CRISPR-edited lung cells (green) with fluorescent protein. Many, but not all, are alveolar lung cells. Photo credit: Penn Medicine
Using CRISPR gene editing, a team from Children’s Hospital of Philadelphia (CHOP) and Penn Medicine have thwarted a lethal lung disease in an animal model in which a harmful mutation causes death within hours after birth.
This proof-of-concept study, published today in Science Translational Medicine, showed that in uteroediting could be a promising new approach for treating lung diseases before birth.
“The developing fetus has many innate properties that make it an attractive recipient for therapeutic gene editing,” said study co-leader William H. Peranteau, MD, an investigator at CHOP’s Center for Fetal Research, and a pediatric and fetal surgeon in CHOP’s Center for Fetal Diagnosis and Treatment. “Furthermore, the ability to cure or mitigate a disease via gene editing in mid- to late gestation before birth and the onset of irreversible pathology is very exciting. This is particularly true for diseases that affect the lungs, whose function becomes dramatically more important at the time of birth.”
The lung conditions the team is hoping to solve — congenital diseases such as surfactant protein deficiency, cystic fibrosis, and alpha-1 antitrypsin — are characterized by respiratory failure at birth or chronic lung disease with few options for therapies. About 22 percent of all pediatric hospital admissions are because of respiratory disorders, and congenital causes of respiratory diseases are often lethal, despite advances in care and a deeper understanding of their molecular causes. Because the lung is a barrier organ in direct contact with the outside environment, targeted delivery to correct defective genes is an attractive therapy.
“We wanted to know if this could work at all,” said study co-leader Edward E. Morrisey, PhD, a professor of Cardiovascular Medicine in the Perelman School of Medicine at the University of Pennsylvania. “The trick was how to direct the gene-editing machinery to target cells that line the airways of the lungs.”
The researchers showed that precisely timed in utero delivery of CRISPR gene-editing reagents to the amniotic fluid during fetal development resulted in targeted changes in the lungs of mice. They introduced the gene editors into developing mice four days before birth, which is analogous to the third trimester in humans.
The cells that showed the highest percentage of editing were alveolar epithelial cells and airway secretory cells lining lung airways. In 2018, a team led by Morrisey identified the alveolar epithelial progenitor (AEP) lineage, which is embedded in a larger population of cells called alveolar type 2 cells. These cells generate pulmonary surfactant, which reduces surface tension in the lungs and keeps them from collapsing with every breath. AEPs are a stable cell type in the lung and turn over very slowly, but replicate rapidly after injury to regenerate the lining of the alveoli and restore gas exchange.
In a second experiment, the researchers used prenatal gene editing to reduce the severity of an interstitial lung disease, surfactant protein C (SFTPC) deficiency, in a mouse model that has a common disease-causing mutation found in the human SFTPC gene. One hundred percent of untreated mice with this mutation die from respiratory failure within hours of birth. In contrast, prenatal gene editing to inactivate the mutant Sftpc gene resulted in improved lung morphology and survival of over 22 percent of the animals.
Future studies will be directed toward increasing the efficiency of the gene editing in the epithelial lining of lungs as well as evaluating different mechanisms to deliver gene editing technology to lungs. “Different gene editing techniques are also being explored that may one day be able to correct the exact mutations observed in genetic lung diseases in infants,” Morrisey said.
Learn more: Researchers Use Gene Editing with CRISPR to Treat Lethal Lung Diseases before Birth
The Latest on: Gene editing
via Google News
The Latest on: Gene editing
- Road map for domesticating multi-genome rice using gene editingon March 5, 2021 at 10:35 am
A road map for doing just that has now been developed using wild rice. The authors first spent time identifying an appropriate starting strain. The ideal candidate needed to be amenable to callus ...
- CRISPR 2.0: Base Editing in the Grooveon March 3, 2021 at 7:56 pm
A series of exciting preclinical and animal model results show that base editing is making rapid strides toward the clinic.
- Gene editing vital for climate-proofing future crops - Researchon March 3, 2021 at 6:15 pm
Gene editing technology will play a vital role in climate-proofing future crops to protect global food supplies, according to scientists at The. Biotechnologist Dr Karen Massel from UQ's Centre for ...
- Unique nanoparticles can package and deliver gene-editing machinery to the liveron March 1, 2021 at 1:22 pm
The genome editing technology CRISPR has emerged as a powerful new tool that can change the way we treat disease. The challenge when altering the genetics of our cells, however, is how to do it safely ...
- Genome editing reveals fitness effects of a gene for sexual dichromatism in Sulawesian fisheson March 1, 2021 at 8:45 am
The mutations underlying sexually selected traits like the red fins on a male medaka fish can be hard to pinpoint. Using a new genome, transcriptomics and gene editing, Ansai et al. find that the gene ...
- Hotter, drier, CRISPR: editing for climate changeon March 1, 2021 at 7:17 am
Just 15 plant crops provide 90 per cent of the world's food calories. A review of genome editing technologies published in Theoretical and Applied Genetics states gene editing technology could play a ...
- Scientists use lipid nanoparticles to precisely target gene editing to the liveron February 28, 2021 at 4:00 pm
The genome editing technology CRISPR has emerged as a powerful new tool that can change the way we treat disease. The challenge when altering the genetics of our cells, however, is how to do it safely ...
- Gene Editing’s Vast, Double-Edged Potentialon February 26, 2021 at 12:51 pm
CRISPR technology should be limited exclusively to healing genetic diseases in breathing humans.
- New gene-editing tool enables programming of sequential cuts over timeon February 23, 2021 at 3:29 pm
Researchers from the University of Illinois Chicago have discovered a new gene-editing technique that allows for the programming of sequential cuts -- or edits -- over time.
- Researchers invent new gene-editing toolon February 23, 2021 at 10:12 am
Researchers from the University of Illinois Chicago have discovered a new gene-editing technique that allows for the programming of sequential cuts—or edits—over time.
via Bing News