Spinal Muscular Atrophy Therapeutics and Patient Care

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterised by the loss of alpha motor neurons in the anterior horn of the spinal cord, leading to progressive muscle atrophy and weakness. The condition arises principally from bi-allelic mutations in the SMN1 gene and the consequent reliance on the partially functional SMN2 gene, which differs by a single nucleotide in exon 7 that influences splicing. Therapeutic strategies have rapidly evolved from purely supportive care to interventions aiming to restore SMN protein levels. These include antisense oligonucleotides that modulate SMN2 splicing to enhance inclusion of exon 7, small molecules that similarly promote exon retention, and single-dose gene therapy using viral vectors to deliver a functional SMN1 copy. Parallel advances in biomarkers and outcome measures are informing early diagnosis, newborn screening, and the design of clinical trials to capture meaningful functional changes. Multidisciplinary patient care encompassing nutritional support, respiratory management and physiotherapy remains central to optimising quality of life. As therapies become available earlier in the disease course, integration of real-world evidence and longitudinal natural history data will be essential to refine dosing regimens, monitor long-term safety and address the psychosocial needs of patients and families worldwide.

Research from Nature Portfolio

Recent studies have introduced mechanistically interpretable quantitative models for the small-molecule therapies risdiplam and branaplam used in SMA. Massively parallel splicing assays and RNA sequencing have elucidated their sequence-specific and concentration-dependent effects on SMN2 exon 7 inclusion, revealing distinct modes of interaction at the 5′ splice site and widespread examples of drug cooperativity and synergy that inform rational drug design.

A Phase III trial of onasemnogene abeparvovec in presymptomatic infants with two SMN2 copies demonstrated that early gene replacement resulted in universal achievement of independent sitting within the normal developmental window and survival without permanent ventilation at 14 months, with no reliance on nutritional or respiratory support.

A companion SPR1NT trial in infants with three SMN2 copies at risk of SMA type 2 reported independent standing and walking in the majority of participants before 24 months, sustained weight gain without feeding support and a favourable safety profile, underscoring the benefits of newborn screening and presymptomatic intervention.

Spinal Muscular Atrophy Therapeutics and Patient Care publication trend

The graph below shows the total number of articles in spinal muscular atrophy therapeutics and patient care across all publications each year (not limited to Nature Index journals).

Technical terms

SMN1: Survival motor neuron 1 gene whose loss causes spinal muscular atrophy by depriving motor neurons of essential protein.

SMN2: Paralogous gene producing primarily truncated SMN protein; therapeutic strategies aim to enhance full-length transcript via exon 7 inclusion.

Exon: Coding region of a gene that is retained in the mature messenger RNA after splicing.

Splicing: Process by which introns are removed and exons are joined to generate mature mRNA transcripts.

Antisense oligonucleotide: Short synthetic nucleic acid designed to bind a specific RNA sequence and modulate splicing or expression.

Onasemnogene abeparvovec: AAV9-based gene therapy delivering a functional SMN1 copy to motor neurons in a single intravenous infusion.

Phosphorylated neurofilament heavy chain (pNF-H): Blood or cerebrospinal fluid biomarker reflecting axonal injury; used to monitor disease activity and treatment response.

References

1. Spinal muscular atrophy. Orphanet Journal of Rare Diseases (2011).
2. Enhancement of SMN2 Exon 7 Inclusion by Antisense Oligonucleotides Targeting the Exon. PLOS Biology (2007).
3. Specificity, synergy, and mechanisms of splice-modifying drugs. Nature Communications (2024).
4. Diverse targets of SMN2-directed splicing-modulating small molecule therapeutics for spinal muscular atrophy. Nucleic Acids Research (2023).
5. Onasemnogene abeparvovec for presymptomatic infants with two copies of SMN2 at risk for spinal muscular atrophy type 1: the Phase III SPR1NT trial. Nature Medicine (2022).
6. Onasemnogene abeparvovec for presymptomatic infants with three copies of SMN2 at risk for spinal muscular atrophy: the Phase III SPR1NT trial. Nature Medicine (2022).
7. Understanding the experiences and needs of individuals with Spinal Muscular Atrophy and their parents: a qualitative study. BMC Neurology (2015).
8. Neurofilament as a potential biomarker for spinal muscular atrophy. Annals of Clinical and Translational Neurology (2019).