Spinal muscular atrophy pharmacotherapy: Getting an earlier start

Spinal muscular atrophy (SMA) is an autosomal recessive disorder involving the SMN1 gene on the fifth chromosome. Dysregulation of pre-RNA processing results in decreased expression of functional SMN protein. Reduced SMN protein levels impair neuronal signaling to muscles controlling movement near the center of the body (shoulders, hips, thighs, upper back), leading to muscle atrophy.¹ The SMN protein is encoded by either the SMN1 or SMN2 gene. Although the SMN1 gene is the primary contributor to functional SMN protein levels, the SMN2 gene can produce a small amount of functional SMN protein. Therefore, increased SMN2 copies may partially compensate for decreased SMN1 copies and are associated with milder disease. Disease severity correlates with the number of SMN2 copies and age of onset, with fewer SMN2 copies corresponding to more severe disease and lower staging. Historically, life expectancy was thought to correlate with severity of disease; however, pharmacologic advances have demonstrated milestone progression and suggest prolonged survival.²

An estimated 5 to 24 per 100,000 births in the US are affected by an SMA diagnosis. All 50 states include SMA in newborn screening panels, which use quantitative polymerase chain reaction to measure SMN1 and SMN2 gene copy numbers. After a positive screen, a formal diagnosis is confirmed through genetic testing specifically targeting the fifth chromosome. A similar technique is utilized for prenatal testing between 14- and 20-week gestational age in at-risk pregnancies.^3,4 At-risk patients include those who have previously conceived an infant diagnosed with SMA or are known carriers of SMN1 mutations.

Although there is no cure for SMA, advances in pharmacologic treatments have demonstrated milestone progression and suggest prolonged survival.⁴ The current treatment landscape includes mobility assistance devices, physical and occupational therapy, and 3 FDA-approved pharmacologic agents (Table).^5-14 These therapies increase functional SMN protein production via splicing modulation or gene therapy.

Current literature has demonstrated the benefits of earlier treatment initiation in preventing irreversible motor neuron loss. This raises important questions regarding prenatal diagnosis and intervention. Although intrathecal and gene therapies have not been studied in prenatal populations, St Jude Children’s Research Hospital has reported 1 case of transplacental administration of risdiplam (Evrysdi; Genentech). This case details a fetus with no SMN1 copies and 2 SMN2 copies (confirmed via fetal amniocentesis). Risdiplam 5 mg oral once daily was administered to the mother beginning at 32 weeks, 5 days of gestation, and continued through delivery at 38 weeks, 6 days. Postnatally, risdiplam was initiated on day of life 8, following a washout period to account for potential exposure via maternal breast milk.

At delivery, risdiplam concentrations were 33% in amniotic fluid and 69% in cord blood, confirming risdiplam’s ability to cross the placental barrier. Although optimal SMN protein levels remain undefined, phase 2 FIREFISH trial (NCT02913482) data showed symptomatic infants with 1 to 3 ng/mL, whereas this case reported 9.4 ng/mL. Neurofilament light and heavy chain levels were elevated compared with symptomatic infants in FIREFISH.^11,14 The elevated SMN protein, associated with better disease prognosis and decreased neurofilament levels, indicates reduced active axonopathy, supporting the potential benefit of transplacental administration, consistent with the principle that earlier treatment yields better outcomes.

Currently, literature describes only this single case report of transplacental administration of risdiplam with very limited anecdotal off-label use. Optimal prenatal dosing, timing of initiation, and specifics surrounding breastfeeding and an associated washout period remain unknown. Furthermore, long-term effects and disease-specific outcomes have yet to be observed due to the timing of intervention relative to the present. Maternal safety data, including adverse drug reactions and fertility following transplacental administration, have not been reported. Despite the remaining uncertainties, a few facts remain:

SMA is a rare autosomal recessive disorder involving decreased expression of functional SMN protein, diagnosable via amniocentesis when risk is known.

Earlier treatment initiation has been shown to improve outcomes and prolong life expectancy by preventing or decreasing irreversible neuronal damage.

No formal recommendation exists favoring one treatment agent over another.

However, transplacental administration of risdiplam may offer the earliest possible treatment intervention, potentially preventing neuronal injury before birth and impacting long-term outcomes.

References

1. The genetics of 5q spinal muscular atrophy. SMAUK. Updated July 2025. Accessed July 4, 2025. https://smauk.org.uk/support-information/about-sma/the-genetics-of-5q-sma/

2. Spinal muscular atrophy (SMA). Muscular Dystrophy Association. Updated July 2025. Accessed July 9, 2026. https://www.mda.org/disease/spinal-muscular-atrophy/types

3. Aragon-Gawinska K, Mouraux C, Dangouloff T, et al. Spinal muscular atrophy treatment in patients identified by newborn screening—a systematic review. Genes. 2023;14(7):1377 doi:10.3390/genes14071377

4. Murphy B. Spinal muscular atrophy (SMA). Rare Disease Advisor. Updated July 1, 2021. Accessed July 4, 2025. https://www.rarediseaseadvisor.com/disease-info-pages/spinal-muscular-atrophy-epidemiology/

5. Nusinersen. Lexi-Drugs. UpToDate Lexidrug. Accessed June 15, 2026. https://online.lexi.com

6. Finkel RS, Mercuri E, Darras BT, et al. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N Engl J Med. 2017;377(18):1723-1732. doi:10.1056/nejmoa1702752

7. Onasemnogene abeparvovec. Lexi-Drugs. UpToDate Lexidrug. Accessed June 15, 2026. https://online.lexi.com

8. Mendell JR, Al-Zaidy SA, Lehman KJ, et al. Five-year extension results of the phase 1 START trial of onasemnogene abeparvovec in spinal muscular atrophy. JAMA Neurol. 2021;78(7):834-841. doi:10.1001/jamaneurol.2021.1272

9. Mercuri E, Baranello G, Masson R, et al. Onasemnogene abeparvovec gene therapy for spinal muscular atrophy type 1: phase 3 study update (str1ve-EU). J Neurol Neurosurg Psychiatry. 2022;93(6):A1. doi:10.1136/jnnp-2022-ABN.2

10. Risdiplam. Lexi-Drugs. UpToDate Lexidrug. 2026. Accessed June 15, 2026. https://online.lexi.com

11. Baranello G, Darras BT, Day JW, et al. Risdiplam in type 1 spinal muscular atrophy. New England Journal of Medicine. 2021;384(10):915-923 doi:10.1056/nejmoa2009965

12. A study of risdiplam in infants with genetically diagnosed and presymptomatic spinal muscular atrophy (Rainbowfish). ClinicalTrials.gov. Updated April 8, 2026. Accessed April 21, 2026. https://clinicaltrials.gov/study/NCT03779334

13. Evrysdi (risdiplam) for oral solution. Prescribing information. Genentech; 2022. Accessed June 15, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/213535s003s005lbl.pdf

14. Finkel RS, Hughes SH, Parker J, et al. Risdiplam for prenatal therapy of spinal muscular atrophy. N Engl J Med. 2025;392(11):1138-1140. doi:10.1056/nejmc2300802