Can gene therapy halt diseases in babies before they’re even born?

Gene therapies — in which a corrective gene hitches a ride on a virus into a patient’s cells — are being tested as potential cures or treatments for sickle cell, Duchenne muscular dystrophy, and a range of other diseases. Some patients have already been treated with a gene therapy for an inherited form of blindness, the first to be approved in the U.S.

Now, imagine the virus-gene rig slipping into a pregnant woman’s womb, where it would reach the fetus and start remedying a disease before the baby is even born.

That kind of procedure remains an untested goal for now — one whose feasibility has been debated by scientists for years. But advances in fetal gene therapies in animal models have raised the real possibility that clinical trials may be soon at hand.

“I think we’re ready to go,” said Simon Waddington, a University College London scientist who, as he says, focuses on “making genetic medicines for sick children.”

Of course, any human trial of a fetal gene therapy would require regulatory and ethical approval — significant hurdles given that such a procedure would involve risks to both the fetus and pregnant woman. Other researchers say they want to see more data from animal studies before a clinical trial begins. And plenty of questions remain, not just about whether a particular therapy would work in people but about how long benefits would last.

But Waddington’s enthusiasm in part stems from a study published last week in which he and colleagues transferred a corrective gene in a fetal mouse model of a severe form of Gaucher disease — a condition in which the body doesn’t produce a key enzyme that breaks down a certain fat.

They found that affected mice that were treated with a gene therapy in utero were in many ways indistinguishable from their littermates that did not have the disease. What’s more, the researchers found that treating the mice soon after they were born had some benefits, but not to the extent that treating them in utero did.

The researchers also showed they could deliver the gene therapy to the brains of monkey fetuses — a model more similar to people than mice.

Waddington said the team chose to study a model of neuronopathic Gaucher disease because it is so devastating; babies born with the condition are already suffering from brain and organ damage and typically die within a few years. The study, he and his colleagues hoped, could “showcase the awesomeness of gene therapy.”

There is little doubt that more scientists see potential in the idea. Just a decade ago, there was disagreement over pursuing fetal gene therapy. A scientific review then found that “many view the concept as having only academic value, with no potential for translation into the clinic.”

“As the entire field of gene therapy, both prenatal and postnatal, has advanced over the last 10 to 15 years, there has been an acknowledgement that it is a true possibility for the future,” said Dr. William Peranteau, a pediatric and fetal surgeon at Children’s Hospital of Philadelphia, who co-authored a more recent review about fetal gene therapy.

However promising fetal gene therapy may be, experts say that the technology — if developed and ultimately approved — would only be used in certain cases and in a limited number of diseases.

The most likely contenders would be diseases that start inflicting serious, irreversible damage to the fetus during pregnancy. In those cases, scientists would need to understand the underlying genetic cause of the condition — and how to fix it. And they would have to be able to diagnose the condition in the fetus before it starts killing cells or destroying tissue.

As Dr. Kjersti Aagaard, a maternal-fetal medicine specialist, put it: “How early is too late?” In other words, even if doctors are able to detect the disease early in the pregnancy, will it already have caused irreparable harm?

“You have to know that undertaking this intervention will not cause more harm than good,” said Aagaard, of Baylor Obstetrics and Gynecology at Texas Children’s Pavilion for Women in Houston. “And you have to know that the disease groundwork isn’t already in place by the time you intervene.”

Among the diseases that might be treated with gene therapy in utero are lysosomal storage disorders like Gaucher disease, hemophilia, spinal muscular atrophy, and some neurodegenerative diseases, experts say.

“It’s technically and scientifically feasible,” said Dr. Tippi MacKenzie, a pediatric and fetal surgeon at University of California, San Francisco, who is involved with the first clinical trial of a fetal stem cell therapy. “It’s just a question of what diseases are ethically the most relevant for consideration.”

Indeed, as scientists have made progress in mice and macaques, they have also been confronting thorny ethical questions that have risen as they’ve moved toward the clinic. Among them: What are the moral and financial implications of giving a person who might have died at age 2 a longer life if the treatment only allows the person to live to 25 and with severe disabilities? And would such a procedure be worth the risks to the fetus — and the mother?

“The deal with obstetrics is that you’ve always got two patients,” Waddington said.

It’s possible, for instance, that some of the mother’s cells could take up the corrective gene delivered to the fetus. Researchers said they weren’t sure how frequently that would occur and what might happen in the long run if it did.

On the flip side, fetal gene therapy offers the possibly of stopping a disease before it really starts. It also offers other biological advantages over trying to treat a condition after a baby is born, some experts said.

A fetus’s immune system is still developing, for example, so it is less likely to recognize the therapy as foreign and attack than a fully developed immune system. Delivering a therapy into the brain is much easier in a fetus than in even a newborn.

(Some experts cautioned that gene therapies could provoke some immune response in the fetus. The immune system is developing, not absent, during a pregnancy, they noted.)

The question of how the therapy is delivered would depend in part on the organ being targeted and the viral vector clinicians are using. Doctors could inject it with a fine needle directly into the umbilical cord in a step similar to a fetal blood transfusion, which is a fairly routine procedure. In some cases, the vectors can be designed so that once they reach the fetus, they can travel to the desired organ, where the corrective genes would be adopted.

Gene therapy is only one fetal medical technology being pioneered right now. In addition to MacKenzie’s fetal stem cell trial, researchers recently showed that injecting a drug directly into the amniotic fluid helped babies with a rare genetic condition. Doctors are also recruiting for the “Everrest” clinical trial, in which pregnant women will receive a gene therapy aimed at improving blood flow to the fetus to stem a condition called fetal growth restriction.

But experts also noted that it’s important not to move too aggressively with experimental treatments. After a patient died in a gene therapy clinical trial in 1999, it set the whole field back for years.