A novel approach for prevention of Bronchopulmonary dysplasia in at-risk pre-term infants

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ABSTRACT Bronchopulmonary Dysplasia (BPD) is the most common chronic respiratory disease in infants and is a devastating condition that disrupts the developmental program of the lung secondary to preterm birth. BPD affects neonates exposed to mechanical ventilation and, to date, there are no specific drugs available to prevent or treat this life-threatening condition. The pathologic hallmarks of BPD are hyperoxia-induced pulmonary inflammation, increased cell death, dysregulated angiogenic factors culminating in impaired alveolarization, dysregulated vascularization of the lung and pulmonary hypertension. AyuVis Research, Inc, is developing a novel class of low molecular weight natural oligosaccharide-derived small molecules which activate macrophage to a non-inflammatory phenotype via TLR4 signalling. In both mouse and preterm lamb BPD models, the lead candidate AVR-48 binds to TLR4 resulting in selective activation of the target cell to block inflammatory mediators in lung and upregulation of endogenous vascularization pathways improving lung vascularization/alveolization leading to improved lung function. Additionaly, it enhances production of certain host anti-inflammatory molecule such as IL-10 and growth factor VEGF with vascularization effects remaining local to lungs. AVR-48 also prevents the development of BPD associated pulmonary hypertension. We have demonstrated all these above mentioned therapeutic effects in two BPD models: intraperitoneal injection of AVR-48 prevents hyperoxia- induced BPD in a neonatal mice pup model at 10mg/kg dose and intravenous injection in invasive mechanical ventilator induced BPD in pre-term lambs at 3.0 mg/kg dose. In order to advance the lead candidate AVR-48, AyuVis is proposing three complimentary aims: (1) Determine safety and long-term efficacy in the preterm lamb model by testing whether prophylactic treatment with AVR-48 improves the long-term respiratory, cardiac and neurodevelopmental outcomes measured after 2 months of life to mimic 1-2 years of infant life; (2) Demonstrate anti-inflammatory effect of AVR-48 in human cord blood after LPS and hyperoxia challenges by measuring cytotoxicity, inflammatory and anti-inflammatory mediators and macrophage phenotypes (M1, M2, M1/M2); and (3) Determine toxicokinetic parameters in juvenile rats following GLP protocol that will be used to model human equivalent dose in clinic. These studies are expected to provide mechanistic and confirmatory efficacy data which would enable AVR-48 to progress to GMP manufacturing and file an Investigational New Drug application with the FDA.