Gene Therapy in Mouse Fetuses Treats Deadly Disease

Gene therapy administered in the uterus could be used to treat a fatal genetic disease, suggests a study in fetal mice

The findings could add to the increasingly popular notion of prenatal gene therapy as way to minimize the damage caused. by certain genetic diseases.

This is a concept that is gaining popularity, says lead author Simon Waddington, who is studying gene therapy at University College London. The US Food and Drug Administration approved the first gene therapy for adults and children last year, and other treatments are clogging pharmaceutical pipelines around the world.

Waddington says that he met shocked looks when he was talking about treating fetuses with gene therapy. "I got to the point where I gave up telling people that fetal gene therapy was a good idea," he says. "And now, it's not uncommon, people are turning to me and saying, 'You know what would be a good idea?

The study on the mouse, published on the 16th July in Nature Medicine ¹ Uses Prenatal Gene Therapy to Treat a Pathology – Acute Neuronopathic Gaucher Disease – Caused by Mutations in a Gene Called GB A. These mutations disrupt the breakdown of a particular fat molecule, or lipid, as a result, the lipid accumulates in brain cells and other parts of the body, contributing to organ dysfunction. [] 19659002] The study examines whether the disease can be treated by using a virus to provide normal copies of GBA ] to a developing fetus.This could minimize the irreparable brain damage that occurs when lipid it accumulates.

This Some forms of Gaucher disease can be treated by providing normal copies of the GBA enzyme to degrade lipids, but this enzyme can not cross the brain. Children with acute neuronopathic Gaucher disease rarely live for two years. The disease is so devastating that colleagues were skeptical about her team's ability to treat it, says Waddington. "People have said to me, 'You will not touch that. "

Difficult passage

An obstacle was simply to get the virus to carry the healthy gene into the brain. The viruses used in previous tests had to be injected directly into the brain and then spread a short distance from the injection site. But in 2009, researchers showed ^{2 3} that a particular virus, simply injected into the bloodstream, could reach the central nervous system. From there, he scattered throughout the brain.

Waddington began working with mice, loading their virus with a normal copy of GBA, and searching for ways to express it specifically in the central nervous system. His team tested his virus in fetal mice carrying GBA mutations that cause symptoms similar to neuropathic Gaucher disease. These mice normally live only 15 days after birth; However, the treated mice survived for at least 18 weeks and were able to move normally.

The work is impressive, says Tippi MacKenzie, a specialist in fetal medicine at the University of California at San Francisco. MacKenzie has conducted a clinical trial on prenatal stem cell transplants. "Fetal gene therapy or enzymatic replacement therapy could be the next step," she says. "It's wonderful to see this type of rigorous research, to go even further."

Early Action

The treatment of fetuses has several potential advantages. The main one of them is the potential to minimize the damage caused by a genetic disease. Some diseases – such as neuronopathic Gaucher disease and spinal muscular atrophy – can cause irreversible symptoms before birth.

It is also easier to administer certain brain therapies in a developing fetus than in an adult or a child. barrier – a membrane that prevents certain molecules from crossing into the blood brain – has not yet fully formed. "Even a day after birth, it's harder to get into the brain," says Jerry Chan, obstetrician and gynecologist at the Duke-NUS Medical School in Singapore.

And the fetal immune system is still developing recognize the newly expressed protein as foreign. Adult immune systems sometimes generate antibodies against the new protein, which could prevent it from performing its function.

Chan and others have already tested fetal gene therapy to treat haemophilia in mice and macaques, and Chan is expecting doing so for several metabolic diseases similar to those of Gaucher

But there are risks. Researchers who develop prenatal gene therapy need to think not only about the fetus, but also about the mother, who will inevitably receive a dose of treatment, says Chan.

And clinicians must be absolutely certain that the mutation that they have found will cause the disease, Waddington notes. This may mean combining genetic testing with other tests done in utero to confirm the disorder. "We are now at the point where it is possible to diagnose these diseases," he says. "It makes people think: maybe we should do that."