Washington: Scientists have identified the cause and a potential treatment of a fatal respiratory disorder — Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACDMPV) — in newborn infants that turns their lips and skin blue.
Researchers from Cincinnati Children’s Hospital in the US developed clinically accurate mouse models of disease ACDMPV which allowed them s to overcome a longtime hurdle — understanding how the disease develops and to pinpoint the ailment’s cause. It also helped them in developing a potential and desperately needed nanoparticle-based treatment.
ACDMPV usually strikes infants within a month of birth. The disease starves the pulmonary system of oxygen after the lung’s blood vessels do not form properly during organ development. The lack of tiny blood vessels called alveolar capillaries causes hypoxia, inflammation and death.
“There are no effective treatments other than a lung transplant, so the need for new therapeutics is urgent,” said Vlad Kalinichenko, at the Cincinnati Children’s.
“We identified a nanoparticle therapeutic strategy to increase the number of alveolar capillaries and help preserve respiratory function for at least a subset of the babies with this congenital lung disease,” said Kalinichenko, lead study investigator in the study published in the American Journal of Respiratory and Critical Care Medicine.
The disease has long been linked to mutations in the FOXF1 gene, an important regulator of embryonic lung development.
Researchers analysed genetic information from human ACDMPV cases to generate the first clinically relevant animal model of ACDMPV. They used gene editing tool CRISPR/Cas9 to recreate human FOXF1 mutations in the mouse.
By studying protein-DNA interactions linked to the FOXF1 gene in pulmonary cells, researchers found a specific point mutation, which blocked molecular signaling to multiple downstream target genes involved in formation of pulmonary blood vessels.
Researchers then turned to nanoparticle technology to deliver a STAT3 mini-gene to lungs of newborn mice. They created a novel gelatin-like formulation known as polyethylenimine (PEI) nanoparticles that can carry therapeutic genetic material to different parts of the body by administering them to patients intravenously.
Different formulations of PEI nanoparticles are currently being tested in clinical trials for adult cancer at other institutions, researchers said.
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