Nusinersen (Spinraza®) – Spinal Muscular Atrophy (SMA)


 Spinal muscular atrophy (SMA)
Excerpt from "Spinal muscular atrophy" by licensed under CC BY-SA 4.0

Spinal muscular atrophy (SMA) refers to a group of inherited neurological disorders that begin in infancy or childhood and lead to the degeneration of spinal motor neurons, the neurons that control skeletal muscles. This degeneration results in weakness, muscle wasting, and in the most severe cases, paralysis and death before two years of age. SMA affects approximately 1 in 10,000 newborns and is a leading genetic cause of death in infants and toddlers. Nusinersen, marketed in the U.S. as Spinraza® (Biogen) is the first therapy approved for the treatment of SMA.

SMA results from mutations in a gene known as SMN1, which encodes a protein (Survival Motor Neuron, or SMN) important for motor neuron survival. Although a nearly identical gene (SMN2) serves as a back-up for SMN1, it produces a shortened, less stable protein that cannot fully compensate for loss of the full-length protein normally produced from the SMN1 gene. Nusinersen targets this back-up gene to promote the production of full-length SMN protein instead. Nusinersen is a type of treatment called antisense oligonucleotide (ASO) therapy, in which short sequences of nucleotides (the letters in the genetic code) are designed to bind to specific regions of a gene and modify its expression.

NINDS and other NIH institutes contributed to nusinersen’s development, through support for research that narrowed in on the disease’s genetic cause and mechanisms, identified a treatment strategy and target, and facilitated later stage translational and clinical research. Many other sources in the U.S. and internationally also played important roles, including Cure SMA, the Muscular Dystrophy Association, and the SMA Foundation. Beyond its impact for SMA, nusinersen’s success signals the potential for ASO therapies to correct gene defects in other neurological disorders.

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Researchers identify the gene (SMN1) associated with SMA, as well as a nearly identical gene (SMN2). They find that RNA transcripts from SMN2 lack one protein-coding segment (exon 7).2


Studies show that SMN2 copy number and SMN protein levels correlate inversely with disease severity.3,4,5,6

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A single nucleotide difference between the SMN1 and SMN2 genes leads to exon 7 skipping.7,8

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A single nucleotide difference between the SMN1 and SMN2 genes leads to exon 7 skipping.

Researchers determine that the protein produced from truncated SMN2 transcripts is unstable, explaining why SMN2 can only partially offset mutations in SMN1.9,10,11

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Researchers report that antisense oligonucleotides (ASOs) targeting SMN2 can promote translation of full-length SMN protein.16,17

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Researchers identify a regulatory element in the SMN2 gene that will become the specific target of nusinersen.20

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Researchers identify a regulatory element in the SMN2 gene that will become the specific target of nusinersen.

Researchers first describe the ASO that will become nusinersen and demonstrate successful treatment in SMA mouse models.21,22,23

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image of research mouse model

The first clinical trial of nusinersen (Spinraza) begins.25

First clinical trial of Nusinersen (Spinraza) begins.

A Phase 3 clinical trial testing Spinraza in infants with SMA type 1 (ENDEAR) meets its primary endpoint early, as treated infants show significant improvement in motor function within six months.33,34


FDA approves nusinersen (Spinraza) for the treatment of SMA.35

Food and Drug Administration logo

A second Phase 3 trial in children with SMA type 2 (CHERISH) meets its primary endpoint early, and ongoing studies, including one treating infants prior to symptom onset, add to evidence of nusinersen’s disease-modifying effects.36,37,38

History of Development

NINDS and other NIH institutes contributed to nusinersen’s development, through support for research that narrowed in on the disease’s genetic cause and mechanisms, identified a treatment strategy and target, and facilitated later stage translational and clinical research.

Discovering the genetic cause of SMA

By the 1990s, studies1 supported by NIH and others had localized the gene responsible for SMA to a region on chromosome 5. However, the complexity of this chromosomal region made pinpointing the actual gene difficult. The breakthrough came in 1995 when researchers successfully mapped the region and described the disease-causing gene2, now known as SMN1. Interestingly, they also described a nearly identical version of the gene (SMN2), for which the number of copies varied across individuals. Subsequent studies showed that SMN2 could partially compensate for disease-causing mutations in SMN1. Individuals with the most severe form of SMA (type 1) tended to have one or two copies of SMN2 and low levels of SMN protein, while individuals with more moderate forms (types 2 and 3) tended to have three or four SMN2 copies and higher levels of SMN protein.3,4,5,6

Nevertheless, SMN2 did not serve as a complete back-up, and scientists questioned why. The answer would lie in the molecular mechanisms that produce proteins from genes. The first step in this process is called transcription, when the sequence of a gene is copied (or transcribed) from DNA into RNA. Next, the RNA copy (or transcript) undergoes a series of modifications. In particular, most genes in humans and other animals are composed of segments known as exons, which contain protein-coding sequences, and introns, which do not. Before an RNA transcript is translated into a protein, the introns are cut (or spliced) out, and in some genes, exons may also be removed or joined together in different combinations. Such alternative splicing allows a single gene to produce multiple proteins with important functional variations, but in some cases, genetic mutations result in alternative splicing that leads to disease.

