# Development of novel therapeutic approaches for treatment of Alveolar Capillary Dysplasia

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2021 · $539,466

## Abstract

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.

## Key facts

- **NIH application ID:** 10218489
- **Project number:** 1R01HL152973-01A1
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Tanya Kalin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $539,466
- **Award type:** 1
- **Project period:** 2021-05-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10218489

## Citation

> US National Institutes of Health, RePORTER application 10218489, Development of novel therapeutic approaches for treatment of Alveolar Capillary Dysplasia (1R01HL152973-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10218489. Licensed CC0.

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