Skip to main content

Advertisement

Log in

Emerging treatment options for spinal muscular atrophy

  • Published:
Current Treatment Options in Neurology Aims and scope Submit manuscript

Opinion statement

The motor neuron disease spinal muscular atrophy (SMA) is one of the leading genetic killers of infants worldwide. SMA is caused by mutation of the survival motor neuron 1 (SMN1) gene and deficiency of the survival motor neuron (SMN) protein. All patients retain one or more copies of the SMN2 gene, which (by producing a small amount of the SMN protein) rescues embryonic lethality and modifies disease severity. Rapid progress continues in dissecting the cellular functions of the SMN protein, but the mechanisms linking SMN deficiency with dysfunction and loss of functioning motor units remain poorly defined. Clinically, SMA should to be distinguished from other neuromuscular disorders, and the diagnosis can be readily confirmed with genetic testing. Quality of life and survival of SMA patients are improved with aggressive supportive care including optimized respiratory and nutritional care and management of scoliosis and contractures. Because SMA is caused by inadequate amounts of SMN protein, one aim of current SMA therapeutics development is to increase SMN protein levels in SMA patients by activating SMN2 gene expression and/or increasing levels of full-length SMN2 transcripts. Several potential therapeutic compounds are currently being studied in clinical trials in SMA patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Lefebvre S, Burglen L, Reboullet S, et al.: Identification and characterization of a spinal muscular atrophy-determining gene. Cell 1995, 80:155–165.

    Article  PubMed  CAS  Google Scholar 

  2. 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, 96:6307–6311.

    Article  PubMed  CAS  Google Scholar 

  3. Monani UR, Lorson CL, Parsons DW, et al.: A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2. Hum Mol Genet 1999, 8:1177–1183.

    Article  PubMed  CAS  Google Scholar 

  4. Le TT, Pham LT, Butchbach ME, et al.: SMNDelta7, the major product of the centromeric survival motor neuron (SMN2) gene, extends survival in mice with spinal muscular atrophy and associates with full-length SMN. Hum Mol Genet 2005, 14:845–857.

    Article  PubMed  CAS  Google Scholar 

  5. Lorson CL, Strasswimmer J, Yao JM, et al.: SMN oligomerization defect correlates with spinal muscular atrophy severity. Nat Genet 1998, 19:63–66.

    Article  PubMed  CAS  Google Scholar 

  6. Pellizzoni L, Kataoka N, Charroux B, et al.: A novel function for SMN, the spinal muscular atrophy disease gene product, in pre-mRNA splicing. Cell 1998, 95:615–624.

    Article  PubMed  CAS  Google Scholar 

  7. Sun Y, Grimmler M, Schwarzer V, et al.: Molecular and functional analysis of intragenic SMN1 mutations in patients with spinal muscular atrophy. Hum Mutat 2005, 25:64–71.

    Article  PubMed  CAS  Google Scholar 

  8. Feldkotter M, Schwarzer V, Wirth R, et al.: Quantitative analyses of SMN1 and SMN2 based on real-time lightCycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy. Am J Hum Genet 2002, 70:358–368.

    Article  PubMed  CAS  Google Scholar 

  9. Oprea GE, Krober S, McWhorter ML, et al.: Plastin 3 is a protective modifier of autosomal recessive spinal muscular atrophy. Science 2008, 320:524–527.

    Article  PubMed  CAS  Google Scholar 

  10. Miguel-Aliaga I, Culetto E, Walker DS, et al.: The Caenorhabditis elegans orthologue of the human gene responsible for spinal muscular atrophy is a maternal product critical for germline maturation and embryonic viability. Hum Mol Genet 1999, 8:2133–2143.

    Article  PubMed  CAS  Google Scholar 

  11. Paushkin S, Charroux B, Abel L, et al.: The survival motor neuron protein of Schizosacharomyces pombe. Conservation of survival motor neuron interaction domains in divergent organisms. J Biol Chem 2000, 275:23841–23846.

    Article  PubMed  CAS  Google Scholar 

  12. Schrank B, Gotz R, Gunnersen JM, et al.: Inactivation of the survival motor neuron gene, a candidate gene for human spinal muscular atrophy, leads to massive cell death in early mouse embryos. Proc Natl Acad Sci U S A 1997, 94:9920–9925.

