UH3HL145266

1/2 Prospective Treatment Efficacy in IPF Using Genotype for NAC Selection (PRECISIONS) Trial and Molecular Endophenotyping in Idiopathic Pulmonary Fibrosis and Interstitial Lung Diseases Study - 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 unaffected 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.

University Of Massachusetts Medical School

THE DIVISION OF LUNG DISEASES SUPPORTS RESEARCH AND RESEARCH TRAINING ON THE CAUSES, DIAGNOSIS, PREVENTION, AND TREATMENT OF LUNG DISEASES AND SLEEP DISORDERS. RESEARCH IS FUNDED THROUGH INVESTIGATOR-INITIATED AND INSTITUTE-INITIATED GRANT PROGRAMS AND THROUGH CONTRACT PROGRAMS IN AREAS INCLUDING ASTHMA, BRONCHOPULMONARY DYSPLASIA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, CYSTIC FIBROSIS, RESPIRATORY NEUROBIOLOGY, SLEEP AND CIRCADIAN BIOLOGY, SLEEP-DISORDERED BREATHING, CRITICAL CARE AND ACUTE LUNG INJURY, DEVELOPMENTAL BIOLOGY AND PEDIATRIC PULMONARY DISEASES, IMMUNOLOGIC AND FIBROTIC PULMONARY DISEASE, RARE LUNG DISORDERS, PULMONARY VASCULAR DISEASE, AND PULMONARY COMPLICATIONS OF AIDS AND TUBERCULOSIS. THE DIVISION IS RESPONSIBLE FOR MONITORING THE LATEST RESEARCH DEVELOPMENTS IN THE EXTRAMURAL SCIENTIFIC COMMUNITY AS WELL AS IDENTIFYING RESEARCH GAPS AND NEEDS, OBTAINING ADVICE FROM EXPERTS IN THE FIELD, AND IMPLEMENTING PROGRAMS TO ADDRESS NEW OPPORTUNITIES. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Worcester, Massachusetts 01655 United States

Single Zip Code

Clinical Coordinating Center for Multi-Site Investigator-Initiated Clinical Trials (Collaborative UG3/UH3) - Clinical Trial Required (PAR-18-407)

Amendment Since initial award the total obligations have increased 324% from $2,748,291 to $11,649,214.