The study that identified the SMN1 and SMN2 genes found that SMN2 was often alternatively spliced, skipping the gene’s seventh exon. By systematically testing the impact of each difference in the sequences of SMN1 and SMN2, researchers determined in 1999, that a single nucleotide change is critical for exon 7 skipping,7,8 and later studies showed that exon 7 skipping resulted in a truncated and unstable form of SMN protein.9,10,11 These findings, partly supported by NINDS, explained why SMN2 only partially compensates for mutations in SMN1. Since most protein produced from SMN2 is truncated and unstable, it is usually insufficient to maintain healthy motor neurons in the absence of a functional SMN1 gene. 

Acting on a therapeutic target

With this understanding, researchers pursued multiple approaches to make more full-length SMN protein from the SMN2 gene or to make the truncated protein more stable. The creation of several genetic mouse models accelerated progress by enabling studies of disease mechanisms and preclinical tests of potential treatments.12 During this time (2003-2012), NINDS led the SMA Project, a contract-based program to develop a small molecule drug to induce SMN2 to produce full-length SMN. Although the project did not identify a suitable drug candidate, it fueled interest in the opportunity provided by a clear, rational target for treating SMA. NINDS and others continue to support research to design and test different candidate drugs for SMA, with some advancing to clinical trials.13,14 In addition, lessons learned through the SMA Project informed subsequent NIH programs to support small drug development,15 including the NIH Blueprint Neurotherapeutics Network and the Therapeutics for Rare and Neglected Diseases (TRND) program.

As a different approach, researchers sought to create compounds called antisense oligonucleotides (ASOs) that would correct exon 7 skipping in SMN2. By 2003, investigators with NIH and other support showed that ASOs targeting SMN2 RNA could promote the inclusion of exon 7 in cell cultures and extracts.16,17 The results of the latter study, conducted by scientists at the Cold Spring Harbor Laboratory (CSHL), sparked the attention of Ionis Pharmaceuticals (formerly Isis Pharmaceuticals), which was working to develop ASO therapies for other diseases. Ionis and CSHL scientists began collaborating to design more effective ASOs for SMA,18 supported in part by NINDS and NIGMS.19 Meanwhile, studies continued to identify sequence elements in SMN2 that regulate alternative splicing, including a potent element called ISS-N1 discovered in 2004, at the University of Massachusetts, also supported in part by NINDS.20 In 2008, the CSHL and Ionis team first described the ASO that would become nusinersen – a sequence targeting ISS-N1 that resulted in close to 90% inclusion of exon 7 in mice carrying the SMN2 gene. The ASO also increased exon 7 inclusion and SMN protein levels in cells from patients with SMA,21 and when delivered directly to the central nervous system, the ASO improved symptoms in SMA mouse models.22,23

Advancing a disease-modifying treatment

Ionis moved forward to develop nusinersen for clinical application,24 and the first clinical trials began25 in 2011. Ionis later entered a partnership with Biogen,26 and larger clinical trials followed.27,28,29,30,31 While NINDS did not directly support these trials, a study on SMA biomarkers conducted through the NINDS Network for Excellence in Neuroscience Clinical Trials (NeuroNext) provided helpful natural history data and other information.32 In August 2016, Biogen and Ionis announced early positive results from a Phase 3 clinical trial in infants with SMA type 1. Within six months, children treated with nusinersen were showing significantly improved motor function compared to no improvement in children receiving placebo.33,34 Biogen and Ionis filed for accelerated FDA approval, which was granted35 in December 2016. By this time, a second Phase 3 trial in children with SMA type 2 had also met its endpoint early,36 and in open label studies, some children achieved milestones such as sitting, standing, or even walking, at ages when such abilities would have been unexpected or lost without treatment.37 Results from these and other trials suggest that nusinersen works best when given early in the course of disease. For example, in one study, infants with SMA-causing mutations who began treatment before symptom onset showed signs of motor development resembling timelines in healthy children.38

The development of nusinersen was made possible by a large body of research to understand the cause and mechanisms underlying SMA, which pointed to a clear target for a disease-modifying therapy. NINDS and other NIH institutes provided essential support for this research as well as for earlier basic science studies of RNA splicing39 that laid the foundation for antisense oligonucleotide approaches. The success of nusinersen also reflects integral roles for patients and their families in clinical research and for disease-focused organizations – such as Cure SMA (formerly Families of SMA), the SMA Foundation, and the Muscular Dystrophy Association – whose funding and other support helped to catalyze this exciting clinical advance. Looking ahead, continued focus on SMA research may soon yield additional treatments, including gene therapy40 and other approaches that could complement or enhance the effectiveness of nusinersen or allow a less invasive route of administration.

