounts for approximately 2% of hospital admissions in the US, and the annual costs for hospital-acquired AKI are approximately $10 billion. Therapeutic interventions for all forms of AKI remain inadequate, in part due to low drug specificity and poor pharmacokinetic profiles. We have developed a novel nanoscale drug delivery platform that selectively targets the proximal tubular epithelium in rodents (Williams, Nano Letters, 2015; Williams, Hypertension, 2018). This strategy localizes drugs up to 26-fold more efficiently in mouse kidneys than any other organ. The particles release their drug cargo within the proximal and distal tubules while exhibiting no toxic effects on the kidneys or other organs. We and our collaborators have successfully treated murine models of both cisplatin-induced AKI (CI-AKI) and ischemia-reperfusion-induced AKI (IR-AKI). Specifically, we administered mesoscale nanoparticles loaded with the reactive oxygen species (ROS) scavenger edaravone, resulting in striking efficacy against a murine CI-AKI model using a dose of edaravone that was approximately 154 times lower than that previously shown to treat AKI systemically in a rodent model (Williams, bioRxiv, 2020). Further, the platform demonstrated effective treatment against IR-AKI in mice via delivery of either an immunomodulatory oligonucleotide (Han, Kidney International, 2020) or a peptide modulator of NF-κB (Han, JCI Insight, 2020). The data presented in our published studies along with preliminary data in this proposal demonstrate that this mesoscale nanoparticle (MNP) platform exhibits exceptional clinical potential. The overall goal of our company is to address the unmet need for treatment strategies for renal diseases by targeting both approved and experimental therapeutic payloads to the kidneys. The objective of this proposal is to evaluate the pharmacokinetic, biodistribution and efficacy of edaravone-encapsulated MNPs in a pig model of cisplatin- induced AKI. We will pursue the following specific aims: Aim 1: Assess Pharmacokinetics and Biodistribution of Edaravone-Loaded MNPs in a Porcine AKI Model. We will evaluate the pharmacokinetics and biodistribution of edaravone-loaded mesoscale nanoparticles in a pig model of AKI. Aim 2: Assess Efficacy and Safety of Edaravone-Loaded MNPs in a Porcine AKI Model. We will determine efficacy and safety of edaravone-MNPs and compare with soluble edaravone in a cisplatin-induced pig AKI model. The outcomes of this Phase I SBIR include an assessment of the biodistribution, pharmacokinetics and efficacy of edaravone-MNPs in pigs as the best characterized large-animal model to approximate human renal physiology. This work will substantially de- risk this technology. It will also allow the company to initiate CMC and IND-enabling studies and will set the stage for planning appropriate clinical trials in AKI patients.PROJECT NARRATIVE Acute kidney injury (AKI) represents a serious public health problem in the United States for which there is no effective clinical treatment. We are developing a new drug delivery strategy, mesoscale nanoparticles, to target therapies directly to the proximal tubular epithelium, where all AKI originates. This project will investigate the biodistribution, pharmacokinetics and efficacy of mesoscale nanoparticles in a porcine model of cisplatin-induced AKI as a crucial next step toward advancing this new therapeutic strategy into clinical studies in patients with AKI.