    Article  PubMed  CAS  Google Scholar 

  13. Liu Q, Dreyfuss G: A novel nuclear structure containing the survival of motor neurons protein. Embo J 1996, 15:3555–3565.

    PubMed  CAS  Google Scholar 

  14. Monani UR: Spinal muscular atrophy: a deficiency in a ubiquitous protein, a motor neuron-specific disease. Neuron 2005, 48:885–896.

    Article  PubMed  CAS  Google Scholar 

  15. Paushkin S, Gubitz AK, Massenet S, Dreyfuss G: The SMN complex, an assemblyosome of ribonucleoproteins. Curr Opin Cell Biol 2002, 14:305–312.

    Article  PubMed  CAS  Google Scholar 

  16. Zhang Z, Lotti F, Dittmar K, et al.: SMN deficiency causes tissue-specific perturbations in the repertoire of snRNAs and widespread defects in splicing. Cell 2008, 133:585–600.

    Article  PubMed  CAS  Google Scholar 

  17. Gabanella F, Butchbach ME, Saieva L, et al.: Ribonucleoprotein assembly defects correlate with spinal muscular atrophy severity and preferentially affect a subset of spliceosomal snRNPs. PLoS ONE 2007, 2:e921.

    Article  PubMed  Google Scholar 

  18. Munsat TL, Davies KE: International SMA consortium meeting. (26–28 June 1992, Bonn, Germany). Neuromuscul Disord 1992, 2:423–428.

    Article  PubMed  CAS  Google Scholar 

  19. Markowitz JA, Tinkle MB, Fischbeck KH: Spinal muscular atrophy in the neonate. J Obstet Gynecol Neonatal Nurs 2004, 33:12–20.

    Article  PubMed  Google Scholar 

  20. Wang CH, Finkel RS, Bertini ES, et al.: Consensus statement for standard of care in spinal muscular atrophy. J Child Neurol 2007, 22:1027–1049.

    Article  PubMed  Google Scholar 

  21. Oskoui M, Levy G, Garland CJ, et al.: The changing natural history of spinal muscular atrophy type 1. Neurology 2007, 69:1931–1936.

    Article  PubMed  CAS  Google Scholar 

  22. Wan L, Ottinger E, Cho S, et al.: Inactivation of the SMN complex by oxidative stress. Mol Cell 2008, 31:244–254.

    Article  PubMed  CAS  Google Scholar 

  23. Crawford TO: Concerns about the design of clinical trials for spinal muscular atrophy. Neuromuscul Disord 2004, 14:456–460.

    Article  PubMed  Google Scholar 

  24. Minucci S, Pelicci PG: Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 2006, 6:38–51.

    Article  PubMed  CAS  Google Scholar 

  25. Kernochan LE, Russo ML, Woodling NS, et al.: The role of histone acetylation in SMN gene expression. Hum Mol Genet 2005, 14:1171–1182.

    Article  PubMed  CAS  Google Scholar 

  26. Brichta L, Hofmann Y, Hahnen E, et al.: Valproic acid increases the SMN2 protein level: a well-known drug as a potential therapy for spinal muscular atrophy. Hum Mol Genet 2003, 12:2481–2489.

    Article  PubMed  CAS  Google Scholar 

  27. Chang JG, Hsieh-Li HM, Jong YJ, et al.: Treatment of spinal muscular atrophy by sodium butyrate. Proc Natl Acad Sci U S A 2001, 98:9808–9813.

    Article  PubMed  CAS  Google Scholar 

  28. Sumner CJ, Huynh TN, Markowitz JA, et al.: Valproic acid increases SMN levels in spinal muscular atrophy patient cells. Ann Neurol 2003, 54:647–654.

    Article  PubMed  CAS  Google Scholar 

  29. Andreassi C, Angelozzi C, Tiziano FD, et al.: Phenylbutyrate increases SMN expression in vitro: relevance for treatment of spinal muscular atrophy. Eur J Hum Genet 2004, 12:59–65.

    Article  PubMed  CAS  Google Scholar 

  30. Narver HL, Kong L, Burnett BG, et al.: Sustained improvement of spinal muscular atrophy mice treated with trichostatin A plus nutrition. Ann Neurol 2008, 64:465–470.