List of References

  1. Reviewed in: Lunn MR, Wang CH. Spinal muscular atrophy. Lancet. 2008 Jun 21;371(9630):2120-33. PMID: 18572081 (NINDS, NHGRI, and several other U.S. and international public and private sources)

  2. Lefebvre S, Bürglen L, Reboullet S, Clermont O, Burlet P, Viollet L, Benichou B, Cruaud C, Millasseau P, Zeviani M, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995 Jan 13;80(1):155-65. PMID: 7813012 (France, public and private sources)

  3. Lefebvre S, Burlet P, Liu Q, Bertrandy S, Clermont O, Munnich A, Dreyfuss G, Melki J. Correlation between severity and SMN protein level in spinal muscular atrophy. Nat Genet. 1997 Jul;16(3):265-9. PMID: 9207792 (France, public and private sources; HHMI, NIH, grant number not given)

  4. Coovert DD, Le TT, McAndrew PE, Strasswimmer J, Crawford TO, Mendell JR, Coulson SE, Androphy EJ, Prior TW, Burghes AH. The survival motor neuron protein in spinal muscular atrophy. Hum Mol Genet. 1997 Aug;6(8):1205-14. PMID: 9259265 (NIH/NICHD, core facilities grant HD24061; Families of SMA, Muscular Dystrophy Association)

  5. Wirth B, Brichta L, Schrank B, Lochmüller H, Blick S, Baasner A, Heller R. Mildly affected patients with spinal muscular atrophy are partially protected by an increased SMN2 copy number. Hum Genet. 2006 May;119(4):422-8. PMID: 16508748 (Germany, public sources; Families of SMA)

  6. McAndrew PE, Parsons DW, Simard LR, Rochette C, Ray PN, Mendell JR, Prior TW, Burghes AH. Identification of proximal spinal muscular atrophy carriers and by analysis of SMNT and SMNC gene copy number. Am J Hum Genet. 1997 Jun;60(6):1411-22. PMID: 9199562 (Muscular Dystrophy Association; Families of SMA; other private sources)

  7. 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 May 25;96(11):6307-11. PMID: 10339583 (Germany, public sources; Muscular Dystrophy Association; Families of SMA)

  8. Monani UR, Lorson CL, Parsons DW, Prior TW, Androphy EJ, Burghes AH, McPherson JD. A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2. Hum Mol Genet. 1999 Jul;8(7):1177-83. PMID: 10369862 (NIH/NINDS, grant NS38650; Families of SMA; Muscular Dystrophy Association)

  9. Lorson CL, Androphy EJ. An exonic enhancer is required for inclusion of an essential exon in the SMA-determining gene SMN. Hum Mol Genet. 2000 Jan 22;9(2):259-65. PMID: 10607836 (Families of SMA; Muscular Dystrophy Association)

  10. Vitte J, Fassier C, Tiziano FD, Dalard C, Soave S, Roblot N, Brahe C, Saugier-Veber P, Bonnefont JP, Melki J. Refined characterization of the expression and stability of the SMN gene products. Am J Pathol. 2007 Oct;171(4):1269-80. PMID: 17717146 (France, public and private sources)

  11. Burnett BG, Muñoz E, Tandon A, Kwon DY, Sumner CJ, Fischbeck KH. Regulation of SMN protein stability. Mol Cell Biol. 2009 Mar;29(5):1107-15. PMID: 19103745 (NIH/NINDS, intramural and extramural, including grant NS0048199; Families of SMA)

  12. Reviewed in: Schmid A, DiDonato CJ. Animal models of spinal muscular atrophy. J ChildnNeurol. 2007 Aug;22(8):1004-12. PMID: 17761656; and Bebee TW, Dominguez CE, Chandler DS. Mouse models of SMA: tools for disease characterization and therapeutic development. Hum Genet. 2012 Aug;131(8):1277-93. PMID: 22543872

  13. Reviewed in: Calder AN, Androphy EJ, Hodgetts KJ. Small Molecules in Development for the Treatment of Spinal Muscular Atrophy. J Med Chem. 2016 Nov 23;59(22):10067-10083. PMID: 27490705

