3 Things You Should Know About Spinal Muscular Atrophy

Disclosures: Ad Hoc Scientific Advisory Board Member: AveXis/Novartis Gene Therapies, Biogen, Merck, Roche/Genentech, Sarepta, Scholar Rock; Steering Committee Member: Roche MANATEE studies; DSMB Member: Argenx BV, Lexeo Therapeutics, Vironexis; Research Support Recipient: Cure SMA, National Institutes of Health/National Institute of Neurological Disorders and Stroke, Spinal Muscular Atrophy Foundation; Grant Recipient: Biogen, Novartis (AveXis), PTC Therapeutics, Roche, Sarepta, Scholar Rock; Royalty Benefits: Elsevier; UpToDate, Inc.

This activity was written by PER® editorial staff based on an online activity developed with Dr. Darras.

Faculty, Staff, and Planners’ Disclosures: In accordance with ACCME Guidelines, PER® has identified and resolved all conflicts of interest for faculty, staff, and planners prior to the start of this activity by using a multistep process.

The staff of Physicians’ Education Resource®, LLC have no relevant financial relationships with ineligible companies.

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Release Date: March 13, 2026

Expiration Date: March 13, 2027

Learning Objectives

• Upon successful completion of this activity, you should be better prepared to:
• Identify the burden of disease associated with spinal muscular atrophy (SMA)
• Describe the etiology and pathophysiology of SMA
• Analyze clinical trial data for disease-modifying therapies for SMA

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1. The impact of SMA on patients’ lives is significant.

For the approximately 9000 to 10,000 individuals with spinal muscular atrophy (SMA) currently living in the United States^1-3 and more than 11,000 patients affected worldwide,^3,4 clinical manifestations significantly affect functioning.³ The degree to which functioning is impacted depends on SMA type (Table 1) and greatly influences health-related quality of life (HRQoL).⁵

The PROfuture project represents one of the most comprehensive evaluations of health-related quality of life (HRQoL) in SMA. This qualitative, focus group–based study examined which aspects of the disease most strongly affect quality of life for patients and their caregivers. Analysis of focus group findings identified 10 domains as most critical for assessing the overall burden of SMA on patients’ lives (Figure 1).⁶

Results were reported in terms of impact on physical, psychological, and social domains. Physical health had the greatest impact on HRQoL, especially for parents of nonambulatory children. Pain was a major concern for nonambulatory children with types II and III disease. Frequent hospitalizations were particularly disruptive for children with SMA type I, because they interfere with school and social activities. Mobility was highlighted by both patients and caregivers as a significant burden across SMA types and ages; it was followed by fatigue. Notably, the reduction in fatigue was one of the most meaningful benefits that parents ascribed to the newer SMA treatments. Regular medical and therapy appointments placed a significant burden on daily life. Respiratory infections—and the fear of them—strongly affected QoL. The study also revealed a substantial psychological effect; this was in line with psychosocial thematic areas (ie, fearing the loss of functional ability, confronting premature death, and dealing with stigma) identified in previous studies. The data highlighted by the study are compelling. The investigators assert these data confirm the necessity for clinicians to “consider and evaluate aspects of SMA that are not assessed in the functional motor scale such as pain, fatigue, swallowing, respiration, in addition to social and psychological impact.”⁶

2. Deeper understanding of SMA etiopathology has led to treatment advances.

The trajectory of advances in our understanding of the cause and drivers of SMA has been impressive. In 1995, the SMN gene was identified,⁷ and researchers discovered that homozygous deletions or mutations in SMN1 (located on chromosome 5) lead to reduced production of the SMN protein, which is essential for motor neuron survival.⁸ Loss or mutation of SMN1 was identified as the primary cause of SMA. Humans also carry a paralog, SMN2, which produces limited amounts of full-length SMN protein due to alternative splicing (Figure 2).⁹

Higher SMN2 copy number increases SMN protein production; it is associated with milder phenotypes, whereas fewer copies are linked to earlier onset and greater severity. There are typical associations between SMA type and SMN2 copy number.¹⁰

• Type 0 to I: Usually 1 to 2 copies of SMN2, associated with prenatal or infantile onset and severe weakness
• Type II: Most often 3 copies, associated with later infantile onset and ability to sit but not walk independently
• Type III: Commonly 3 to 4 copies, associated with childhood or adolescent onset and initial independent ambulation
• Type IV: Typically at least 4 copies, associated with adult onset and mild, slowly progressive weakness.

