Advent Therapeutics Inc. (Advent) is a biotech company focusing on the development, reformulation and optimized delivery of legacy drugs to address serious unmet medical needs in underserved patient populations. Advent is developing an aerosol formulation of its proprietary optimized, water miscible vitamin A (vitA) palmitate for non-invasive (inhaled) delivery of the drug to preterm infants. Our innovative inhaled vitA formulation 1) avoids the drawbacks of invasive intramuscular (IM) injections, the current dosing modality, and 2) provides both direct-to-target-organ delivery to prevent bronchopulmonary dysplasia (BPD), known also as chronic lung disease (CLD) of prematurity, and systemic delivery for treating vitA deficiency (VAD) in premature neonates. Our preliminary in vitro testing shows that our vitA formulation can be efficiently aerosolized by a commercial nebulizer (Aerogen Aeroneb Pro), producing optimally sized particles for efficient inhalation dosing. Early in vivo studies with our collaborator, Dr. Virender Rehan at Harbor-UCLA Medical Center, in a pre-weaned rat model, show that inhaled vitA leads to a rise in serum vitA levels, indicating systemic delivery. Additionally, in the lung, levels of protein and mRNA of genes involved in lung maturation are upregulated, providing direct evidence that inhaled vitA stimulates the developing lung. All metrics showed significant improvements in these early studies. Our proposal describes an expanded collaboration, with in vivo work in Dr. Rehan?s lab and shared efforts on assays/analysis. The consequences of VAD including BPD, retinopathy of prematurity, and sepsis are all costly complications of prematurity, with significant risk of poor clinical outcomes. Currently available vitA therapies either require invasive IM injection, or are generally inadequate for premature neonates (enteral or IV routes). Inhalation dosing overcomes all of these hurdles, enabling higher vitA utilization, reducing risk and cost for BPD/CLD. Our goals in Phase I are to demonstrate in a well characterized pre-weaned rat model that: 1) our vitA formulation delivered by non-invasive inhalation is at least as effective as invasive IM injection, and 2) that inhaled vitA can attenuate hyperoxic lung injury, thereby reducing the risk for development of BPD. To achieve this, our specific Aim 1 will measure the effectiveness of inhalation of our proprietary vitA formulation, aerosolized by the Aeroneb Pro, on raising serum vitA and stimulating lung maturation in pre-weaned rats, comparing to effects of IM vitA dosing as a baseline. Analysis of lung and liver tissue will be by Western blot, RT-PCR, and immunohistochemistry. Vitamin A and retinol binding protein will by assayed by using ELISA. Our measure of success will be direct demonstration of at least similar effects with aerosolized vitA vs. typical IM dosing (in comparison to untreated control groups).
In specific Aim 2, we will evaluate the effect of inhaled vitA on attenuating hyperoxia-induced neonatal lung injury as compared to IM delivery. Our measure of success will be efficacy in reducing hyperoxic lung damage equal to or better than IM dosing and relevant controls.
The consequences of inadequately treated vitamin A deficiency (VAD) in premature neonates including increased risk for bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP) and sepsis, are associated with poor clinical outcomes in these fragile patients and require costly long-term treatment. Advent Therapeutics is developing an aerosol formulation of its proprietary optimized, water miscible vitamin A palmitate for non-invasive delivery of the drug to preterm infants. The aerosol formulation obviates the need for invasive intramuscular (IM) injection, and allows potential increased effectiveness by delivery directly to the lung (a direct- to-target-organ treatment for BPD), while simultaneously providing systemic vitamin A availability important for treating VAD and the other related complications. Dosing vitamin A by inhalation should overcome current hurdles limiting vitamin A supplementation use in the NICU, enabling much higher vitamin A utilization, thereby reducing risk and cost of BPD and ROP in preterm infants.