  14. Pinard E, Green L, Reutlinger M, Weetall M, Naryshkin NA, Baird J, Chen KS, Paushkin SV, Metzger F, Ratni H. Discovery of a Novel Class of Survival Motor Neuron 2 Splicing Modifiers for the Treatment of Spinal Muscular Atrophy. J Med Chem. 2017 May 25;60(10):4444-4457. PMID: 28441483

  15. Ranganathan R. NINDS translational programs: priming the pump of neurotherapeutics discovery and development. Neuron. 2014 Nov 5;84(3):515-20. PMID: 25442927

  16. Lim SR, Hertel KJ. Modulation of survival motor neuron pre-mRNA splicing by inhibition of alternative 3' splice site pairing. J Biol Chem. 2001 Nov 30;276(48):45476-83. PMID: 11584013 (Families of SMA)

  17. Cartegni L, Krainer AR. Correction of disease-associated exon skipping by synthetic exon-specific activators. Nat Struct Biol. 2003 Feb;10(2):120-5. PMID: 12524529 (NIH, grant number not given)

  18. Ken Garber. Big win possible for Ionis/Biogen antisense drug in muscular atrophy. Nature Biotechnology 34, 1002–1003 (2016) doi:10.1038/nbt1016-1002 (news article)

  19. Hua Y, Vickers TA, Baker BF, Bennett CF, Krainer AR. Enhancement of SMN2 exon 7 inclusion by antisense oligonucleotides targeting the exon. PLoS Biol. 2007 Apr;5(4):e73. PMID: 17355180 (NIH/NINDS and NIGMS, grants NS041621 and GM42699; SMA Foundation; with employees of Ionis Pharmaceuticals [then Isis])

  20. Singh NK, Singh NN, Androphy EJ, Singh RN. Splicing of a critical exon of human Survival Motor Neuron is regulated by a unique silencer element located in the last intron. Mol Cell Biol. 2006 Feb;26(4):1333-46. PMID: 16449646 (NIH/NINDS, grant NS40275; Families of SMA; Muscular Dystrophy Association)

  21. Hua Y, Vickers TA, Okunola HL, Bennett CF, Krainer AR. Antisense masking of an hnRNP A1/A2 intronic splicing silencer corrects SMN2 splicing in transgenic mice. Am J Hum Genet. 2008 Apr;82(4):834-48. PMID: 18371932 (NIH/NIGMS, grant GM42699; SMA Foundation; Muscular Dystrophy Association; Louis Morin Charitable Trust; with employees of Ionis Pharmaceuticals [then Isis])

  22. Hua Y, Sahashi K, Hung G, Rigo F, Passini MA, Bennett CF, Krainer AR. Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model. Genes Dev. 2010 Aug 1;24(15):1634-44. PMID: 20624852 (Muscular Dystrophy Association; with employees of Ionis Pharmaceuticals [then Isis], and Genzyme)

  23. Passini MA, Bu J, Richards AM, Kinnecom C, Sardi SP, Stanek LM, Hua Y, Rigo F, Matson J, Hung G, Kaye EM, Shihabuddin LS, Krainer AR, Bennett CF, Cheng SH. Antisense oligonucleotides delivered to the mouse CNS ameliorate symptoms of severe spinal muscular atrophy. Sci Transl Med. 2011 Mar 2;3(72):72ra18. PMID: 21368223 (Ionis Pharmaceuticals [then Isis] and Genzyme)

  24. Franzen, L. New Therapeutic Avenues for Spinal Muscular Atrophy in Development by ISIS Pharmaceuticals, Inc. July 16, 2010. Available at Accessed January 26, 2017.

  25. Chiriboga CA, Swoboda KJ, Darras BT, Iannaccone ST, Montes J, De Vivo DC, Norris DA, Bennett CF, Bishop KM. Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy. Neurology. 2016 Mar 8;86(10):890-7. PMID: 26865511 (Ionis Pharmaceuticals; numbers NCT01494701, NCT01780246)

  26. Biogen Idec. Biogen Idec and Isis Pharmaceuticals Announce Global Collaboration for Antisense Program Targeting Spinal Muscular Atrophy. January 4, 2012. Available at Accessed January 26, 2017.

