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Delivering inhalable nanoparticles containing AI-optimized CFTR mRNA with a novel microfluidic device for treatment of CF

Award Number: R01HL146736
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2019
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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Delivering inhalable nanoparticles containing AI-optimized CFTR mRNA with a novel microfluidic device for treatment of CF - Project summary Cystic fibrosis (CF) is an autosomal genetic inherited disease caused by over 1,000 known mutations in the CFTR gene, which encodes an ion transporter. Gene therapy offers a single therapeutic solution to treat all CF patients, regardless of underlying mutation. Previous gene therapy approaches delivering CFTR DNA via viral or liposomal delivery have not proven clinically viable. Airway administration of CFTR mRNA packaged in lipid nanoparticles (LNPs) offers a promising therapeutic approach for CF patients that is non-invasive, repeatable, and safe. A recent Phase 1/2 clinical trial of CFTR mRNA delivery using repeated administration of inhaled CFTR mRNA-LNPs demonstrated clinical safety but did not adequately improve CF endpoints. Advances have been made in LNP material design and formulation for mRNA delivery to the lungs but clinical feasibility for CF treatment requires additional therapeutic improvements. One neglected area of innovation is modification and optimization of the delivered CFTR mRNA cargo. Current therapies use wild-type mRNA or basic codon optimization to increase translation efficiency of the CFTR mRNA. However, recent advances in AI-based design provide a significantly better method to optimize both protein translation levels and mRNA half-life. This optimization would improve the efficacy of CFTR mRNA therapy and potentially reduce dosage and administration frequency compared to current mRNA cargoes. Another technical limitation is the current nebulizer technology for aerosolization of LNPs, which physically disrupts nanoparticles, reducing their effectiveness and necessitating reformulation of LNPs that can diminish their efficacy and provoke immune responses. New nebulizer technology with reduced LNP disruption would enhance mRNA- LNP delivery and remove the need for deleterious reformulations. We propose to address the efficacy gap of inhaled mRNA-LNP therapies by completing the following objectives: 1) employ AI-based mRNA design with rapid in vitro screening to generate a therapeutic CFTR mRNA optimized for protein expression, half-life, and ion channel function; 2) utilize mRNA barcoding for rapid in vivo screening of longevity of these novel CFTR mRNA sequences delivered by nebulizer; and 3) evaluate therapeutic efficacy and safety of repeated inhaled administration of CFTR mRNA-LNPs using a novel microfluidic nebulizer device in a rat model of CF. These studies will advance inhalable mRNA-LNP therapies by applying new nebulizer and computational technologies to address overlooked aspects of airway mRNA-LNP delivery. This work evaluates new strategies in vitro and in vivo to improve clinical viability of inhalable LNP delivery of mRNA that provides a noninvasive and repeatable treatment for CF and other pulmonary diseases.


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 = $579,499 )
2026	2026	OREGON STATE UNIVERSITY	1500 SW JEFFERSON AVE	CORVALLIS	OR	97331	BENTON	USA	Lung Diseases Research	000	7	4/7/2026	NON-COMPETING CONTINUATION	$579,499
														Subtotal = $579,499

Issue Date FY: 2025 ( Subtotal = $599,652 )
2025	2025	OREGON STATE UNIVERSITY	1500 SW JEFFERSON AVE	CORVALLIS	OR	97331	BENTON	USA	Lung Diseases Research	000	6	7/23/2025	COMPETING CONTINUATION	$599,652
2025	2023	OREGON STATE UNIVERSITY	1500 SW JEFFERSON AVE	CORVALLIS	OR	97331	BENTON	USA	Lung Diseases Research	002	5	8/21/2025	NON-COMPETING CONTINUATION	$1,188
2025	2023	OREGON STATE UNIVERSITY	1500 SW JEFFERSON AVE	CORVALLIS	OR	97331	BENTON	USA	Lung Diseases Research	001	5	8/21/2025	NON-COMPETING CONTINUATION	-$1,188
														Subtotal = $599,652

Issue Date FY: 2023 ( Subtotal = $658,627 )
2023	2023	OREGON STATE UNIVERSITY	1500 SW JEFFERSON ST	CORVALLIS	OR	97331	BENTON	USA	Lung Diseases Research	000	5	2/24/2023	NON-COMPETING CONTINUATION	$658,627
														Subtotal = $658,627

Issue Date FY: 2022 ( Subtotal = $658,627 )
2022	2022	OREGON STATE UNIVERSITY	1500 SW JEFFERSON ST	CORVALLIS	OR	97331	BENTON	USA	Lung Diseases Research	000	4	2/4/2022	NON-COMPETING CONTINUATION	$592,762
2022	2022	OREGON STATE UNIVERSITY	1500 SW JEFFERSON ST	CORVALLIS	OR	97331	BENTON	USA	Lung Diseases Research	001	4	6/15/2022	NON-COMPETING CONTINUATION	$65,865
														Subtotal = $658,627

Issue Date FY: 2021 ( Subtotal = $658,627 )
2021	2021	OREGON STATE UNIVERSITY	1500 SW JEFFERSON ST	CORVALLIS	OR	97331	BENTON	USA	Lung Diseases Research	000	3	2/26/2021	NON-COMPETING CONTINUATION	$658,627
														Subtotal = $658,627

Issue Date FY: 2020 ( Subtotal = $666,748 )
2020	2020	OREGON STATE UNIVERSITY	1500 SW JEFFERSON ST	CORVALLIS	OR	97331	BENTON	USA	Lung Diseases Research	000	2	3/10/2020	NON-COMPETING CONTINUATION	$666,748
														Subtotal = $666,748

Issue Date FY: 2019 ( Subtotal = $675,953 )
2019	2019	OREGON STATE UNIVERSITY	1500 SW JEFFERSON ST	CORVALLIS	OR	97331	BENTON	USA	Lung Diseases Research	000	1	3/21/2019	NEW	$675,953
														Subtotal = $675,953

Grand Total All Awards = $4,497,733

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Delivering inhalable nanoparticles containing AI-optimized CFTR mRNA with a novel microfluidic device for treatment of CF

Award Number: R01HL146736

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2019

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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