R01HL161362

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. Approximately 40% of those expected to respond continue to have exacerbations, while approximately 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. This cohort includes 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. This includes 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 the cohort via the characterization of genomic signals that influence clinical asthma subtypes and via the identification of molecular endotypes. These endotypes will be compared to the traditional clinical subtypes and evaluated for their response to the biologics. Analyses for each aim will include both traditional statistical models as well as novel systems medicine and network biology approaches.

The strengths of our study include a melding of 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 unprecedented level, provide novel therapeutic biomarkers leading to direct clinical application, and detail previously unknown cellular and genomic pathway mechanisms underlying severe asthma.

San Diego University Of California

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]

California United States

State-Wide

Research Project Grant (Parent R01 Clinical Trial Required) (PA-20-183)

Amendment Since initial award the End Date has been extended from 12/31/26 to 12/31/27 and the total obligations have increased 200% from $2,115,286 to $6,355,182.