    Article  PubMed  Google Scholar 

  31. Avila AM, Burnett BG, Taye AA, et al.: Trichostatin A increases SMN expression and survival in a mouse model of spinal muscular atrophy. J Clin Invest 2007, 117:659–671.

    Article  PubMed  CAS  Google Scholar 

  32. Swoboda K: SMA CARNI-VAL TRIAL: Randomized double-blind placebo-controlled trial of L-carnitine and valproic acid in children with SMA type II. Presented at the 12th Annual International SMA Research Group Meeting, Boston, MA, June 19–21, 2008.

  33. Mercuri E, Bertini E, Messina S, et al.: Randomized, double-blind, placebo-controlled trial of phenylbutyrate in spinal muscular atrophy. Neurology 2007, 68:51–55.

    Article  PubMed  CAS  Google Scholar 

  34. Grzeschik SM, Ganta M, Prior TW, et al.: Hydroxyurea enhances SMN2 gene expression in spinal muscular atrophy cells. Ann Neurol 2005, 58:194–202.

    Article  PubMed  CAS  Google Scholar 

  35. Liang WC, Yuo CY, Chang JG, et al.: The effect of hydroxyurea in spinal muscular atrophy cells and patients. J Neurol Sci 2008, 268:87–94.

    Article  PubMed  CAS  Google Scholar 

  36. Wahl F, Stutzmann JM: Neuroprotective effects of riluzole in neurotrauma models: a review. Acta Neurochir Suppl 1999, 73:103–110.

    PubMed  CAS  Google Scholar 

  37. Haddad H, Cifuentes-Diaz C, Miroglio A, et al.: Riluzole attenuates spinal muscular atrophy disease progression in a mouse model. Muscle Nerve 2003, 28:432–437.

    Article  PubMed  CAS  Google Scholar 

  38. Russman BS, Iannaccone ST, Samaha FJ: A phase 1 trial of riluzole in spinal muscular atrophy. Arch Neurol 2003, 60:1601–1603.

    Article  PubMed  Google Scholar 

  39. Miller RG, Moore D, Young LA, et al.: Placebo-controlled trial of gabapentin in patients with amyotrophic lateral sclerosis. Neurology 1996, 47:1383–1388.

    PubMed  CAS  Google Scholar 

  40. Taylor CP, Gee NS, Su TZ, et al.: A summary of mechanistic hypotheses of gabapentin pharmacology. Epilepsy Res 1998, 29:233–249.

    Article  PubMed  CAS  Google Scholar 

  41. Miller RG, Moore DH, Dronsky V, et al.: A placebo-controlled trial of gabapentin in spinal muscular atrophy. J Neurol Sci 2001, 191:127–131.

    Article  PubMed  CAS  Google Scholar 

  42. Merlini L, Solari A, Vita G, et al.: Role of gabapentin in spinal muscular atrophy: results of a multicenter, randomized Italian study. J Child Neurol 2003, 18:537–541.

    Article  PubMed  Google Scholar 

  43. Angelozzi C, Borgo F, Tiziano FD, et al.: Salbutamol increases SMN mRNA and protein levels in spinal muscular atrophy cells. J Med Genet 2008, 45:29–31.

    Article  PubMed  CAS  Google Scholar 

  44. Kinali M, Mercuri E, Main M, et al.: Pilot trial of albuterol in spinal muscular atrophy. Neurology 2002, 59:609–610.

    PubMed  CAS  Google Scholar 

  45. Pane M, Staccioli S, Messina S, et al.: Daily salbutamol in young patients with SMA type II. Neuromuscul Disord 2008, 18:536–540.

    Article  PubMed  Google Scholar 

  46. Lunn MR, Root DE, Martino AM, et al.: Indoprofen upregulates the survival motor neuron protein through a cyclooxygenase-independent mechanism. Chem Biol 2004, 11:1489–1493.

    Article  PubMed  CAS  Google Scholar 

  47. Jarecki J, Chen X, Bernardino A, et al.: Diverse small-molecule modulators of SMN expression found by high-throughput compound screening: early leads towards a therapeutic for spinal muscular atrophy. Hum Mol Genet 2005, 14:2003–2018.

