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The Impact of SLC26A9 on Response to CFTR Correction

Award Number: R01HL180559
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2025
PERIOD OF PERFORMANCE END DATE: 05/31/2030

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The Impact of SLC26A9 on Response to CFTR Correction - PROJECT ABSTRACT / SUMMARY Although CFTR modulator therapies have improved respiratory outcomes for the Cystic Fibrosis (CF) population, the benefit to individual patients can vary widely. In “real world” studies of modulator therapies, patients continue to experience lung function decline, and as many as 1 in 5 receive no therapeutic benefit in FEV1. The factors that determine who has a strong or poor therapeutic response are not well defined, and limit both the current benefit from modulator drugs and future benefit from gene therapies. One proposed but poorly understood factor is the solute carrier SLC26A9, and specifically the risk locus rs7512462 within that gene. This locus is associated with extrapulmonary disease severity in CF, and appears to be linked to CFTR modulator response, though the mechanism of this association and its future impact on CF gene therapy remains unclear. Our long-term goal is to create personalized medicine strategies to optimize care while reducing disparities in disease burden for individuals with airway disorders. The overarching goal of this project is to identify the cellular mechanism and real-world impact of SNP rs7512462 in SLC26A9 on modulator response, and to understand the impact of this interaction on future CFTR-focused therapies. Our central hypothesis for this work is that rs7512462 influences SLC26A9 expression, which is a major determinant of lung function response to modulators via modification of airway ion/fluid homeostasis. We will address this hypothesis through two aims. First, we will recruit individuals with CF and above- or below- average response to modulators based on rate of lung function decline. We will evaluate the relative impact of SLC26A9 genotype on lung function decline in this cohort, and the physiologic impact on the respiratory epithelium using patient-specific ex vivo airway culture. Second, we will determine the mechanism of this interaction through in vitro studies utilizing isogenic cell lines co-expressing risk and protective alleles at rs7512462 with key CFTR variants. We will determine the impact of SLC26A9 genotype on CFTR rescue by modulators and by CFTR gene replacement therapy using an AAV-CFTR construct. We will also assess SLC26A9 as a potential therapy, delivering this gene construct in a similar AAV vector and quantifying its impact on airway epithelial physiology. Through these studies, we will identify the magnitude, mechanism, and real-world relevance of SLC26A9’s influence on patient-specific disease variance, as well as generate proof-of-concept of SLC26A9 as a therapeutic agent. This approach will lead to novel targets to stratify risk and optimize care at the individual level, facilitating precision care in muco-obstructive lung diseases impacted by SLC26A9, including 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 = $717,742 )
2026	2026	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	000	2	6/11/2026	NON-COMPETING CONTINUATION	$717,742
														Subtotal = $717,742

Issue Date FY: 2025 ( Subtotal = $727,575 )
2025	2025	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	000	1	8/15/2025	NEW	$727,575
														Subtotal = $727,575

Grand Total All Awards = $1,445,317

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The Impact of SLC26A9 on Response to CFTR Correction

Award Number: R01HL180559

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2025

PERIOD OF PERFORMANCE END DATE: 05/31/2030

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