IN UTERO GENE RESCUE : ROLE OF RISDIPLAM IN TREATMENT OF FETAL SPINAL MUSCLE ATROPHY

 

Spinal Muscular Atrophy (SMA) is one of the most crippling genetic disorders of early life. It strikes about 1 in 10,000 births and is characterized by progressive degeneration of motor neurons within the spinal cord. On the outside, infants with SMA wrestle with fundamental movements — crawling, sitting, or even breathing. On the inside, the disease is propelled by the demise of lower motor neurons, which causes muscle wasting and, in advanced cases, premature death.

The cause of SMA is mutations or deletions within the SMN1 gene encoding the Survival Motor Neuron protein. This is necessary for processing RNA in motor neurons. In humans, however, there exists a very similar gene, called SMN2, but its transcripts, except for a very small percentage because of a nucleotide substitution in the gene, lack exon 7 — a result that causes a truncated form of the SMN protein which is unstable. Only about 10% of SMN2-derived protein is functional, which is insufficient to maintain healthy motor neuron populations.

This is where risdiplam, the first-of-a-kind small molecule medicine, fits in. Risdiplam is a systemically active medicine that is capable of crossing both the blood–brain barrier and placenta — a big plus for treating fetuses. It binds to SMN2 pre-mRNA and alters splicing by favoring exon 7 inclusion. The outcome: higher levels of full-length, functional SMN protein produced from the SMN2 gene, salvaging motor neuron survival.

In a first-of-a-kind clinical case, scientists gave risdiplam to a fetus with SMA during late gestation. For the first time, a small molecule treatment had been applied to treat a birth defect of genes. After being born, the child remained on oral risdiplam. She is now 2.5 years old and has no signs of SMA — walking, playing, and growing normally.

This is not just a medical first, but a proof-of-concept for molecular fetal therapy. By curing the disease before damage is irreversible, clinicians can now provide afflicted infants a life without disability. Risdiplam's success in utero marks a new direction for prenatal medicine — one where genetic destiny is no longer set, but therapeutically re-written.

REFERENCE

Wood, H. Spinal muscular atrophy treatment in utero. Nat Rev Neurol 21, 173 (2025). https://doi.org/10.1038/s41582-025-01076-9