Spinal Muscular Atrophy (SMA)

Nusinersen, commercialized by Biogen as Spinraza®, is an antisense oligonucleotide developed to treat pediatric and adult patients with spinal muscular atrophy (SMA).1

Spinraza was approved by the US Food and Drug Administration (FDA) on December 23, 2016. In June of 2017, the drug was approved by the European Medicines Agency (EMA).

Mechanism of Action and Pharmacokinetics

SMA is a rare autosomal disease associated with defects in the survival motor neuron 1 (SMN1) gene. Typically,  patients with SMA have a homozygous deletion of exon 7 in the SMN1 gene.2 Abnormalities of the SMN1 gene lead to decreased production of the SMN protein, which is essential for the development of motor neurons in the spinal cord. Reduced levels of SMN protein result in degeneration of the motor neurons and consequently a decrease in stimuli of the skeletal muscles. Muscle weakness and atrophy are characteristic features of SMA.

The SMN2 gene is also responsible for producing SMN protein, although at lower levels. Only about 10% of fully functional SMN protein can be produced from the SMN2 gene.3 Patients with SMA typically have no functional copies of the SMN1 gene but a variable number of SMN2 copies,4 which partially compensate for the deficit in SMN protein production. The severity of SMA can be related to the SMN2 copy number: Patients with a higher number of SMN2 copies have milder forms of the disease.

Get detailed prescribing information on the Spinraza monograph page at Rare Disease Advisor.

Nusinersen was developed after the identification in 2006 of an intron-splicing gene silencer N1 sequence, located in intron 7 of the SMN2 gene. The gene silencer N1 sequence plays an important role in the modulation of alternative splicing by promoting the skipping of exon 7.5,6 The inclusion of exon 7 and subsequent upregulation of SMN protein production can be induced by using antisense oligonucleotides that bind to the gene silencer N1 sequence.7

The mode of action of nusinersen relies on the correction of exon 7 splicing. With nusinersen, SMN2 exon 7 is incorporated in pre-mRNA splicing, and the production of fully functional SMN protein is upregulated.5,7

Because nusinersen cannot cross the blood-brain barrier, it is administered intrathecally.5,7 Metabolism occurs through 3′ and 5′ exonuclease-mediated hydrolysis. The drug and inactive metabolites are eliminated through the kidneys. The mean elimination half-life is 135 to 177 days from the central nervous system and 63 to 87 days from plasma.5

Spinraza Safety

No significant interactions with nusinersen have been reported. However, several adverse reactions to the drug have been described. These include headache, back pain, respiratory tract infections, and post lumbar puncture (LP) syndrome.1,9 Possible thrombocytopenia and renal toxicity have been indicated by the FDA, but information on the effects of nusinersen in patients with compromised renal function is limited.1

Because no dose-related toxicity has been established, a fixed dose is recommended.10 Nusinersen is supplied as a solution with a concentration of 12 mg/5 mL. Administration begins with 4 loading doses. The first 3 doses are given every 14 days, and the fourth dose is administered 30 days after the third injection. Maintenance injections should be provided every 4 months.1

Nusinersen can be administered at a hospital or an outpatient site with expertise in intrathecal administration. Ultrasound guidance, fluoroscopy, and/or patient sedation may be necessary. 

Read about all of the FDA approved therapies for spinal muscular atrophy.

Spinraza Clinical Trials

Phase 1, 2, and 3 clinical trials have been conducted to assess the safety, efficacy, and pharmacokinetics of nusinersen in patients with SMA types 1 through 3.11-15 

Phase 1 Clinical trials 

An open-label. escalating-dose phase 1 trial in humans was reported by Chiriboga et al.11 Patients received from 1 to 9 mg of nusinersen, and the drug safety profile and pharmacokinetics, in addition to clinical outcomes and SMN protein levels, were evaluated. The level of SMN protein in cerebrospinal fluid was twice increased at 9 to 14 months after administration of the 2 higher doses of nusinersen (6 and 9 mg). Clinical outcomes were evaluated with the Hammersmith Functional Motor Scale-Expanded (HFMSE), and the scores were shown to be improved after administration of the 9-mg dose. Mild to moderate adverse effects were reported by 89% of the patients; 2 of these (palpitations and paresthesia) may have resulted from the drug itself.

Another phase 1 trial was conducted to assess the safety of intrathecal delivery of nusinersen.12 Of 73 LP procedures performed to administer nusinersen, 23% resulted in adverse effects related to the procedure (nausea and vomiting, back pain, dizziness, headache, cerebral spinal fluid leakage).16 These effects were resolved with bed rest, analgesics, and hydration.

Phase 2 Clinical Trial

An open-label, escalating-dose phase 2 trial was conducted in infants between 3 weeks and 6 months old who had an SMN1 homozygous gene deletion or mutation.13 The results of this trial supported the safety, tolerability, and clinical efficacy of nusinersen and provided information about its pharmacokinetic and pharmacodynamic profiles. All patients experienced adverse effects, of which respiratory infections and respiratory distress were the most common. A single case of transient asymptomatic neutropenia and cases of mild vomiting were additionally reported. 

