Written and Reviewed By: Vikas Londhe (M.Pharm, Pharmacology)
Spinal muscular atrophy (SMA) is a rare but serious genetic neuromuscular disorder characterized by the degeneration of motor neurons in the spinal cord. This leads to progressive muscle weakness, respiratory failure, and early mortality. The severity of the disease varies depending on the number of SMN2 gene copies an individual has, with type 0 SMA being the most severe and typically fatal in the prenatal or neonatal period.
A pioneering new study, recently published in The New England Journal of Medicine, presents the administration of risdiplam, a gene-modifying therapy, during pregnancy to a fetus who is at risk of being diagnosed with SMA. Risdiplam, an orally available small-molecule drug, works by modifying the splicing of the SMN2 gene to increase production of functional SMN protein, which is essential for motor neuron survival.
This is the first-of-its-kind prenatal intervention that has shown potential to revolutionize the treatment of SMA, particularly for the most lethal forms of the disease. By initiating therapy before birth, researchers hope to prevent the irreversible loss of motor neurons in utero, offering the potential for normal neuromuscular development and vastly improved outcomes. The implications of this study are thoughtful which indicates a proactive and early management of this devastating condition.
Background: Understanding SMA and Risdiplam
Spinal muscular atrophy (SMA) is primarily caused by a genetic mutation in the SMN1 gene, which leads to a deficiency of the survival motor neuron (SMN) protein. This protein is essential for the health and function of motor neurons, nerve cells that control voluntary muscle activity such as walking, breathing, and swallowing.
In healthy individuals, the SMN1 gene produces adequate amounts of full-length SMN protein. However, in individuals with SMA, the SMN1 gene is either missing or nonfunctional, resulting in a reduction in SMN protein levels.
The body does have a natural backup in the form of the SMN2 gene, a nearly identical copy of SMN1. But due to a single nucleotide difference, the SMN2 gene undergoes inefficient splicing, leading to the exclusion of exon 7 in most transcripts. As a result, only a small fraction of functional SMN protein is produced from SMN2 typically not enough to fully counterbalance for the loss of SMN1. This imbalance in SMN protein production leads to motor neuron degeneration and the progressive muscle weakness characteristic of SMA. The number of SMN2 copies a person has can influence disease severity: more copies generally correlate with milder forms of SMA.
Risdiplam is a small molecule SMN2 splicing modifier approved for treating SMA in patients two months and older. It works by promoting exon 7 inclusions during SMN2 pre-mRNA splicing, thus increasing the production of functional SMN protein.
Study Highlights: N-of-1: A case study of prenatal risdiplam
This study represents the first documented case of prenatal risdiplam therapy in a foetus that was at risk of developing type 1 spinal muscular atrophy (SMA). This inference was drawn because the fetus’s older deceased sibling had a genetically confirmed diagnosis of type 1 SMA. The fetus was tested by amniocentesis and confirmed to have Type 1 SMA, which is characterized by a complete absence of the SMN1 gene and two copies of the SMN2 gene. This genetic profile leads to minimal production of functional SMN protein, resulting in early motor neuron degeneration, evident as reduced fetal movement, joint contractures, and respiratory failure shortly after birth. Without intervention, type 1 SMA usually leads to death in the neonatal period, making early diagnosis and potential treatment critical.
Key Aspects of the Study
This landmark case of prenatal risdiplam therapy began with early genetic detection and a carefully monitored treatment strategy:
Prenatal Diagnosis: The foetus was diagnosed with spinal muscular atrophy (SMA) type 1 through amniocentesis and also from the previous family history of type 1 SMA diagnosed in older sibling who is unfortunately died at 16 months of age. To add this, the parents were both known carriers of SMA genetic variants. Genetic testing revealed a complete absence of the SMN1 gene and the presence of two copies of SMN2. This pattern is diagnostic of type 1 SMA, the severe form, which often results in death shortly after birth.
Approval and availability of risdiplam: The local institutional board, followed by the USFDA, has approved the single-patient investigational therapy. F. Hoffmann-La Roche has provided advice on the safety of prenatal exposure to risdiplam, along with a supply of risdiplam at no cost due to a confidentiality agreement with sponsor St. Jude Children’s Research Hospital. Parents have provided informed consent.
