Rare Bronchiectatic Diseases Consortium - ABSTRACT Four rare bronchiectatic diseases (RBDs), including primary ciliary dyskinesia, alpha-1 antitrypsin, humoral immune deficiency, and STAT3-HIES, manifest bronchiectasis (BE) as a severe pulmonary complication. BE, defined by airways dilation/ectasia on chest CT imaging, is associated with cough, sputum production, acute exacerbations (AE), loss of lung function, and increased mortality. Progress in therapeutics for the most prevalent form of BE (non-cystic fibrosis bronchiectasis, NCFB), and by implication, the 4 RBDs selected for study, has been slow. Part of this “tardiness” in therapeutics development has been the incomplete nature of the “Vicious Vortex” hypothesis, a paradigm for investigating BE pathogenesis which we posit is missing key elements that initiate and perpetuate the “Vortex”. Presently, there is an urgent need to accelerate BE therapeutics development. Key missing elements include data describing the clinical trajectory of each RBD and disease- informative BE biomarkers. Using new insights and biomarkers derived from a novel “Vicious Vortex 2.0” hypothesis, combined with new observational studies, this U54 proposes to fill in the gaps to accelerate BE drug discovery, build a pipeline of rare disease investigators, and conduct ancillary studies, some in partnership with industry. This work will be conducted in partnership with the Patient Advocacy Groups (PAGs) associated with the 4 RBDs. To accomplish these goals, we propose 2 projects: Project 1, “Longitudinal Study of Clinical Outcome Measures and Biomarkers in Rare Bronchiectatic Diseases” (K. Olivier, MD, MPH, PI), will define clinical trajectories of the 4 RBDs over a 3-year longitudinal observational period as quantitated by pulmonary function tests, patient-reported outcomes, AEs, and novel CT analyses. Ancillary goals are to collect sputum, BAL, oral, and blood samples for biomarker testing. Emphasis for biomarker development is focused on novel mucus parameters, anaerobic microbiomes, and metabolomics. Airway epithelial and microbiome samples will be collected for collaborative studies with Project 2. Project 2, “Rare Bronchiectatic Disease Biomarkers and Novel Treatable Traits” (R. Boucher, MD, PI), provides complementary laboratory-based studies of patient- derived materials obtained from Project 1, supplemented by studies of excised lung specimens from the 4 RBDs. Goals are to utilize high-content RNA/protein technologies, coupled with studies of cultured airway epithelia from RBD patients designed to measure responses to BE provocants (aspiration, viral infections, and oral microbiome challenge) to identify/validate novel biomarkers and treatable traits. Cores focused on Career Enhancement, Pilot and Feasibility Study Development, and Administration have been assembled to achieve our goals. Deliverables will be: 1) high-quality/high-content clinical data describing the 3-year clinical trajectory of the 4 RBDs, coupled to identification/validation of a suite of novel biomarkers vetted by in vitro and in vivo studies; 2) identification of novel RBD common and specific “treatable traits”; 3) training the next generation of rare disease investigators; and 4) conducting ancillary studies that will lead to clinical trials.
