Researchers use gene editing with CRISPR to treat lethal lung diseases before birth

Researchers use gene editing with CRISPR to treat lethal lung diseases before birth
CRISPR-edited lung cells (green) with fluorescent protein. Many, but not all, are alveolar type 2 cells. 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 utero editing could be a promising new approach for treating lung diseases before birth.

"The 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 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 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 is an attractive therapy.

"We wanted to know if this could work at all," said study co-leader Edward E. Morrisey, Ph.D., 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 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 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 towards 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 in infants," Morrisey said.

Morrisey collaborated on a recent study led by Peranteau and Kiran Musunuru, MD, Ph.D., an associate professor of Cardiovascular Medicine at Penn, demonstrating the feasibility of in utero gene editing to rescue a lethal metabolic liver disease in a mouse model - the first time in utero CRISPR-mediated gene editing prevented a lethal metabolic disorder in animals. Similar to that study, Peranteau says "the current research is a proof-of-concept study highlighting the exciting future prospects for prenatal treatments including gene editing and replacement gene therapy for the treatment of congenital diseases."

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Guided by CRISPR, prenatal gene editing used in treating congenital disease before birth

More information: D. Alapati at Nemours Alfred I duPont Hospital for Children in Wilmington, DE el al., "In utero gene editing for monogenic lung disease," Science Translational Medicine (2019). … scitranslmed.aav8375
Journal information: Science Translational Medicine

Citation: Researchers use gene editing with CRISPR to treat lethal lung diseases before birth (2019, April 17) retrieved 22 October 2019 from
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Apr 17, 2019
It is good that science is 'interfering' with the natural course of events within the human organism, particularly for the benefit of the parents of the child whose future may be uncertain due to disease. The emotional trauma that is caused by such natural events as disease that occurs in the pre- and post-born is oftentimes too unbearable.
However, this interference to mitigate in the health of the organic human organism is detrimental to the avoidance of future incidences of disease in next generation organisms, provided that the initially inflicted happens to survive through scientific intervention.
The same type of disease is then passed on to the following and succeeding generations due to the survival of the ancestor in whom the disease had first been generated and observed.
But certainly, the parents of the inflicted offspring will not see it that way, and will most often insist that everything be done to save and make whole their loved one. And the disease is passed on

Apr 17, 2019
When humans were wild

Were savage
when all they knew was the call of wild
their life
was brutal, cruel, short disease ridden maggot infested
physically shattering
cracked and shattered bones
worn out cartilage
crippling torn muscles and tendons
cracked, broken decaying teeth
most importantly
Their human life was short

Despite this horrific life style of wild humans
they were
physically strong
free from disease
there offspring
were of the best DNA stock free from abnormalities
these savage humans
lived by the call of the wild
survival of the fittest
so as they died young
only the genetically strong passed their genes onto their offspring
because of these things
Wild humans were genetically strong and pure

Apr 17, 2019
Wild humans have been tamed

Live peaceful lives
all their little desires are catered for
these once wild humans have been tamed
they wont for nothing
there happy contented
there clean
their hair is no longer matted
with soft glowing complexions
when humans were wild
take any of these wild human children
bring them up in modern houses
in our modern life style
these wild ancient human children
had the same soft glowing complexion
the same intellectual outlook
they were indistinguishable from tame humans
their secret invisible advantage over tame humans
because they lived by the call of the wild
they did not pass on these genetic abnormalities
that tame humans pass on to their offspring
the moral these wild human children raise
because tame humans live long life styles
have to eliminate these genetic abnormalities medically
Wild humans did by their short brutal life style

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