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A Ginsenoside TMEM16A Potentiator for Cystic Fibrosis

Award Number: R21AT012234
ORGANIZATION: CENTER FOR DRUG EVALUATION AND RESEARCH, NIH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/26/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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A Ginsenoside TMEM16A Potentiator for Cystic Fibrosis - PROJECT SUMMARY Dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel impedes mucus clearance and leads to the airway disease, cystic fibrosis (CF). New CFTR modulators improve mucociliary transport (MCT) and pathophysiologic manifestations of the disease in genetic mutation-specific patients, but do not completely restore airway function. We recently discovered ginsenosides derived from Korean Red Ginseng serve as potentiators of the Ca2+-activated Cl− channel (CaCC) [TMEM16A] and can restore MCT in vitro and in vivo through this alternative Cl- pathway. Yet, poor clinical trial results with activators of TMEM16A and a recently described role for the channel in mucus hypersecretion in infected airways has led to some to suggest that inhibiting TMEM16A is a better strategy. However, we hypothesize that potentiating TMEM16A, rather than channel activation through purinergic, intracellular Ca2+- driven pathways, will rescue MCT in infected CF airways. Specific Aim 1 will isolate the ginsenoside that most effectively potentiates TMEM16A and measure its effects on MCT parameters and mucus pathology. We anticipate finding the optimal ginsenoside through Ussing chamber and patch clamp experiments, while also measuring the impact on markers of MCT and mucus viscosity. Specific Aim 2 will assess whether a TMEM16A potentiator improves epithelial Cl- secretion, histopathology, and MCT parameters in infected CF rat airways. We will determine single dose pharmacokinetics for the selected ginsenoside and administer to Pseudomonas-infected CF rats to evaluate nasal potential difference, MCT, lung micro-CTs, histopathology, mucus properties (viscosity, solids, mass, density), and inflammatory cytokines. We will answer questions about the therapeutic utility of targeting the TMEM16A pathway and identify a new TMEM16A potentiator as an effective treatment for CF airway disease.


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 = -$88 )
2026	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Research and Training in Complementary and Integrative Health	000	2	4/15/2026	NON-COMPETING CONTINUATION	-$88
														Subtotal = -$88

Issue Date FY: 2024 ( Subtotal = $181,913 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Research and Training in Complementary and Integrative Health	001	2	5/13/2024	NON-COMPETING CONTINUATION	$14,850
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Research and Training in Complementary and Integrative Health	000	2	12/5/2023	NON-COMPETING CONTINUATION	$167,063
														Subtotal = $181,913

Issue Date FY: 2023 ( Subtotal = $222,750 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Research and Training in Complementary and Integrative Health	000	1	1/26/2023	NEW	$222,750
														Subtotal = $222,750

Grand Total All Awards = $404,575

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A Ginsenoside TMEM16A Potentiator for Cystic Fibrosis

Award Number: R21AT012234

ORGANIZATION: CENTER FOR DRUG EVALUATION AND RESEARCH, NIH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/26/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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