This Direct to Phase II SBIR Application is responsive to NHLBI Small Business Topics of Special Interest (therapeutics) of high programmatic interest. Preterm infants are at great risk of developing bronchopulmonary dysplasia (BPD). BPD leads to a significant impact on lifelong respiratory health. BPD is an oxidative stress- dependent disease that inhibits alveolarization and induces a combination of other pernicious processes that results in sustained states of inflammation in the lungs of preterm infants. About 15,000 BPD cases are reported per year in the US. The costs of caring for BPD patients in the Neonatal Intensive Care Unit (NICU) are over $350,000 each just in the first months of life. Such costs are over twice the amount required for NICU patients without BPD. In preliminary studies, we show that N-acetyl-lysyltyrosylcysteine amide (KYC), a novel, bioengineered tripeptide inhibitor of myeloperoxidase (MPO) toxic oxidant production, is an effective agent for improving lung growth, increasing weight gain, and improving survival in hyperoxic pups by inhibiting multiple points of a newly defined destructive inflammatory cycle initiated by supplemental oxygen (S-O2) and the tissue damage caused by S-O2. Accordingly, the goal of this Direct to Phase II proposal is to perform the preclinical safety, pharmacokinetic, pharmacodynamic, and preliminary toxicology studies necessary to generate data required for pre-IND meetings with the FDA for using KYC to treat BPD patients presenting in the NICU. In Aim 1, we will determine the efficacy of IV KYC in hyperoxic rat pups and its pharmacokinetics. Preliminary studies reveal that KYC has an excellent intravenous (IV) and subcutaneous (SQ) bioavailability in adult mice. Our previous published BPD studies utilized KYC given to hyperoxic rat pups by the intraperitoneal (IP) route. Aim 1A will be to determine the efficacy of KYC given by the IV route to hyperoxic rat pups compared to IP administration. We will examine the pups for translational effects of KYC on inflammation and lung development to confirm published IP administration findings. In Aim 1B, we will determine the pharmacokinetics (PK) of KYC in rat pups. In Aim 2, we will determine the efficacy of KYC in preterm hyperoxic rabbit kittens. We will determine the effectiveness of IV administered KYC in the 29-day gestation preterm hyperoxic rabbit kitten model of BPD. We will study the translational effects on inflammation and lung development as per Aim 1. In Aim 3, we will perform preclinical toxicology studies of KYC. Repeated-dose general toxicology studies will be carried out in juvenile rats and beagles. These studies will follow a standard design, with the assessment of clinical signs, body weight, food consumption, toxicokinetics, clinical pathology (hematology, clinical chemistry, and urinalysis), and organ weights. With data from Aims 1-3 in hand, ReNeuroGen will be prepared for both a commercialization readiness pilot program propo...