Currently, there are very few FDA-approved genetic diseases for which gene therapy is possible. A treatment called Zolgensma treats spinal muscular atrophy in newborns and children up to 2 years of age. But stopping the disease in childhood may still be too late to avoid lifelong health problems. “When babies are born, in the most severe forms of the disease, the neurons affected by the disease are already diseased,” said Bertrand Borges, a postdoctoral fellow in Pediatric Surgery at the University of California, San Francisco. talk to. “We wondered, if we could intervene earlier, perhaps we could prevent the outbreak and allow the child to lead a normal life?”
In 2019, Turkish researchers published evidence that in utero gene editing for this disease could work in mice. “We wanted to take this a step further and try sheep, which are a well-studied subject for this disease,” Borges said.
Borges investigated where gene-editing machines would go if injected through the umbilical vein or directly into the skull. Injection into the navel is less direct, but much more accessible. His team tested the two routes by injecting a benign virus carrying genetic instructions that make the recipient cells glow green to indicate where they landed.
Preliminary results Borges shared at the conference said that the commands sent by the navel injection went where he wanted them, including the brain, spinal cord and muscle cells. However, there was a catch. They went to places they weren’t supposed to go. Borges reported a small number of locations where genetic material entered the egg cells of fetal female lambs. “They should never be touched. It’s like the big red line you see on the field and everyone respects it,” says Borges. It is important to avoid actions that allow editing of germ cells, or “germline” cells, as DNA changes can be passed on to the next generation. Gene replacement therapy, including this experiment, does not edit an individual’s genome and should not be inherited.
Borges is still researching why this happened with just the egg, not the sperm, and what could prevent it. But ongoing research highlights that researchers are proceeding cautiously. One of the other big challenges researchers anticipate is the immune response. Many people have antibodies against her Cas9 protein, which Crispr uses to cleave her DNA, so their bodies may reject this therapy altogether.
Two presentations on in utero gene therapy in mice highlighted the role that immunity can play in determining whether a treatment works. For example, a series of results investigating long-term treatments for the hereditary liver disease tyrosinemia show that gene therapy continues to work in the fetus even if the mother is immune to the Cas9 editing machinery. It has been shown. However, in a separate publication, the same researchers found that maternal immunity is otherwise useless in intrauterine gene therapy. When pregnant mice were immune to the AAV9 virus, a common gene therapy virus, more fetuses died due to maternal immunity. response. The researchers are considering one possible workaround for future human trials. The question is whether injecting the drug directly into the umbilical cord early in pregnancy can protect the fetus from the mother’s immune response.
In utero gene therapy is still in its infancy, and most of the research so far has been in mice and non-human primates, Perantau stresses. It will take some time to overcome the challenges posed by drug delivery, immune rejection and risks of germline editing. Further research will then be needed to ensure both fetal and parental safety and to test whether the effects of treatment are long-lasting after treatment. “It’s just a proof of concept,” he says, speculating that the first human in utero experiment is probably still five to 10 years away. So while presentations at these conferences offer some hope, “the most important thing is not to give false hope,” he says.
