The potential of gene therapy to cure severe genetic diseases is a promising frontier in medical science. Recent developments in the field are paving the way for the possibility of treating these diseases in utero – the earliest possible intervention. This emerging area of research was highlighted at the annual meeting of the American Society of Gene & Cell Therapy, where researchers presented their progress on in-utero gene therapy.
Currently, physicians can detect genetic abnormalities in a developing human fetus, such as conditions like sickle cell anaemia and spinal muscular atrophy. While gene therapies can treat adults and children with these conditions, they come with certain drawbacks. They are often expensive, and many are only accessible to clinical trial participants. Furthermore, by the time a person receives the therapy, they might have already spent a significant amount of time living with the disease.
The potential advantage of administering gene therapies in the womb lies in preventing these diseases before they manifest. “The main advantage of administering these therapies in the womb or before birth would be to prevent disease before it happens,” says Bill Peranteau, a pediatric and fetal surgeon with the Children’s Hospital of Philadelphia, whose team presented at the conference.
Gene therapy drugs, which are often DNA-editing tools like CRISPR, are carried to the target cells using a delivery vehicle, usually a virus or nanoparticle. However, one of the main challenges of this treatment is the delivery of these “drugs” to the correct cells in organs like the brain, lungs, and skin.
Despite the challenges, progress has been made. One team, for example, has been successful in using lipid nanoparticles to deliver gene therapy to treat congenital brain disease. The nanoparticles were able to reach human neurons in lab cultures, as well as the brains of newborn and fetal mice, with a significantly stronger effect than an industry standard approved by the US Food and Drug Administration.
Another promising development comes from the field of neurodevelopmental diseases, which often manifest before birth and are hard to reverse afterwards. For conditions like these, prenatal therapy could be an ideal solution. However, the road to in-utero gene therapy is a complex one, filled with challenges that need to be overcome, including issues of drug delivery, immune rejection, and the risk of germline edits.
One of the major concerns in this field is the safety of both the fetus and the parent. Ensuring that the gene therapy is delivered to the correct organ and does not affect the parent is of utmost importance. Additionally, researchers are keen to avoid any edits to germline cells, as such changes could be passed down to the next generation.
There are currently few heritable diseases with gene therapies approved by the FDA. One such therapy, Zolgensma, treats spinal muscular atrophy in newborns and children up to age 2. However, even this intervention may be too late to avoid lifelong health issues in the most severe forms of the disease. Researchers are therefore looking at in-utero gene therapy as a way to intervene earlier and potentially prevent the disease from manifesting, thus allowing the child to lead a normal life.
While the future of in-utero gene therapy looks promising, it is still very early days for this field. Most of the work so far has been done in mice and nonhuman primates. It may take years to overcome the challenges posed by drug delivery, immune rejection, and the risk of germline edits. More research will be needed to ensure the safety of both the fetus and the parent before these therapies can be offered in clinical practice.
