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Targeting inflammation to improve rescue of CFTR by modulator therapy

Award Number: K23HL163445
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 05/18/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Targeting inflammation to improve rescue of CFTR by modulator therapy - PROJECT SUMMARY Cystic fibrosis (CF) is a genetic disease caused by mutations in the gene encoding CF transmembrane conductance regulator (CFTR), an ion channel essential for mucus hydration. Improper hydration of mucus leads to airway inflammation, chronic pulmonary infections and abnormal mucociliary function. The major contributor to morbidity and mortality in CF is a progressive decline in lung function. Recent advances in therapies that modulate mutant CFTR for those with the most common CFTR mutations have led to dramatic improvements in lung function. Despite the considerable improvements afforded by these CFTR modulators, there is no evidence that they improve underlying airway inflammation as lung function continues to decline over time. The identification of therapies that target this inflammation will be critical to ensuring that the long-term benefits of CFTR modulators are fully realized. Preliminary in vitro evidence from the applicant demonstrates that losartan, a common anti-hypertensive medication with known anti-inflammatory properties, can improve the efficacy of CFTR modulators in the presence of inflammation. This proposal aims to further our understanding of the impact of inflammation on response to CFTR modulator therapy and, using a novel enrollment strategy, evaluate if losartan is able to further improve CFTR function in those with CF on the modulator elexacaftor/tezacaftor/ivacaftor (ETI). In aim 1, we will sample the nasal fluid of those with CF on ETI and, using regression analysis, examine the association of expression levels of the inflammatory marker TGF-1 on change in lung function after starting ETI. In aim 2a, we will conduct a randomized, double-blind clinical trial of losartan to improve CFTR function, as measured by sweat chloride, in those with CF on ETI. We will utilize a prognostic enrichment strategy by including only those with the persistently elevated sweat chloride levels after starting ETI. Additionally, in aim 2b, we will correlate the response in aim 2a with in vitro measurement of CFTR current in patient-derived nasal epithelial cells (NECs) treated with losartan and ETI in order to understand if it could be utilized as a prediction of in vivo response. The long-term goal of the applicant is to become an independent investigator who, through application of novel, adaptive, clinical trial techniques, evaluates therapies which have the potential to improve outcomes of those with CF. He has prior experience in using in vitro and in vivo methods to further understanding of the effects of inflammation and hyperglycemia on mucociliary clearance and formal training in basic biostatistics and clinical research. The career development plan associated with this proposal pairs an experienced, diverse mentoring team with additional training in advanced biostatistics, adaptive clinical trial design and utilization of patient-derived NECs. This will uniquely position the applicant to design and lead clinical trials using efficient, adaptive strategies to test the next generation of therapies for those with CF.


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: 2026 ( Subtotal = $171,995 )
2026	2026	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Lung Diseases Research	000	4	3/30/2026	NON-COMPETING CONTINUATION	$171,995
														Subtotal = $171,995

Issue Date FY: 2025 ( Subtotal = $170,452 )
2025	2025	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Lung Diseases Research	000	3	3/20/2025	NON-COMPETING CONTINUATION	$170,452
														Subtotal = $170,452

Issue Date FY: 2024 ( Subtotal = $173,865 )
2024	2024	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Lung Diseases Research	000	2	3/18/2024	NON-COMPETING CONTINUATION	$173,865
														Subtotal = $173,865

Issue Date FY: 2023 ( Subtotal = $177,075 )
2023	2023	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Lung Diseases Research	000	1	5/18/2023	NEW	$177,075
														Subtotal = $177,075

Grand Total All Awards = $693,387

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Targeting inflammation to improve rescue of CFTR by modulator therapy

Award Number: K23HL163445

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 05/18/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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