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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

Award Number: UH3HL145266
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $1,141,496 )
2024	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Lung Diseases Research	000	5	4/13/2024	NON-COMPETING CONTINUATION	$1,141,496
														Subtotal = $1,141,496

Issue Date FY: 2023 ( Subtotal = $3,032,451 )
2023	2023	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Lung Diseases Research	000	4	4/27/2023	NON-COMPETING CONTINUATION	$3,032,451
														Subtotal = $3,032,451

Issue Date FY: 2022 ( Subtotal = $3,487,084 )
2022	2022	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Lung Diseases Research	001	3	5/5/2022	NON-COMPETING CONTINUATION	$3,487,084
2022	2021	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Lung Diseases Research	000	2	10/21/2021	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $3,487,084

Issue Date FY: 2021 ( Subtotal = $2,800,903 )
2021	2021	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Lung Diseases Research	001	2	8/9/2021	EXTENSION WITH OR WITHOUT FUNDS	$52,612
2021	2021	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Lung Diseases Research	000	2	4/6/2021	EXTENSION WITH OR WITHOUT FUNDS	$2,748,291
														Subtotal = $2,800,903

Grand Total All Awards = $10,461,934

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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

Award Number: UH3HL145266

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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