Nebulized azetidine-based transcription factor inhibitor loaded nanoproduct for severe asthma - Abstract Approximately 24.6 million Americans have asthma, including 7.6% of adults and 8.4% of children. Despite multiple ther- apies, about 40% of adults remain symptomatic, with up to 5% suffering from severe asthma. Most current treatments, such as steroids, target only a single cell type or mediator, leaving significant unmet needs in asthma care. Some patients develop resistance to all FDA-approved therapies, and high steroid use is limited by severe side effects. STAT3, a critical signaling molecule, drives severe chronic asthma by acting on key asthma-related Th, B, and airway epithelial cells ('TBE'). Although preclinical studies suggest targeting STAT3 could be effective, no FDA-approved STAT3 inhibitors currently exist, and prior therapies have yet to advance to clinical trials. The goal of this meritorious R15 REAP project is to investigate first-class nebulized STAT3 (ST3) inhibitor (ST3in)-loaded endogenous lipid and ionizable lipid with disulfide linkage-based pegylated nanoliposomes (pegNL) product (ST3in-pegNL) with endosomal escape capacity and redox-stimuli triggered release of STAT3 inhibitor in distinct chronic asthma-relevant cells to attenuate severe chronic asthma and overcome challenges of delivery of STAT3 inhibitor to the cytoplasm. The central hypothesis is that the new class of nebulized, self-administrable, patient-compliant, bioinspired pH and cytoplasmic redox-stimuli-responsive ST3in-loaded peg-NL delivers the new ST3in, a novel chemical entity, to asthma-associated lung TBE cells and will exert an effective antiasthmatic effect against severe chronic asthma while sparing off-target side effects. The two aims will be used. The two aims will test this hypothesis. Aim 1 focuses on the ST3in evaluation, development of the nebulized ST3in-pegNL product, physico-biochemical and aerody- namic testing, and delineating its effectiveness against severe chronic asthma-associated TEB cells. Aim 2 focuses on establishing the maximum tolerable dose, lung deposition, and distribution, as well as interrogating the in vivo efficacy and safety of targeted nebulized ST3in-pegNL in a clinically relevant severe chronic asthma model. The innovation is an inhal- able new class of triple-pronged pH and cytoplasmic redox-responsive ST3in-pegNL product, utilizing endogenous and ion- izable lipids to provide efficient endosomal escape and cytoplasmic GSH-triggered ST3inh release from NL in three distinct asthma-related cells, thereby inhibiting the phosphorylation of ST3 and blocking pathways to exert significant antiasthmatic efficacy against severe chronic asthma. The development of innovative, inhalable nanoparticle-based antiasthmatic products has high translational potential and is expected to lead to the availability of new treatments for severe asthma. This proposal utilizes the high-impact ST3in-pegNL product to deliver ST3in to triple TEB asthma-affected cells to treat severe asthma by decreasing key transcription factors and asthma mediators. For the first time, this meritorious approach will serve as the basis for future preclinical and clinical testing of the developed nebulized ST3in-pegNL suspension Nano-product for severe asthma. This high-impact, effective strategy will pave the way for new directions in ST3 inhibitor delivery and other anti-asthmatic agents. This project holds significant clinical importance, as it aims to improve treatment outcomes when used in conjunction with standard therapies, particularly in patients with severe chronic asthma. Aligned with the NHLBI mission, the proposed work also supports critical training opportunities for undergraduate and graduate students, advances the princi- pal investigator's (PI) research program, and enhances the biomedical research environment at Mercer University.
