A growing body of research suggests that serious genetic disorders may be treated prenatally by administering medicine directly into the amniotic fluid, potentially preventing damage that begins before birth. A recent study led by researchers at the University of California, San Francisco (UCSF) demonstrated that this method is both safe and effective for spinal muscular atrophy (SMA), a severe neurodegenerative disease.

In the study, published in Science Translational Medicine, researchers administered a therapeutic intervention for SMA using antisense oligonucleotides (ASOs), molecules that can modulate gene expression by interacting with RNA. ASOs are currently approved for postnatal treatment of SMA and other nervous system disorders.

The research team conducted experiments in both SMA-model mice and healthy sheep. In mice, prenatal administration of ASOs through the amniotic fluid improved survival rates, motor function, and motor neuron counts compared to postnatal or no treatment. In sheep, the approach was shown to be safe and capable of delivering therapeutic concentrations of the drug to the spinal cord and other organs.

“This work shows that we can potentially intervene before birth to prevent irreversible damage in conditions like SMA,” said Dr. Tippi MacKenzie, a fetal and pediatric surgeon at UCSF Benioff Children’s Hospitals and senior author of the study. “Our goal was to identify the earliest, least invasive approach possible to begin treatment.”

Previous research confirmed that SMA can be diagnosed in utero and that gene expression can be altered during fetal development. However, this study marks the first to demonstrate the feasibility of delivering ASOs via the amniotic fluid—a less invasive method compared to the umbilical vein.

The research also included biodistribution studies, using fluorescent imaging to trace the spread of the medication after it was injected into the amniotic fluid. The medicine was observed in multiple areas of the fetal mouse body, including the brain, lungs, intestines, and spinal cord, indicating widespread therapeutic reach.

Dr. Beltran Borges, the study’s first author and a UCSF postdoctoral scholar in Dr. MacKenzie’s lab, likened the approach to “an inverse amniocentesis.” He noted that, if approved, the procedure could resemble existing outpatient prenatal procedures and offer a novel route for treating early-onset diseases.

“This strategy could open the door to treating other severe prenatal conditions that affect different organ systems,” Dr. MacKenzie added.

The study represents the first to evaluate the safety of prenatal ASO therapy in large animal models and to detail how the drug disperses through the body when delivered via the amniotic fluid. Earlier studies had only explored this method in mouse models of Angelman and Usher syndromes.

To advance toward clinical trials and eventual FDA approval, researchers must demonstrate both efficacy and safety. In this study, treated mice showed disease correction, and treated sheep exhibited favorable biodistribution with no significant toxicity.

The research effort was a multi-institutional collaboration, with contributions from UCSF, UC Davis, Johns Hopkins School of Medicine, Cold Spring Harbor Laboratory, and industry partners including Ionis and Biogen.

It takes immense trust and coordination to integrate work from multiple academic labs and industry collaborators,” said Dr. MacKenzie. “This type of multi-disciplinary partnership is the most rewarding way to conduct science.

Source: https://www.ucsf.edu/news/2025/05/429986/step-forward-treating-serious-genetic-disorders-birth