Advancements in Prenatal Diagnosis and Potential Fetal Therapies for Spinal Muscular Atrophy

Spinal Muscular Atrophy (SMA) is a rare autosomal recessive disorder caused by SMN1 gene mutations, resulting in muscle weakness and atrophy, respiratory failure, and death. SMA disease modifying therapies (DMTs) include the antisense oligonucleotide (ASO) nusinersen administered intrathecally, onasemnogene abeparvovec, single-dose intravenous gene replacement therapy that introduces functional SMN1 via an adeno-associated viral vector, and oral risdiplam, which modifies SMN2 splicing to increase SMN protein production. With DMTs, infants can achieve previously unattainable developmental milestones and survive beyond infancy. Prenatal carrier screening and universal newborn screening allow early identification and prompt postnatal treatment. However, with severe early-onset SMA, motor neuron loss begins in utero and irreversible damage may occur prior to treatment initiation. Therefore, fetal therapies for SMA are a focus of ongoing research. This review article focuses on current postnatal therapies, summarizes research on potential fetal therapies and their potential clinical integration, and reviews the ethical implications of fetal therapy for SMA.

This is a narrative review. Prospective study data for FDA-approved DMTs are discussed, focusing on presymptomatic patients. For articles related to fetal therapies, Pubmed and Ovid/MEDLINE were searched using the terms "spinal muscular atrophy" and "in utero therapy," "prenatal therapy," or "fetal therapy." Eleven articles were identified; nine were included.

Prenatal SMA is diagnosed via chorionic villus sampling or amniocentesis. SMN2 copy number testing can identify fetuses with severe disease who may benefit from fetal therapy. The three FDA-approved DMTs are potential fetal therapy targets. ASOs have been administered by intracranial and intraamniotic injection to lambs, demonstrating feasibility of prenatal ASOs; however, this approach requires refinement before human use. SMA gene therapy has been studied in mice and lambs; CNS transduction following cordocentesis in lambs was observed. However, further study of potential maternal and fetal adverse effects is required to ensure safety. Finally, a case of third trimester maternal risdiplam use was recently published with promising results: the two-year-old infant has no clear SMA manifestations and normal motor function.

Early postnatal treatment is currently standard of care for prenatally- and postnatally diagnosed SMA with improvement in outcomes demonstrated following early treatment initiation. Fetal therapy is an emerging research area and shows promise for infants with severe disease in whom motor neuron loss begins in utero. Fetal therapy for SMA is ethically acceptable and likely feasible based on animal studies and a single case report. Ongoing rigorous attention to maternal and fetal safety is of utmost importance as fetal therapy for SMA approaches clinical use.