Gene Therapy in the Womb Is Inching Closer to Reality

Currently, very few heritable diseases have gene therapies that have been approved by the FDA. One therapy, called Zolgensma, treats spinal muscular atrophy in newborns and children up to age two. But halting the disease in childhood may still be too late to avoid lifelong health issues. “When the baby is born, in the most severe forms of the disease, the neurons that are affected in this disease are already sick,” says Beltrán Borges, a postdoctoral researcher of pediatric surgery at the University of California, San Francisco. “We were wondering: If we intervene earlier, can we perhaps prevent that disease from happening—and have the kid have a normal life?”

In 2019, Turkish researchers published evidence that in utero gene editing for this disorder could work in mice. “We wanted to take this one step further and take it to sheep,” which are well-studied test subjects for the disease, Borges says.

Borges examined where the gene editing machinery would go if injected through either the umbilical vein or directly into the cranium. Umbilical injections are less direct, but far more accessible. His team tested the two routes by injecting a benign virus carrying genetic instructions that would make the recipient cells glow green, indicating where they had landed. 

According to preliminary results Borges shared at the conference, the instructions sent by umbilical injections went where he hoped, like the brain, spinal cord, and muscle cells. But there was a catch: They also went where they shouldn’t. Borges reported a small number of locations where genetic material entered female fetal lambs’ egg cells. “Those should never be touched,” Borges says.“That’s kind of like a big red line that is seen in the field and everybody respects.” It’s essential to avoid doing anything that might enable the editing of reproductive, or “germline,” cells, because those DNA changes could be passed down to the next generation. Gene replacement therapies, including this experiment, don’t edit an individual’s genome, and should not be heritable.

Borges is still working out why this happened in just eggs and not sperm, and what could prevent it. But the ongoing work highlights the caution with which researchers are proceeding. One of the other big challenges researchers are anticipating is immune response. Many people have antibodies for the Cas9 protein that Crispr uses to cut DNA, which means that their bodies may reject the therapy altogether.

A pair of presentations about in utero gene therapy in mice highlighted the role immunity can play in determining if a therapy will work. For example, one set of results investigating a long-term cure for tyrosinemia, a genetic liver disease, showed that the gene therapy kept working in the fetus even when the mother was immune to the Cas9 editing machinery. But in a different presentation, the same researcher found that maternal immunity does foil in utero gene therapy in other cases: When pregnant mice had immunity to the AAV9 virus often used to deliver gene therapy, more of their fetal offspring died due to the maternal immune response. One possible workaround researchers are considering for future tests in humans: Whether injecting the therapy directly into the umbilical cord early in pregnancy may safeguard the fetus from the mother’s immune response.

It’s still very early days for gene therapy in the womb, and Peranteau stresses that so far most of the work has been done in mice and non-human primates. It’s going to take a while to surmount the challenges posed by drug delivery, immune rejection, and the risk of germline edits. Then more research will be needed to ensure the safety of both fetus and parent, and to test whether the benefits of the therapy last long after treatment. “It is all very proof of concept,” he says, estimating that the first human in utero trials are probably still 5 to 10 years away. So while these conference presentations offer some hope, he says, “The most important thing is to not give false hope.”

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