1/2 Prospective tReatment EffiCacy in IPF uSlng genOtype for Nac Selection (PRECISIONS) trial and Molecular Endophenotyping in Idiopathic Pulmonary Fibrosis and Interstitial Lung Diseases study

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ABSTRACT Despite being the most frequent and deadly of the interstitial lung diseases (ILD), Idiopathic Pulmonary Fibrosis (IPF) remains challenging to diagnose and treat. The diagnostic process for IPF relies on subjective interpretations of clinical data while current antifibrotic therapies employ a “one size fits all” paradigm. Members of our team have been at the forefront of developing `omics approaches to diagnose and define prognosis in ILDs. Importantly, we identified the first pharmacogenomic interaction suggesting that IPF patients with TOLLIP rs3750920 T/T genotype strongly benefited from NAC. There is a critical need for molecular classifications that define IPF, thus allowing precision-based management. Our long-term goals are to move ILD diagnosis and therapy into the “era of precision medicine.” In a highly innovative approach we have partnered with the Pulmonary Fibrosis Foundation (PFF) Clinical Care Network (CCN) and Registry. This group has recruited ILD patients who have provided extensive baseline phenotypic and longitudinal outcome data, biological samples and have consented to be re-contacted for future research. Our overall objective is to efficiently conduct a novel, precision genotype-based trial in IPF while leveraging the CCN and its unique biospecimen collection to characterize a broad range of ILDs molecularly and identify genetic variants of IPF risk. To address our goal of precision-based ILD management, we will complete three complementary Specific Aims. In Aim 1 we will determine if NAC is an effective treatment in IPF patients characterized by a precision genotype approach. In partnership with the PFF, we will identify PFF registry subjects with the TOLLIP T/T genotype to begin randomizing 200 IPF patients followed by enrolling new subjects at the same clinical sites to receive NAC or placebo in a double-blind fashion. This study, the “Prospective tReatment EffiCacy in IPF uSIng genOtype for Nac Selection (PRECISIONS)” trial, will document the benefits of an innovative “precision” genotype-specific study design of a well-tolerated and inexpensive therapy. In Aim 2 we will distinguish IPF from non-IPF ILDs using unbiased combinations of blood transcriptomics and proteomics. We propose to conduct RNA-seq and proteomics to characterize gene expression and protein biomarkers on the entire PFF registry cohort. We will define “signatures” for distinguishing IPF from non-IPF ILDs. Our unbiased approaches to `omics traits will be integrated to reveal `omics risk scores that define individual diseases, predict disease course, and response to therapy. In Aim 3 we will identify genetic variants playing a role in IPF risk. We will conduct whole genome sequencing of the entire PFF cohort to detect novel genetic associations for IPF and ILD risk. With sufficient power, we will assess both common and rare/infrequent variants in comparison to ethnically matched un-afflicted cases, and between ILD cohorts to meet our objective. This will establish the largest collection of its kind and establish quantitative trait loci for all `omics' data. The results of our proposed experiments will move ILD management, and IPF therapy, in particular, into the precision medicine era.