Importantly, SMN2 copy number is a modifier, not an absolute predictor. Clinical variability exists within each copy number group, and it is influenced by additional genetic modifiers and environmental factors. In the current treatment era, SMN2 copy number remains central to newborn screening algorithms, prognostication, and treatment urgency, particularly for presymptomatic infants.⁵

3. Gene replacement therapy is now available for SMA.

The recognition that SMN2 copy number modifies disease severity directly linked genetics to clinical variability and laid the scientific foundation for SMN-targeted therapies and gene replacement therapy. Onasemnogene abeparvovec is a gene replacement therapy that delivers a functional copy of the SMN1 gene to motor neurons using a self-complementary adeno-associated virus serotype 9 (AAV9) vector. After a single intravenous (IV) infusion, the AAV9 vector crosses the blood-brain barrier and enters motor neurons, where the introduced SMN1 gene remains episomal (does not integrate into the genome). This enables sustained production of SMN protein.¹¹

The phase 3 SPR1NT trial was conducted in presymptomatic patients with SMA with 2 or 3 copies of SMN2.¹² Among infants with 2 SMN2 copies, all were alive and free of permanent ventilation at last follow-up, and the majority achieved key motor milestones, including independent sitting and standing, milestones that are rarely seen in untreated SMA type I. In infants with 3 SMN2 copies, outcomes were even more robust, with most children achieving independent walking within the normal developmental window. Across both cohorts, motor development followed a trajectory close to that of typically developing children. Treatment was generally well tolerated, with adverse events consistent with the known safety profile of onasemnogene abeparvovec and manageable with monitoring and supportive care.¹² Overall, SPR1NT provided compelling evidence that early, presymptomatic gene replacement therapy can dramatically alter disease course, reinforcing the clinical importance of newborn screening and early intervention in SMA.¹³

The phase 3 STR1VE trial¹⁴ evaluated infants with genetically confirmed SMA type I and bi-allelic SMN1 mutations who were symptomatic at baseline. Following a single IV dose, the majority of treated infants (20/22) were alive and free of permanent ventilation at 14 months, a major improvement over historical outcomes. There were 13 of 22 patients who achieved functional independent sitting for 30 minutes or longer when age 18 months. Many participants achieved other clinically meaningful motor milestones, including head control and roll from back to sides, which are rarely observed in untreated SMA type I. Motor function gains were supported by improvements in standardized assessments such as Children’s Hospital of Philadelphia (CHOP) Infant Test of Neuromuscular Disorders. The safety profile was consistent with prior studies, with liver enzyme elevations and thrombotic microangiopathy risk managed through monitoring and corticosteroid use.

Onasemnogene abeparvovec is a suspension administered as an IV infusion over 60 minutes. The recommended dose is 1.1 × 10¹⁴ vg/kg of body weight.¹⁵ The therapy carries a boxed warning for acute and serious hepatotoxicity; it states that acute liver failure and elevated liver aminotransferase levels have occurred following administration, including cases resulting in death. Hepatotoxicity is believed to be related to the AAV9 vector–mediated immune response. As a result, patients require systemic corticosteroid prophylaxis prior to infusion and continued after treatment, along with regular monitoring of liver function tests (alanine aminotransferase, aspartate aminotransferase, and total bilirubin levels; prothrombin time) for at least 3 months postinfusion or longer if abnormalities persist.¹⁵ Intrathecal onasemnogene abeparvovec is being investigated in phase 3b STRENGTH¹⁶ and phase 1 STRONG¹⁷ studies.

