Rare Bronchiectatic Diseases Consortium

PROJECT 2 ABSTRACT Rare genetic diseases are associated with bronchiectasis (BE) as a severe pulmonary disease manifestation. People with rare genetic diseases with BE experience increased sputum production, loss of lung function, an increased frequency of respiratory exacerbations, and life limitation. There is a great need for novel therapies for people with rare genetic diseases and BE. Project 2 will study four rare diseases with diverse genetic mutations, including: 1) primary ciliary dyskinesia (PCD); 2) alpha-1 antitrypsin deficiency (α1AT); 3) humoral- immune deficiency (HID); and 4) STAT3-hyper IgE syndrome (STAT3-HIES). Each disease exhibits unique and variable components of dysfunction in elements that mediate airways host defense, including epithelial defects (PCD), humoral defects (HID, α1AT), and cellular immune defects (STAT3-HIES). Project 2 proposes to use a new paradigm describing key initiating factors that fuel a vicious vortex cycle (Vicious Vortex 2.0) to identify biomarkers and treatable traits common to all four rare genetic diseases juxtaposed to a goal to identify biomarkers/treatable traits unique to each rare disease. The technologies employed to accomplish these goals combine: 1) high-content RNA/protein spatial technologies applied to a unique set of excised lungs from each of the four genetic diseases; with 2) studies of airway epithelia obtained at bronchoscopy from Project 1 for in vitro investigations of disease-common or -specific epithelial responses to mimics of aspiration (pH, bile acids), viruses (RSV), and normal vs disease-specific oral microbiomes. Accordingly, Project 2 proposes three specific aims: Specific Aim 1: Test the hypothesis that each rare disease has a common core of Vicious Vortex 2.0- associated features, but with disease-specific modifications/additions, in excised lungs. Spatial RNA and protein technologies will interrogate lungs excised from subjects with PCD, α1AT, HID, and STAT3-HIES. Specific Aim 2: Test the hypothesis that there are rare disease-common and disease-specific responses to mimics of aspiration and viral infection. This aim will utilize cells obtained from the four rare diseases at bronchoscopy (Project 1) to identify common disease-specific airway epithelial responses to triggers of obstruction/hypoxia, including mimics of aspiration and viral infection. Specific Aim 3: Test the hypothesis that there will be rare disease commonalities and differences in airway epithelial responses to “normal” oral microbiome challenges and disease-specific differences in oral microbiome that are disease pathogenesis-relevant. Like SA2, SA3 will utilize bronchoscopy-derived airway cells and disease-specific oral microbiomes. Project 2’s ultimate deliverables are the identification of clinical trial vetted/novel biomarkers and novel treatable traits common to the BE experienced by patients with these four rare diseases and unique biomarkers/treatable traits tailored to unique rare disease patient populations.