About My Health Careers Internship MedBlogs Contact us
Medindia LOGIN REGISTER
Advertisement

Cause of Rare, Fatal Disease That Turns Babies' Lips and Skin Blue Identified

by Colleen Fleiss on June 20, 2019 at 1:11 AM
Font : A-A+

Cause of Rare, Fatal Disease That Turns Babies' Lips and Skin Blue Identified

Mice that mimic a fatal respiratory disorder in newborn infants that turns their lips and skin blue has been generated using a gene editing method called CRISPR/Cas9. The new laboratory model allowed researchers to pinpoint the ailment's cause and develop a potential and desperately needed nanoparticle-based treatment.

Mostly untreatable, Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACDMPV) usually strikes infants within a month of birth, according researchers at Cincinnati Children's Hospital Medical Center, who publish findings in the American Journal of Respiratory and Critical Care Medicine. The disease starves the pulmonary system of oxygen after the lung's blood vessels don't form properly during organ development. The lack of tiny blood vessels called alveolar capillaries causes hypoxia, inflammation and death.

Advertisement


"There are no effective treatments other than a lung transplant, so the need for new therapeutics is urgent," said Vlad Kalinichenko, MD, PhD, at the Cincinnati Children's Perinatal Institute Center for Lung Regenerative Medicine and lead study investigator. "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."

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, according to the researchers.
Advertisement

Uncovering the STAT3 Connection

In collaboration with the team of Pawel Stankiewicz, MD, at the Baylor College of Medicine in Houston, the Kalinichenko lab analyzed 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 a 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, authors write.

The work also relied on extensive bioinformatics analyses of clinical and laboratory data from biological tests. This includes a technique called ChIP-Seq (which analyzes protein-DNA interactions), and whole exome sequencing (which reveals the arrangement of all protein-coding regions of genes).

By studying protein-DNA interactions linked to the FOXF1 gene in pulmonary cells, study authors found a specific point mutation involving FOXF1 at the S52F DNA binding location of FOXF1's nuclear protein. The mutation blocked molecular signaling to multiple downstream target genes involved in formation of pulmonary blood vessels.

They also discovered that the S52F FOXF1 mutant protein did not interact with a protein called STAT3. The link is critical to stimulating the development of blood vessels in the neonatal lung. This led to a deficiency of STAT3 in developing lungs and improper formation of the pulmonary circulatory system.

Researchers also found STAT3 deficiency in donated samples from ACDMPV patients who had specific point mutations in the FOXF1 gene. The authors theorized that treating newborn mice with STAT3 would stimulate blood vessel development in the lungs, but they had to figure out how to get the protein to the lungs.

STAT3 Nanoparticle Solution

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, according to study authors.

Therapeutic administration of STAT3 DNA to newborn mice with the S52F FOXF1 mutation restored the ability of endothelial cells to form pulmonary blood vessels. This stimulated blood vessel growth in the animals and the formation of air sacs called alveolar.

"If the efficacy of PEI nanoparticles is confirmed in the clinical trials under way for adult cancer, PEI could be considered for STAT3 gene therapy in infants with ACDMPV," Kalinichenko said. "Considering that ACDMPV is a rare disease, a multicenter clinical trial would be needed to assess the efficacy of STAT3 gene therapy in ACDMPV newborns and infants."

The study's first author is Arun Pradhan, PhD, a researcher who works in the Kalinichenko laboratory.

Funding support for the study came from the National Institutes of Health (HL84151, HL141174, HL123490, HL137203, HL132849 and grants from the National Organization for Rare Disorders.

Source: Eurekalert
Advertisement

Advertisement
News A-Z
A B C D E F G H I J K L M N O P Q R S T U V W X Y Z
Advertisement
News Category
What's New on Medindia
International Day of Persons with Disabilities 2021 - Fighting for Rights in the Post-COVID Era
Effect of Blood Group Type on COVID-19 Risk and Severity
Woman with Rare Spinal Cord Defect from Birth Sues Doctor
View all

Medindia Newsletters Subscribe to our Free Newsletters!
Terms & Conditions and Privacy Policy.

More News on:
Boils / Skin Abscess Pityriasis rosea Pemphigus Hives Scleroderma Holistic Management for Depression Vitiligo Skin Self Examination Dermatomyostitis Swollen Lips Symptom Evaluation 

Recommended Reading
Lack of Oxygen Delays Brain Development in Premature Infants
Life-long impacts of brain injury in premature infants can be reduced and restored by supplying ......
Medical Negligence: 4 Die Due To Lack Of Oxygen At a Government Hospital In Bihar
District magistrate has directed IAS officer to probe the incident and submit a report at the ......
Test Your Knowledge on Rare Diseases
Rare or orphan diseases are the least understood of all the categories of chronic diseases. gene ......
Artificial Intelligence can Detect Rare Diseases Effectively: Here’s How
Artificial intelligence (AI) can be used to detect rare diseases more efficiently and reliably, ......
Boils / Skin Abscess
Encyclopedia section of medindia gives general info about Boils / Skin Abscess ...
Dermatomyostitis
Dermatomyostitis (DM) is an uncommon, inflammatory disease affecting the connective tissues. It is c...
Hives
Hives or Urticaria are allergic skin reaction that appear suddenly in clusters or as single bumps on...
Holistic Management for Depression
Depression is a common disorder and many worldwide suffer from depression. Early recognition of symp...
Pemphigus
Pemphigus is a rare group of autoimmune diseases that affect the skin and mucous membranes causing b...
Pityriasis Rosea
Pityriasis rosea is a common skin disease that is not contagious. It manifests as oval-shaped, pink ...
Scleroderma
Scleroderma or CREST syndrome is a chronic, auto immune disease which manifests as thick, dry, fibro...
Skin Self Examination
The skin self examination means checking one’s own skin for any visible abnormal growths or unusual ...
Swollen Lips Symptom Evaluation
Do you have swelling of lips? This can be alarming symptoms that involve one or both the lips. If pr...
Vitiligo
Vitiligo is a skin disease characterized by patches of unpigmented skin. Vitiligo is usually slowly ...

Disclaimer - All information and content on this site are for information and educational purposes only. The information should not be used for either diagnosis or treatment or both for any health related problem or disease. Always seek the advice of a qualified physician for medical diagnosis and treatment. Full Disclaimer

© All Rights Reserved 1997 - 2021

This site uses cookies to deliver our services. By using our site, you acknowledge that you have read and understand our Cookie Policy, Privacy Policy, and our Terms of Use