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Nearly 40 years after the first surgery of a fetus on fetuses to cure devastating abnormalities, the researchers took a first step in the treatment of genetic disease before birth via the editing of the genome: scientists announced Monday that they have used the CRISPR genome editing technique for the uterus, eliminating liver disease often fatal even before the animals are born.
The research, conducted by a team from the University of Pennsylvania and CHOP (Children's Hospital of Philadelphia), is a very early proof of concept. But although CRISPRing human fetuses are years away, at best, success in mice reinforces what Dr. William Peranteau, who co-directed the study, calls his dream to cure genetic diseases before birth.
"We still need a lot of work on animals before we can think about applying this [fetal genome editing] clinically, "said Peranteau, pediatric and fetal surgeon at CHOP. "But I think that fetal genome editing may be the place where fetal surgery [which is now routine] once, and we will use it one day to treat diseases that cause significant morbidity and mortality. "
Simon Waddington of University College London, a leader in research on the development of fetal gene therapy who did not participate in the new study, called the CRISPR approach "refinement." elegant 'brute force' technology that has been the focus of animal therapy studies.
The success of mouse fetuses suggests that even before traditional gene therapy is ready to uselessly treat hereditary disorders, genome editing could become a safer and more effective approach. In traditional gene therapy, a healthy whole gene is transferred, usually by a virus, into cells containing a gene causing disease. With CRISPR, only the mutated bit of a faulty gene is changed. It's the difference between retyping an entire 5,000-word document and using Word's "find and replace" to correct a typo.
"We think this is a safer and more accurate way to make genome modifications," said Dr. Kiran Musunuru of Penn and Co-Leader of the study. "This is the best way to go if you want to integrate CRISPR at the clinic."
The rationale for fetal gene therapy is simple: it could stop a disease before it causes irreversible or even life-threatening damage. In humans, the hereditary liver disease targeted by scientists, called hereditary tyrosinemia type 1, begins to damage the liver several months before birth. Another reason is that since the fetal immune system is immature, it is less likely that the newborn will attack foreign CRISPR molecules.
For their study, published in Nature Medicine, Musunuru and colleagues gently opened the uterus of a pregnant mouse, removed the fetus from the amniotic sac and injected CRISPR into the vitelline vein, located on the surface of the sac, and connecting to the liver. "We wanted to make sure that the genome publisher was integrated into the liver rather than anywhere else," Musunuru said. The fetus was then returned to the uterus and was born normally.
Instead of using the original form of CRISPR, which cuts DNA when a gene is mutated and inserts a replacement chain of A, T, C, and G, scientists used the form of CRISPR, called Basic Edition. Invented just two years ago, base editing modifies an incorrect letter, or base letter, into a correct letter, such as a C or a T in A. The advantage is that It is not necessary to cut the DNA to do it. this, as CRISPR 1.0 does; these cuts can cause genetic damage, with unknown consequences for CRISPR'd cells.
For a dry test period, the scientists first created a CRISPR basic editor that modifies a gene called PCSK9, which makes a protein that helps regulate the amount of cholesterol in the blood, in a way. hypocholesterolemic form. When it was injected into mouse fetuses, the basic editor altered the liver cells as expected and left the other organs alone. Crucially, the mother of mice showed no effect of CRISPR treatment. After birth, the baby mice had ultra-low cholesterol levels, which showed that the basic CRISPR editor had worked. Only about 15% of the liver cells of baby mice had been published, but this fraction remained stable until adulthood.
The amount of genetic havoc resulting from the basic edition was low: about 2%, compared to 40% for many traditional CRISPR uses. And none of the places likely to have "untargeted" effects – DNA sites that look like the target and could therefore be inadvertently modified – showed no signs of change.
Philadelphia scientists then tried their technique on hereditary tyrosinemia type 1. HT1, which strikes 1 newborn in 100,000 newborns worldwide, is caused by any mutations of a gene called FAH . All mutations lead to the formation of toxic degradation products of tyrosine, an amino acid component of the protein, and eventually destroy the liver. Nitisinone treatment and a strict tyrosine-free diet are not always effective, so children sometimes develop fatal liver failure or liver cancer.
Scientists have used their basic editor on a gene linked to the one that causes the disease. If this gene, called HPD, is turned off, no toxic tyrosine metabolite ever reaches a place where FAH is unable to handle it.
Changing a C to T in the HPD gene has disabled it. No toxic molecules have accumulated in the liver of fetal mice. No other organ showed signs of retouching, no untargeted effect was detected, and modifying only 15% of its liver cells was enough to heal the mice and maintain them until they reached the end. 39, adulthood. "We did not expect that, but the modified genome mice did a lot better" than the nitisinone-treated mice, Musunuru said. "They survived longer and gained more weight."
Scientists hope to study the editing of fetal bases for other serious congenital diseases. It remains to be seen whether this technique or conventional gene therapy, which provides a complete replacement gene, will work better.
"I would consider that CRISPR is not a substitute," said Waddington, "but will be an additional tool" for healing genetic diseases in the womb.
Republished with permission of STAT. This article was published on October 8, 2018
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