  27. Isis Pharmaceuticals, Inc. ISIS Pharmaceuticals Initiates a Clinical Study of ISIS-SMN Rx in Infants with Spinal Muscular Atrophy. April 23, 2013. Available at Accessed January 26, 2017. ( number NCT01839656)

  28. Finkel RS, Chiriboga CA, Vajsar J, Day JW, Montes J, De Vivo DC, Yamashita M, Rigo F, Hung G, Schneider E, Norris DA, Xia S, Bennett CF, Bishop KM. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet. 2016 Dec 17;388(10063):3017-3026. PMID: 27939059 (Ionis Pharmaceuticals, Inc and Biogen; number NCT01839656)

  29. Isis Pharmaceuticals, Inc. Isis Pharmaceuticals Initiates Phase 3 Study of ISIS-SMN Rx in Infants with Spinal Muscular Atrophy. August 1, 2014. Available at Accessed January 26, 2017. ( number NCT02193074)

  30. Isis Pharmaceuticals, Inc. Isis Pharmaceuticals Initiates Phase 3 Study of ISIS-SMN Rx in Children with Spinal Muscular Atrophy. November 25, 2014. Available at Accessed January 26, 2017. ( number NCT02292537)

  31. Biogen. New Data Presented at World Muscle Society Congress Support Potential Benefit of Investigational Treatment Nusinersen in Spinal Muscular Atrophy. October 8, 2016. Available at Accessed May 30, 2017. (Ionis Pharmaceuticals Inc. and Biogen; number NCT02386553)

  32. Kolb SJ, Coffey CS, Yankey JW, Krosschell K, Arnold WD, Rutkove SB, Swoboda KJ, Reyna SP, Sakonju A, Darras BT, Shell R, Kuntz N, Castro D, Iannaccone ST, Parsons J, Connolly AM, Chiriboga CA, McDonald C, Burnette WB, Werner K, Thangarajh M, Shieh PB, Finanger E, Cudkowicz ME, McGovern MM, McNeil DE, Finkel R, Kaye E, Kingsley A, Renusch SR, McGovern VL, Wang X, Zaworski PG, Prior TW, Burghes AH, Bartlett A, Kissel JT; NeuroNEXT Clinical Trial Network and on behalf of the NN101 SMA Biomarker Investigators. Baseline results of the NeuroNEXT spinal muscular atrophy infant biomarker study. Ann Clin Transl Neurol. 2016 Jan 21;3(2):132-45. PMID: 26900585

  33. Biogen. Biogen and Ionis Pharmaceuticals Report Nusinersen Meets Primary Endpoint at Interim Analysis of Phase 3 ENDEAR Study in Infantile-Onset Spinal Muscular Atrophy. August 1, 2016. Available at Accessed May 30, 2017. (Ionis Pharmaceuticals Inc. and Biogen; number NCT02193074)

  34. Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL, Kirschner J, Chiriboga CA, Saito K, Servais L, Tizzano E, Topaloglu H, Tulinius M, Montes J, Glanzman AM, Bishop K, Zhong ZJ, Gheuens S, Bennett CF, Schneider E, Farwell W, De Vivo DC; ENDEAR Study Group. Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. N Engl J Med. 2017 Nov 2;377(18):1723-1732. PMID: 29091570. (Biogen and Ionis Pharmaceuticals; number, NCT02193074)

  35. U.S. Food and Drug Administration. FDA approves first drug for spinal muscular atrophy. December 23, 2016. Available at Accessed February 2, 2017.

  36. Biogen and Ionis Pharmaceuticals. Biogen and Ionis Pharmaceuticals Announce SPINRAZA (nusinersen) Meets Primary Endpoint at Interim Analysis of Phase 3 CHERISH Study in Later-Onset Spinal Muscular Atrophy. November 7, 2016. Available at Accessed May 30, 2017. 

  37. Biogen. Therapies (Spinal Muscular Atrophy). Available at Accessed May 30, 2017.

  38. Biogen. New Data Presented at World Muscle Society Congress Support Potential Benefit of Investigational Treatment Nusinersen in Spinal Muscular Atrophy. October 8, 2016. Available at Accessed May 30, 2017. (Ionis Pharmaceuticals Inc. and Biogen; number NCT02386553)

  39. National Institute of General Medical Sciences. NIGMS-Supported Nobelists (Richard J. Roberts & Phillip A. Sharp). November 15, 2016. Available at Accessed May 30, 2017.

  40. Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. Mendell JR, Al-Zaidy S, Shell R, Arnold WD, Rodino-Klapac LR, Prior TW, Lowes L, Alfano L, Berry K, Church K, Kissel JT, Nagendran S, L’Italien J, Sproule DM, Wells C, Cardenas JA, Heitzer MD, Kaspar A, Corcoran S, Braun L, Likhite S, Miranda C, Meyer K, Foust KD, Burghes AHM, Kaspar BK. N Engl J Med. 2017 Nov 2;377(18):1713-1722. PMID: 29091557