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Leveraging Pharmacogenomics in Asthma for Predication, Mechanism and Endotyping

Award Number: R01HL161362
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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Leveraging Pharmacogenomics in Asthma for Predication, Mechanism and Endotyping - Abstract Asthma affects over 300 million individuals worldwide. An estimated $81.9 billion dollars were spent on the diagnosis and management of asthma in the U.S. in 2013. Uncontrolled asthma is associated with a doubling of direct costs; it has been estimated that 20% of the subjects with asthma contribute 80% of the economic costs of asthma. For severe asthma, multiple new FDA approved biologic therapies exist, but they remain very expensive and there are a significant proportion of nonresponders. Current biomarkers may not distinguish reliably between responders and non-responders; ~40% of those expected to respond continue to have exacerbations and ~40% of those not expected to respond become symptom free. In this proposal, we will use novel genomics approaches to assess and predict responses using therapy-induced phenotypes across a spectrum of asthma severity and endotypes. We hypothesize that comprehensive characterization using clinical metrics, ‘omics’ approaches, and novel systems biology approaches will generate more precise treatment response biomarkers, further define disease heterogeneity, and uncover novel biologic mechanisms as related to the therapy of moderate to severe asthma. To address this hypothesis, we have specified three specific aims, centered around the combination of a well-characterized, within-person evoked phenotype clinical cohort, including subjects with both type 2 (i.e. those expected to respond based on current biomarkers) and non-type 2 moderate to severe asthma, to anti-IL5 (benralizumab) and anti-IL4/IL13 (dupilumab) with deep genomic interrogation, including single cell and bulk RNA sequencing in both sputum and blood across each of the biologic interventions. The first aim will be to identify, and subsequently validate, pharmacogenomic transcripts that predict response to each therapy, thereby yielding clinically relevant biomarkers for response to asthma biologics. Our second aim takes advantage of the biologic interventions as immunomodulators of specific pathways serving as “human knockdown models” to elicit the underlying mechanistic response at the level of the single cell to the biologic therapies. The final aim will provide novel insights into cohort via the characterization of genomic signals that influence clinical asthma subtypes and via the identification of molecular endotypes, which will be compared to the tradtional clinical subtypes and evaluated for their response to the biologics. Analyses for each aim with include both traditional statistical models as well as novel systems medicine and network biology approaches. The strengths of our study include a melding a unique longitudinal clinical evoked phenotype cohort with state of the art genomics analyses. Successful completion of this study will drive understanding of severe asthma response to biologics to an unprecendented level, provide novel therapeutic biomarkers leading to direct clinical application, and detail previously unknown cellular and genomic pathway mechanisms underlying severe asthma.


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: 2025 ( Subtotal = $2,137,425 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Lung Diseases Research	002	3	7/29/2025	NON-COMPETING CONTINUATION	$213,741
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Lung Diseases Research	001	3	1/17/2025	NON-COMPETING CONTINUATION	$1,923,684
2025	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Lung Diseases Research	000	2	10/18/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,137,425

Issue Date FY: 2024 ( Subtotal = $2,102,471 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Lung Diseases Research	001	2	5/13/2024	NON-COMPETING CONTINUATION	$2,102,471
2024	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Lung Diseases Research	000	1	5/6/2024	NEW	$0
														Subtotal = $2,102,471

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Lung Diseases Research	001	1	8/17/2023	NEW	$0
2023	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Lung Diseases Research	000	1	12/29/2022	NEW	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $2,115,286 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Lung Diseases Research	000	1	1/28/2022	NEW	$2,115,286
														Subtotal = $2,115,286

Grand Total All Awards = $6,355,182

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Leveraging Pharmacogenomics in Asthma for Predication, Mechanism and Endotyping

Award Number: R01HL161362

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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