Researchers reveal possible way to treat newborns with rare genetic lung disease

When babies are born with Alveolar Capillary Dysplasia with Pulmonary Vein Misalignment (ACDMPV), their skin begins to turn blue due to under-oxygenated blood in their systems. But unlike most other respiratory problems a newborn may experience, there’s not much that can be done to save these children unless they have a lung transplant.

This is because their lungs lack the capacity to develop enough alveolar capillaries to support healthy gas exchange, which in most cases leads to death within a month of birth. Now, after performing a cell-by-cell analysis of genetic activity occurring among many different cell types in the lungs, Cincinnati Children’s scientists shed new light on how ACDMPV develops and how possible to treat it.

The detailed results were published online on April 19, 2022, in Nature Communication. The study was led by first author Guolun Wang, PhD, corresponding author Vladimir Kalinichenko, MD, PhD, and seven other experts collaborating with the Center for Lung Regenerative Medicine at the Cincinnati Children’s Perinatal Institute.

Treatment with BMP9 effectively restored capillary density, improved alveolarization, increased arterial oxygenation, increased BMP9 receptor expression on the surface of capillary endothelial cells called Acvrl1, and improved survival in the ACDMPV mouse model. The improvements are striking. However, several more research steps are needed before BMP9 therapy is ready for human clinical trials. »

Vladimir Kalinichenko, MD, PhD, corresponding author

Complex detective work isolates key molecular signaling pathway

The study in Nature Communication describes how the research team sifted through a mountain of single-cell RNA sequencing data collected from more than 7,000 mouse lung cells carrying a genetic mutation linked to ACDMPV (a loss of function of the embarrassed FOXF1 in humans) and nearly 6,000 other normal lung cells to find the type of cell where the disease creates its devastating effects.

The work began by isolating around ten cell clusters of potential interest. These clusters included alveolar epithelial cells, fibroblasts, club cells, endothelial cells, pericytes, hair cells, and myofibroblasts. The initial results prompted the team to focus more closely on activity involving pulmonary endothelial progenitor cells (EPCs) that reside in the inner walls of microvascular blood vessels in the lung.

Using data from around 800 of these cells, the team found 93 down-regulated and 43 up-regulated genes in the Foxf1 mutation group compared to the normal group. From these data, the team narrowed the suspects further to a critical signaling pathway involving the proteins BMP9, ACVRL1 and SMAD1.

When the FOXF1 protein disappears or contains one of the harmful mutations, the expression of Acvrl1 is reduced, which in turn reduces the expression of downstream target genes. This pathway is necessary for the formation of healthy blood vessels in the lungs.

Assessing the importance of this pathway required the use of a nanoparticle “delivery platform” developed by the Kalinichenko lab to “silencing” the ACVRL1 protein, but only in mouse lung endothelial cells. .

Confirmation of pathway leads to potential treatment

The good news: the team discovered that adding the synthetic bone morphogenetic protein BMP9 to functionally deficient cells FOXF1 genes helped recreate the signaling pathway, stimulating Acvrl1 activity and asking the lungs to keep making capillaries. The researchers confirmed this by tests on cell cultures in the laboratory and on mice.

BMP9 is one of approximately 20 such proteins found in humans. Originally discovered to play a major role in bone growth, this class of molecules has more recently been shown to play various roles in development.

Two other related proteins; BMP7 and BMP2; have been approved by the United States Food and Drug Administration for the treatment of bone growth disorders. But so far, no drug that boosts BMP9 activity has been approved for human use.

ACDMPV is an extremely rare disease. It has been identified worldwide in a few hundred births, while in the United States over 3.6 million births occurred in 2020 alone.

If a safe BMP9 “agonist” or a synthetic BMP9 molecule suitable for human use can be developed, it could become more than a treatment strictly for ACDMPV, Kalinichenko says. It could also stimulate blood vessel growth that is hampered by bronchopulmonary dysplasia (BPD) – a complication of premature birth that occurs in around 10,000 to 15,000 babies a year. While most infants survive this condition, early interventions that could stimulate repair of lung damage could help prevent increased risks of asthma and lung infections later in life.

The treatment could possibly also benefit infants with congenital diaphragmatic hernia (CDH), a birth defect that strikes about 1,000 newborns a year in the United States. In these children, gaps in the diaphragm allow other internal organs to cram into the space needed for the lungs. Although surgery can repair the hernia, in many cases the lungs struggle to return to a normal growth pattern.


Cincinnati Children’s Hospital Medical Center

Journal reference:

Wang, G. et al. (2022) Endothelial progenitor cells stimulate neonatal pulmonary angiogenesis through FOXF1-mediated activation of BMP9/ACVRL1 signaling. Communication Nature.