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Development of novel therapeutic approaches for treatment of Alveolar Capillary Dysplasia

Award Number: R01HL152973
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2021
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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Development of novel therapeutic approaches for treatment of Alveolar Capillary Dysplasia - PROJECT SUMMARY. Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACDMPV) is a fatal congenital disorder of neonates and infants which leads to respiratory insufficiency due to reduced numbers of alveolar capillaries and is associated with lung hypoplasia, hemorrhage, malposition of pulmonary veins and pulmonary arterial hypertension (PAH). ACDMPV is linked to mutations in the Forkhead Box F1 (FOXF1) gene and is resistant to all available therapies and respiratory support, causing cyanosis and respiratory failure in the first month after birth. In rare cases, ACDMPV patients survive several months or even years, but they require lung transplantation early in life. Given the lack of effective treatments for ACDMPV, there is an urgent need for innovative therapeutic approaches to stimulate pulmonary angiogenesis and preserve respiratory function in ACDMPV infants. In our preliminary data, we have generated a clinically relevant model of ACDMPV by introducing the S52F FOXF1 mutation (found in ACDMPV patients) into the endogenous mouse Foxf1 gene locus. Foxf1WT/S52F newborn mice exhibited alveolar capillary dysplasia, misalignment of pulmonary veins, PAH, and increased mortality, all key features of human ACDMPV. Endothelial proliferation and STAT3 signaling were decreased in Foxf1WT/S52F mice and human ACDMPV lungs. In the present grant application, we will test the hypothesis that increasing neonatal lung angiogenesis will decrease PAH, improve survival and prevent lung remodeling in mouse ACDMPV models. In Aim 1, we have developed a novel nanoparticle gene delivery system targeting >85% of pulmonary endothelial cells in vivo when delivered into the neonatal blood circulation. Nanoparticle delivery of STAT3 cDNA after birth induced endothelial proliferation and increased alveolar microvascular density in Foxf1WT/S52F neonatal lungs. We will use two mouse models of ACDMPV (Foxf1WT/S52F and Foxf1+/-) to test whether nanoparticle delivery of STAT3 or FOXF1 will decrease PAH, improve survival and prevent lung remodeling. We will also determine whether the FOXF1/STAT3/cMYC transcriptional cascade is required for neonatal lung angiogenesis. In Aim 2, we provided preliminary data demonstrating that a cell transplantation with pulmonary endothelial progenitor cells (EPCs) (FOXF1+cKit+CD31+CD45-) increases the capillary density in Foxf1WT/S52F lungs. We will investigate heterogeneity of pulmonary EPCs and test their therapeutic potential in mouse ACDMPV models. We will test if EPCs stimulate neonatal lung angiogenesis via the BMP-9/ACVRL1 signaling pathway. Finally, we will use a novel protocol for in vitro differentiation of EPCs from mouse and human embryonic stem cells (ES) and determine if a cell therapy with ES-derived EPCs will be beneficial in mouse ACDMPV models. Altogether, the proposed studies will directly test whether endothelial delivery of STAT3 or cell therapy with EPCs have therapeutic potential in ACDMPV.


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: 2024 ( Subtotal = $510,389 )
2024	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Lung Diseases Research	003	5	6/21/2024	NON-COMPETING CONTINUATION	$41,663
2024	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Lung Diseases Research	002	5	4/18/2024	NON-COMPETING CONTINUATION	$468,726
2024	2023	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Lung Diseases Research	001	4	2/7/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$180
2024	2023	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	000	3	2/7/2024	NON-COMPETING CONTINUATION	-$180
														Subtotal = $510,389

Issue Date FY: 2023 ( Subtotal = $539,466 )
2023	2023	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	001	3	8/19/2023	NON-COMPETING CONTINUATION	-$531,604
2023	2023	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Lung Diseases Research	002	4	8/21/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$531,604
2023	2023	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	000	3	2/27/2023	NON-COMPETING CONTINUATION	$539,466
														Subtotal = $539,466

Issue Date FY: 2022 ( Subtotal = $539,466 )
2022	2022	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	000	2	2/24/2022	NON-COMPETING CONTINUATION	$485,517
2022	2022	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	001	2	6/14/2022	NON-COMPETING CONTINUATION	$53,949
														Subtotal = $539,466

Issue Date FY: 2021 ( Subtotal = $539,466 )
2021	2021	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	000	1	4/20/2021	NEW	$485,521
2021	2021	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	001	1	6/10/2021	NEW	$53,945
														Subtotal = $539,466

Grand Total All Awards = $2,128,787

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Development of novel therapeutic approaches for treatment of Alveolar Capillary Dysplasia

Award Number: R01HL152973

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2021

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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