William Peranteau is the type parents call when they have received the kind of bad news that rips up stomachs and hearts. Sometimes it is a shadow on an ultrasound or a few base pairs that are wrong in a prenatal genetic test and shows that an unborn child has a life-threatening developmental defect. Pediatric surgeons like Peranteau, who work at Children's Hospital in Philadelphia, usually can not try to remedy these anomalies until their patients leave their mother's body behind. And by that time it might be too late.
With the memory of the families he could not help himself, as Peranteau joined a small group of scientists who wanted to tackle the fast-paced field of gene processing to the womb. Such human editing is still a long way off, but a series recent advances in mouse studies indicate its potential benefits over other methods of using Crispr to cut disease. Parents who are faced with a uterine diagnosis often have only two options: they must stop the pregnancy or prepare for the care of a child who needs several invasive surgeries to survive in the course of his life. Prenatal editing of genes can provide a third potential route. "What we see as the future is a minimally invasive way to treat these anomalies at their genetic origin," says Peranteau.
The WIRED Guide to Crispr
To prove this vision, Peranteau and colleagues from the University of Pennsylvania injected Crispr cut components encoded in a virus into the placentas of pregnant mice unborn puppies were affected by a fatal lung disease. As the fetuses inhaled the amniotic fluid, they also inhaled the Crispr bits, which then processed the DNA in their rapidly dividing alveolar progenitor cells. These cells produce many types of cells that line the lungs ̵
. It is the second proof-of-concept of the scientific group of the past year. In October, they published an article describing a slightly different approach to editing mutations that lead to a fatal metabolic disorder. By changing a single base pair in the liver cells of prenatal mice, Peranteau's team was able to save almost all mouse puppies. Recent successes include unborn mice that have been cured of a blood disorder called beta-thalassemia due to a prenatal Crispr injection performed last year by a team at Yale and Carnegie Mellon.
Although the field is still in its infancy, its pioneers believe that many of the problems that Crispr-based therapies have to overcome – such as achieving the right cells and avoiding the human immune system – are being solved by treating patients while they are still in the womb.
When they try to process cells in an adult organ, they do not multiply. So you have to reach many of them to make an impact, "says Edward Morrisey, a cardiologist at the University of Pennsylvania who helped shape the latest study. In contrast, fetuses are still developing, which means their cells divide rapidly as they grow into new tissue. The earlier you can work in life, the more these genetic changes multiply and spread through the developing organs. Morrisey's mice may have been born in only about 20 percent of their lung cells with genetic engineering, but 13 weeks later, the correction had spread to the entire surface of the lung. "They actually outperformed the unedited cells because those cells are very sick," says Morissey.
This is a great advantage, especially for lung diseases. Once a baby leaves the watery world of the uterus, his lung cells begin to secrete a surfactant-mixed mucus barrier to prevent dust or viruses or other foreign bodies, including Crispr components, from reaching those tissues. A developing fetus also has a less aggressive immune system than a human exposed to the outside world. It is therefore less likely to attack Crispr components that ultimately come from the bacterial kingdom.
Megan Molteni deals with biotechnology, medicine and genetic privacy for WIRED.
Now, you may think, if earlier editing is better, you can work on an embryo right after fertilization, if it's only one or two cells old. But this technique, known as the germline cut (you may remember last year's Chinese Crispr baby scandal), is a much more complicated ethical endeavor. Editing at this time would pass any change to of each cell, including those that would then form sperm or eggs. This type of processing is effectively banned in the United States after the Congress has instructed the US Food and Drug Administration (US Food and Drug Administration) not to permit clinical trials on genetically modified human embryos. (The ban, which must be renewed annually, was last reaffirmed in February 2019). On the other hand, it is difficult to get an accurate diagnosis when an embryo is only a few cells old. If you wait long enough to get a picture of the fetus along with other vital signs, you can provide important clues as to the severity of the condition. "It puts us in the right position to treat a disease at the very beginning, basically at diagnosis," says Peranteau.
However, there are security concerns that need to be resolved. For one, two patients are involved in utero editing, not just one. In curing a child, this technique may expose a healthy onlooker – the mother – to treatment that offers no potential benefit and only potential risks, including dangerous immune responses. And since the processing takes place in their reproductive area, some stubborn Crispr components could move through their fallopian tubes into the ovaries and possibly make changes to other unfertilized eggs. To better assess these risks, much more science is needed. To give you an idea of how long this can take, in utero gene therapy – an older approach in which a defective gene is replaced by a working one with a virus – you should be in the mid-1990s after a series of episodes have suggested positive evidence for concept studies in mice. Today, only a single clinical trial is underway.
"This is not a panacea for curing all the genetic diseases that are out there," says Peranteau. However, he believes that a Crispr approach will be able to address the work of the gene therapy area and at least provide a new way forward for some of its patients. "At some point in the future – not tomorrow or the next day, in a few years – I think editing Uteros gives hope to families that do not have them today."
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