In-utero gene therapy is slowly getting closer to reality

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Currently, very few inherited diseases have gene therapies that have been approved by the FDA. A therapy, named Zolgensma, treats spinal muscular atrophy in newborns and children up to two years of age. But stopping the disease in childhood may still be too late to avoid lifelong health problems. “When the baby is born, in the most severe forms of the disease, the neurons that are affected in this disease are already diseased,” says Beltrán Borges, a postdoctoral researcher in pediatric surgery at the University of California, San Francisco. “We were wondering: if we intervene sooner, maybe we can prevent that disease from happening and make the child 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 go one step further and bring 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 the umbilical vein or directly into the skull. Umbilical injections are less direct, but much more accessible. His team tested both routes by injecting a benign virus that carried genetic instructions that would cause recipient cells to glow green, indicating where they had landed.

According preliminary results Borges shared at the conference, the instructions sent by umbilical injections went where he expected, 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 places where genetic material entered the eggs of fetal sheep. “Those should never be touched,” says Borges. “It’s like a big red line that you see on the field and everyone respects it.” It is essential to avoid doing anything that might allow reproductive or “germ line” cell editing, because those DNA changes could be passed on to the next generation. Gene replacement therapies, including this experiment, do not change an individual’s genome and must not be heritable.

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

A couple of presentations on in utero gene therapy in mice highlighted the role immunity can play in determining whether a therapy will work. For example, a result set Research into a long-term cure for tyrosinemia, a genetic liver disease, showed that gene therapy continued to work 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 frustrates gene therapy in utero in other cases: When pregnant mice had immunity to the AAV9 virus that is often used to deliver gene therapy, more fetal offspring died from to maternal immunity. answer. The researchers are considering a possible workaround for future human testing: whether injecting the therapy directly into the umbilical cord early in pregnancy can protect the fetus from the mother’s immune response.

It’s still very early days for gene therapy in the womb, and Peranteau stresses that most of the work so far has been done in mice and non-human primates. It will take time to overcome 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 the fetus and the parents, and to assess whether the benefits of therapy last long after treatment. “It’s all proof of concept,” she says, estimating that the first in-utero human trials are probably still 5 to 10 years away. So while these conference presentations offer some hope, she says, “The most important thing is not to give false hope.”