The gene edition Crispr arrives for the belly

William Peranteau is the parents that parents call when they have received the kind of bad news that sinks in the stomach and squeezes their hearts. Sometimes it is a shadow on an ultrasound or a few poorly placed base pairs on a prenatal genetic test, which reveals that an unborn child has a life-threatening developmental defect. Pediatric surgeons like Peranteau, who works at the Philadelphia Children's Hospital, can not usually attempt to cure these anomalies until their patients leave their mother's body. And from here, it may be too late.

It was in the memory of the families that he could not forget that Peranteau had joined a small group of scientists who were trying to bring the rapidly changing field of gene editing into the belly. This edition in humans is still far from being realized, but a series of recent advances in mouse studies highlights its potential advantages over other methods of using Crispr to fight against diseases. Parents facing an in utero diagnosis often have only two options: terminate the pregnancy or prepare to look after a child who may require multiple invasive surgeries during their lifetime to survive. . Prenatal gene editing may offer a third potential path. "What we perceive as a future is a minimally invasive way of treating these abnormalities at the level of their genetic origin," says Peranteau.

To prove this vision, Peranteau and his colleagues at the University of Pennsylvania injected Crispr editing components, encoded in a virus, into the placenta of pregnant mice whose unborn babies were suffering from the disease. a mutation causing fatal lung disease. When the fetuses breathed in the amniotic fluid, they also inhaled the Crispr bits, which set to work to modify the DNA inside their rapidly dividing alveolar progenitor cells. These cells produce many types of cells that line the lungs, including those that secrete a sticky substance that prevents the lungs from collapsing every time you breathe. Mutations in the proteins that make up this secretion are a major source of congenital respiratory disorders. All mice carrying the mutation died a few hours after birth. About a quarter of those published with Crispr survived. The results were published in this day's issue of Translational medicine science.

This is the second proof of concept of the group of scientists of the past year. In October, they published an article describing a slightly different procedure for editing mutations leading to a deadly metabolic disorder. By modifying a single base pair in the prenatal mouse liver cells, the Peranteau team was able to save almost all the raccoons. Other recent successes include the unborn mice cured of a blood disorder called beta-thalassemia following a prenatal injection of Crispr, performed last year by a team from Yale and Carnegie Mellon.

Although the field is still in its infancy, its pioneers believe that many of the issues facing Crispr-based treatments – such as reaching enough adequate cells and escaping the human immune system – can be solved by treating patients then that they are still alive. in the womb.

"If you try to modify cells in an adult organ, they do not proliferate. So you have to reach a lot to make an impact, "says Edward Morrisey, a cardiologist at the University of Pennsylvania, who co-authored the latest study. The fetuses, on the other hand, continue to develop, which means that their cells divide rapidly to develop into new tissues. The sooner you can edit, the more these genetic changes will multiply and spread in developing organs. Morrisey mice could only have been genetically modified in about 20% of their lung cells, but 13 weeks later the correction had spread to the entire lung surface. "They actually went beyond unedited cells, because those cells are very sick," says Morissey.

For lung diseases in particular, this represents a considerable advantage. As soon as a baby leaves the watery world of the uterus, his lung cells begin to secrete a mucus barrier mixed with a surfactant, to prevent dust, viruses or other foreign objects, including including the components of Crispr, to reach these tissues. The developing fetus also has a less aggressive immune system than humans exposed to the outside world. It is therefore less likely that we attack the components of Crispr, which, after all, come from the bacterial kingdom.

You may think that if editing earlier is better, why not edit an embryo right after fertilization, when there is only one cell or two years? But this technique, known as germ line modification (as you may remember from the Chinese Crispr baby scandal of last year), is a much more complicated ethical enterprise. Editing at this point would forward all changes to each cell, including those that produce sperm or eggs. In the United States, this type of montage is actually banned as a result of a congressional directive to the US Food and Drug Administration prohibiting any clinical trial involving genetically modified human embryos. (The ban, which must be renewed every year, was recently reaffirmed in February 2019). The other thing is that having an accurate diagnosis when an embryo has only a few cells can be tricky. Waiting long enough to visualize the fetus and other vital signs can provide important clues to the severity of the disease. "We are in this ideal situation to treat a disease at the very beginning, essentially as soon as it is diagnosed," said Peranteau.

But there are still security issues to solve. On the one hand, editing in utero involves two patients, not one. In the process of healing a child, this technique would potentially expose a healthy control – the mother – to treatment that brings no potential benefit and only involves potential risks, including dangerous immune responses. And because the update takes place in its reproductive system, misplaced Crispr components may rise into its fallopian tubes and ovaries, potentially altering other unfertilized eggs. Much more scientific research will be needed to better assess these risks. To give you an idea of ​​how long it may take, consider that gene therapy in utero – an older approach of replacing a defective gene with another one that works with a virus – was first proposed in the middle of 1990s following a series of positive proof-of-concept studies in mice. Today, only one clinical trial is in progress.

"It's not a panacea for curing all the genetic diseases that exist," says Peranteau. But he thinks that a Crispr approach will be able to piggyback on the work of the field of gene therapy and could offer a new way forward for at least some of his patients. "At some point in the future, not tomorrow or the next day, in a few years, I think that publishing in utero would give hope to families who do not have any today. # 39;. hui "

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