Initiation of Therapy: With a confirmed diagnosis and serious prognosis, the risdiplam was administered to the mother orally. The dosing was adjusted to 5 mg once per day. The risdiplam was administered from 32 weeks 5 days of gestation up to delivery at 38 weeks 6 days of gestation. However, the fetus continued to be administered risdiplam daily post-delivery from 8 days of birth to the present time (30 months of age in February 2025).
Monitoring: The mother had weekly checkups to monitor her pregnancy health and for any side effects from the medication. The fetus was also regularly checked using ultrasound to monitor growth, movement, and overall development.
Outcomes and Findings
The infant appeared healthy at birth but was later found to have a heart murmur caused by a ventricular septal defect, which resolved on its own. The child also has slightly reduced vision and experienced brief episodes transient fixation nystagmus, linked to underdevelopment of the optic nerves in both eyes. Additionally, mild weakness on the right side of the body (right hemiparesis) was observed, associated with underdevelopment of the left midbrain. The infant has shown global developmental delays but has not experienced any waning of skills. The child has not shown any signs of spinal muscular atrophy (SMA) such as low muscle tone, muscle weakness, absence of reflexes, or muscle twitching. Motor function, muscle imaging (ultrasound), and nerve tests (electrophysiology) have been conducted every six months and consistently show normal development of nerves and muscles for the child’s age.
The blood sample results revealed increased levels of SMN protein and lower neurofilament levels, which indicates the drug successfully reached its intended target and had a positive effect on motor neuron development. The above-mentioned congenital abnormalities seen in the infant were believed to have occurred early in fetal development before risdiplam treatment began, and no specific cause was identified. Animal studies also support this claim, where risdiplam was given during prenatal and postnatal stages, and no abnormalities have occurred in them.
While this is just a single case and the results cannot be widely applied, the findings suggest that prenatal risdiplam therapy could be a promising option for treating SMA when diagnosed before birth.
Significance and Implications
This study represents the first documented case of prenatal risdiplam therapy in humans, offering proof-of-concept that in utero intervention can alter the course of spinal muscular atrophy (SMA) even in its severe form, type 1. By initiating treatment during fetal development, before irreversible motor neuron loss occurs, this case displays the potential to preserve neuromuscular function, improve survival outcomes, and redefine the clinical management of SMA.
While results are based on a single case, the findings open the door to a new era of prenatal therapies for genetic neurodegenerative disorders. Future research will determine whether prenatal risdiplam should become part of the standard of care for high-risk SMA pregnancies. For now, it offers a glimpse of hope for families facing this devastating diagnosis.
Reference
Finkel RS, Hughes SH, Parker J, Civitello M, Lavado A, Mefford HC, Mueller L, Kletzl H; Prenatal SMA Risdiplam Study Group. Risdiplam for Prenatal Therapy of Spinal Muscular Atrophy. N Engl J Med. 2025 Mar 13;392(11):1138-1140. doi: 10.1056/NEJMc2300802. Epub 2025 Feb 19. PMID: 39970420.
Promising results from first prenatal therapy for spinal muscular atrophy, 19 Feb 2025, St. Jude’s Childrens Hospital, https://www.stjude.org/media-resources/news-releases/2025-medicine-science-news/promising-results-from-first-prenatal-therapy-for-spinal-muscular-atrophy.html
Treating spinal muscular atrophy in the womb, nature medicine, https://www.nature.com/articles/d41591-025-00017-9
Kakazu J, Walker NL, Babin KC, et al, Risdiplam for the Use of Spinal Muscular Atrophy. Orthop Rev (Pavia). 2021 Jul 12;13(2):25579. Doi: 10.52965/001c.25579. PMID: 34745484; PMCID: PMC8567805.
Kolb SJ, Kissel JT. Spinal Muscular Atrophy. Neurol Clin. 2015 Nov;33(4):831-46. Doi: 10.1016/j.ncl.2015.07.004. PMID: 26515624; PMCID: PMC4628728.
Add a Comment