REFERENCES

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2. Lally C, Jones C, Farwell W, Reyna SP, Cook SF, Flanders WD. Indirect estimation of the prevalence of spinal muscular atrophy type I, II, and III in the United States. Orphanet J Rare Dis. 2017;12(1):175. doi:10.1186/s13023-017-0724-z

3. State of SMA: 2024 Report. Cure SMA. March 31, 2025. Accessed January 4, 2026. https://www.curesma.org/wp-content/uploads/2025/04/State-of-SMA-Report2024_vWeb-1.pdf

4. Verhaart IEC, Robertson A, Wilson IJ, et a. Prevalence, incidence and carrier frequency of 5q-linked spinal muscular atrophy - a literature review. Orphanet J Rare Dis. 2017;12(1):124. doi:10.1186/s13023-017-0671-8

5. Mercuri E, Finkel RS, Muntoni F, et al. Diagnosis and management of spinal muscular atrophy: part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord. 2018;28(2):103-115.

6. de Lemus M, Cattinari MG, Pascual SI, et al. Identification of the most relevant aspects of spinal muscular atrophy (SMA) with impact on the quality of life of SMA patients and their caregivers: the PROfuture project, a qualitative study. J Patient Rep Outcomes. 2024;8(1):78. doi:10.1016/j.nmd.2017.11.005

7. Lefebvre S, Bürglen L, Reboullet S, et al. Identification and characterization of a spinal muscular atrophy–determining gene. Cell. 1995;80(1):155-165. doi:10.1016/0092-8674(95)90460-3

8. Wirth B. An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA). Hum Mutat. 2000;15(3):228-237. doi:10.1002/(SICI)1098-1004(200003)15:3<228::AID-HUMU3>3.0.CO;2-9

9. Markowitz JA, Singh P, Darras BT. Spinal muscular atrophy: a clinical and research update. Pediatr Neurol. 2012;46(1):1-12. doi:10.1016/j.pediatrneurol.2011.09.001

10. Taylor JE, Thomas NH, Lewis CM, et al. Correlation of SMNt and SMNc gene copy number with age of onset and survival in spinal muscular atrophy. Eur J Hum Genet. 1998;6(5):467-74. doi: 10.1038/sj.ejhg.5200210

11. Blair HA. Onasemnogene abeparvovec: a review in spinal muscular atrophy. CNS Drugs. 2022;36(9):995-1005.

12. Strauss KA, Farrar MA, Muntoni F, et al. Onasemnogene abeparvovec for presymptomatic infants with two or three copies of SMN2 at risk for spinal muscular atrophy: the phase III SPR1NT trial. Nat Med. 2-22;28(7):1390-1397. doi:10.1038/s41591-022-01867-3

13. Al-Zaidy SA, Mendell JR. From clinical trials to clinical practice: practical considerations for gene replacement therapy in SMA Type 1. Pediatr Neurol. 2019;100:3-11. doi: 10.1016/j.pediatrneurol.2019.06.007

14. Day JW, Finkel RS, Chiriboga CA, et al. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial. Lancet Neurol. 2021;20(4):284-293. doi:10.1016/S1474-4422(21)00001-6

15. Zolgensma. Novartis Gene Therapies; 2025. Accessed January 20, 2026. https://www.novartis.com/us-en/sites/novartis_us/files/zolgensma.pdf

16. Kwon J, Munell F, Yuge K, et al. Intrathecal onasemnogene abeparvovec for treatment-experienced patients with spinal muscular atrophy: phase 3b, open-label STRENGTH study. Poster presented at: 2025 Muscular Dystrophy Association Clinical & Scientific Conference; March 16-19, 2025; Dallas, TX. Poster LB449. https://www.mdaconference.org/abstract-library/intrathecal-onasemnogene-abeparvovec-for-treatment-experienced-patients-with-spinal-muscular-atrophy-phase-3b-open-label-strength-study/

17. Finkel RS, Darras BT, Mendell JR, et al. Intrathecal onasemnogene abeparvovec for sitting, nonambulatory patients with spinal muscular atrophy: phase I ascending-dose study (STRONG). J Neuromuscul Dis. 2023;10(3):389-404. doi:10.3233/JND-221560