Scientists using gene editing tool CRISPR/Cas9 have identified the cause and potential treatment of a fatal respiratory disorder in newborn infants that turns their lips and skin blue.
The team used CRISPR/Cas9 to generate mice that mimic the mostly untreatable disorder called Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACDMPV).
The model allowed researchers from Cincinnati Children's Hospital in the US to pinpoint the ailment's cause and develop 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, researchers said.
"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 journal 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.
The remaining mystery until this study is precise microbiological processes that fuel ACDMPV, researchers said.
Researchers analysed genetic information from human ACDMPV cases to generate the first clinically relevant animal model of ACDMPV. They used CRISPR/Cas9 to recreate human FOXF1 mutations in the mouse.
CRISPR-Cas9 allows precise gene editing by using an enzyme to cut out specific sections of a DNA sequence and reattaching the loose ends at the desired point to change a cell's genetic makeup.
Having clinically accurate mouse models of disease ACDMPV allowed the scientists to overcome a longtime hurdle to understanding how the disease develops, researchers said.
By studying protein-DNA interactions linked to the FOXF1 gene in pulmonary cells, researchers found a specific point mutation, which blocked molecular signalling to multiple downstream target genes involved in the formation of pulmonary blood vessels.
The researchers theorised that treating newborn mice with a protein called STAT3 would stimulate blood vessel development in the lungs.
Researchers turned to nanoparticle technology to deliver a STAT3 mini-gene to lungs of newborn mice. They created a novel formulation for what are known as polyethyleneimine (PEI) nanoparticles.
The gelatin-like PEI nanoparticles 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.