Motor function improved with treatment, as evidenced by improvements on HINE-2 (Hammersmith Infant Neurological Examination Section 2, motor milestones) and on CHOP-INTEND (Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders). Patients also did not require permanent ventilation at the date of assessment. High levels of full-length SMN2 RNA were found in 3 children after the administration of nusinersen. 

Phase 3 Clinical Trials

The successful phase 2 trial by Finkel et al13 paved the way for an efficacy and safety study conducted as a multicenter, double-blind, sham-controlled phase 3 trial of patients with infantile SMA, the ENDEAR trial.14 Patients in the nusinersen group were treated with 4 doses plus 2 maintenance doses. Clinical outcome was evaluated with HINE-2 and by time to death or the need for permanent ventilation. 

In the nusinersen group, 41% of the patients exhibited a motor milestone response, defined according to HINE-2, in comparison with 0% in the control group. On the basis of these favorable interim results, the trial was halted early. In the same group, 47% of patients had a lower risk for death or the requirement for permanent ventilation in comparison with the control group. Patients from the ENDEAR trial were enrolled in an open-label extension trial, SHINE, to assess the possible effects of a longer duration of treatment with nusinersen.

The safety and efficacy of nusinersen in 126 children with later-onset SMA were evaluated in CHERISH, a multicenter, double-blind, sham-controlled phase 3 trial.15 Either nusinersen or a sham agent was administered 4 times. The nusinersen-treated group showed significant improvement in motor function, the primary endpoint, on the HFMSE (57% vs 26% in the control group) at the 15-month evaluation. An interim analysis revealed the superior efficacy of nusinersen in comparison with the sham infusion. The trial was stopped, and patients were invited to enroll in an open-label extension study, the SHINE trial.2,15

Reviewed by Michael Sapko, MD on 7/1/2021


1. SPINRAZA (nusinersen) injection, for intrathecal use. Revised December 2016. Accessed June 9, 2021.

2. Gidaro T, Servais L. Nusinersen treatment of spinal muscular atrophy: current knowledge and existing gaps. Dev Med Child Neurol. 2019;61(1):19-24. doi:10.1111/dmcn.14027

3. Lorson CL, Hahnen E, Androphy EJ, Wirth B.  A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. Proc Natl Acad Sci U S A. 1999;96(11):6307-6311. doi:10.1073/pnas.96.11.6307

4. Castro D, Iannaccone ST. Spinal muscular atrophy: therapeutic strategies. Curr Treat Options Neurol. 2014;16(11):316. doi:10.1007/s11940-014-0316-3

5. Lunn MR, Wang CH. Spinal muscular atrophy. Lancet 2008;371(9630):2120-2033. doi:10.1016/S0140-6736(08)60921-6 

6. Li Q. Nusinersen as a therapeutic agent for spinal muscular atrophy. Yonsei Med J. 2020;61(4):273-283. doi:10.3349/ymj.2020.61.4.273

7. Coady TH, Shababi M, Tullis GE, Lorson CL. Restoration of SMN function: delivery of a trans-splicing RNA re-directs SMN2 pre-mRNA splicing. Mol Ther. 2007;15(8):1471-1478. doi:10.1038/sj.mt.6300222

8. Madocsai C, Lim SR, Geib T, Lam BJ, Hertel KJ.  Correction of SMN2 Pre-mRNA splicing by antisense U7 small nuclear RNAs. Mol Ther. 2005;12(6):1013-1022. doi:10.1016/j.ymthe.2005.08.022

9. Hoy SM. Nusinersen: first global approval. Drugs. 2017;77(4):473-479. doi:10.1007/s40265-017-0711-7

10. Juliano RL. The delivery of therapeutic oligonucleotides. Nucleic Acids Res. 2016;44(14):6518-6548. doi:10.1093/nar/gkw236

11. Chiriboga CA, Swoboda KJ, Darras BT, et al. Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy.  Neurology. 2016;86(10):890-897. doi:10.1212/WNL.0000000000002445

12. Haché M, Swoboda KJ, Sethna N, et al. Intrathecal injections in children with spinal muscular atrophy: nusinersen clinical trial experience. J Child Neurol. 2016;31(7):899-906. doi:10.1177/0883073815627882

13. Finkel RS, Chiriboga CA, Vajsar J, et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet. 2016;388(10063):3017-3026. doi:10.1016/S0140-6736(16)31408-8

14. Finkel RS, Mercuri E, Darras BT, et al for the ENDEAR Study Group. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N Engl J Med. 2017;377(18):1723-1732. doi:10.1056/NEJMoa1702752

15. Mercuri E, Darras BT, Chiriboga CA, et al for the CHERISH Study Group. Nusinersen versus sham control in later-onset spinal muscular atrophy. N Engl J Med. 2018;378(7):625-635. doi:10.1056/NEJMoa171050416.

16. Lowery S, Oliver A. Incidence of postdural puncture headache and backache following diagnostic/therapeutic lumbar puncture using a 22G cutting spinal needle, and after introduction of a 25G pencil point spinal needle.Paediatr Anaesth. 2008;18(3):230-234. doi:10.1111/j.1460-9592.2008.02414.