First In-Utero Small Molecule Treatment for Spinal Muscular Atrophy Shows Promising Results

At St. Jude Children’s Research Hospital in Memphis, Tennessee, a novel approach to treating spinal muscular atrophy (SMA) was tested before birth for the first time. The intervention involved administering the gene-targeting drug risdiplam to a fetus diagnosed with type 1 SMA during late pregnancy. Now two and a half years old, the child shows no clinical signs of the condition—an unprecedented outcome for this severe genetic disorder.

SMA is caused by mutations in the SMN1 gene, resulting in a deficiency of the survival motor neuron (SMN) protein, which is vital for preserving motor neurons in the spinal cord and brainstem.

In its most severe form, type 1 SMA typically affects infants born without functional copies of the SMN1 gene and with only one or two copies of the backup gene SMN2, which cannot fully compensate for the loss. Without treatment, most infants with this form of SMA do not survive past their third birthday. The condition affects approximately 1–2 per 100,000 individuals, with an incidence of about 1 in 10,000 live births.

In this case, prenatal genetic testing confirmed the absence of SMN1 and the presence of two copies of SMN2, indicating a high risk of severe SMA. The child’s parents, who had previously lost another child to the disease, sought options for early intervention. With approval from the U.S. Food and Drug Administration (FDA) and oversight from a local institutional review board, the mother began daily doses of risdiplam—an oral small-molecule drug developed by Roche that enhances SMN protein production by modifying SMN2 gene splicing—at 32 weeks and 5 days of gestation.

The mother continued the treatment for six weeks until delivery at 38 weeks and 6 days, during which she was monitored weekly for side effects and fetal development. After birth, the child began receiving daily risdiplam from eight days old and is expected to continue the treatment for life to maintain motor neuron function and prevent disease progression.

At birth, the child appeared healthy but was later found to have a ventricular septal defect (a heart murmur), which has since resolved naturally. Additional issues included mild optic nerve hypoplasia, affecting visual acuity, and mild right hemiparesis linked to left midbrain hypoplasia. Genetic testing ruled out other disorders commonly associated with these symptoms, and the abnormalities are believed to have developed before treatment began.

Notably, no signs of SMA—such as muscle weakness, hypotonia, or fasciculations—have been detected to date. Regular assessments, including motor function evaluations and muscle imaging, have shown development consistent with the child’s age. Laboratory tests confirmed elevated levels of SMN protein and lower neurofilament markers, suggesting that the treatment successfully supported motor neuron development.

While these results are based on a single case, they suggest that earlier intervention—potentially beginning before birth—could offer improved outcomes for infants diagnosed with SMA in utero. Researchers emphasize, however, that further investigation is needed to determine the broader potential of prenatal treatment.

For a detailed analysis, readers can refer to Smriti Mallapaty’s coverage in Nature or consult the original study, "Risdiplam for Prenatal Therapy of Spinal Muscular Atrophy," published in The New England Journal of Medicine.

Cover image: Serhii Brovko, iStock

Topics: Novel Therapeutics