    Article  PubMed  CAS  Google Scholar 

  48. Thurmond J, Butchbach ME, Palomo M, et al.: Synthesis and biological evaluation of novel 2,4-diaminoquinazoline derivatives as SMN2 promoter activators for the potential treatment of spinal muscular atrophy. J Med Chem 2008, 51:449–469.

    Article  PubMed  CAS  Google Scholar 

  49. 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, 15:1471–1478.

    Article  PubMed  CAS  Google Scholar 

  50. Andreassi C, Jarecki J, Zhou J, et al.: Aclarubicin treatment restores SMN levels to cells derived from type I spinal muscular atrophy patients. Hum Mol Genet 2001, 10:2841–2849.

    Article  PubMed  CAS  Google Scholar 

  51. Lim SR, Hertel KJ: Modulation of survival motor neuron pre-mRNA splicing by inhibition of alternative 3′ splice site pairing. J Biol Chem 2001, 276:45476–45483.

    Article  PubMed  CAS  Google Scholar 

  52. Madocsai C, Lim SR, Geib T, et al.: Correction of SMN2 pre-mRNA splicing by antisense U7 small nuclear RNAs. Mol Ther 2005, 12:1013–1022.

    Article  PubMed  CAS  Google Scholar 

  53. Sangiuolo F, Filareto A, Spitalieri P, et al.: In vitro restoration of functional SMN protein in human trophoblast cells affected by spinal muscular atrophy by small fragment homologous replacement. Hum Gene Ther 2005, 16:869–880.

    Article  PubMed  CAS  Google Scholar 

  54. Miyajima H, Miyaso H, Okumura M, et al.: Identification of a cis-acting element for the regulation of SMN exon 7 splicing. J Biol Chem 2002, 277:23271–23277.

    Article  PubMed  CAS  Google Scholar 

  55. Skordis LA, Dunckley MG, Yue B, et al.: Bifunctional antisense oligonucleotides provide a trans-acting splicing enhancer that stimulates SMN2 gene expression in patient fibroblasts. Proc Natl Acad Sci U S A 2003, 100:4114–4119.

    Article  PubMed  CAS  Google Scholar 

  56. Baughan T, Shababi M, Coady TH, et al.: Stimulating full-length SMN2 expression by delivering bifunctional RNAs via a viral vector. Mol Ther 2006, 14:54–62.

    Article  PubMed  CAS  Google Scholar 

  57. Krainer A: SMN anti-sense. Presentation at the 12th Annual International SMA Research Group Meeting, Boston, MA, June 19–21, 2008.

  58. Wolstencroft EC, Mattis V, Bajer AA, et al.: A nonsequence-specific requirement for SMN protein activity: the role of aminoglycosides in inducing elevated SMN protein levels. Hum Mol Genet 2005, 14:1199–1210.

    Article  PubMed  CAS  Google Scholar 

  59. Azzouz M, Le T, Ralph GS, et al.: Lentivector-mediated SMN replacement in a mouse model of spinal muscular atrophy. J Clin Invest 2004, 114:1726–1731.

    PubMed  CAS  Google Scholar 

  60. Lesbordes JC, Cifuentes-Diaz C, Miroglio A, et al.: Therapeutic benefits of cardiotrophin-1 gene transfer in a mouse model of spinal muscular atrophy. Hum Mol Genet 2003, 12:1233–1239.

    Article  PubMed  CAS  Google Scholar 

  61. Kerr DA, Llado J, Shamblott MJ, et al.: Human embryonic germ cell derivatives facilitate motor recovery of rats with diffuse motor neuron injury. J Neurosci 2003, 23:5131–5140.

    PubMed  CAS  Google Scholar 

  62. Morshead CM: Adult neural stem cells: attempting to solve the identity crisis. Dev Neurosci 2004, 26:93–100.

    Article  PubMed  CAS  Google Scholar 

  63. Corti S, Nizzardo M, Nardini M, et al.: Neural stem cell transplantation can ameliorate the phenotype of a mouse model of spinal muscular atrophy. J Clin Invest 2008, 118:3316–3330.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Charlotte J. Sumner.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Burnett, B.G., Crawford, T.O. & Sumner, C.J. Emerging treatment options for spinal muscular atrophy. Curr Treat Options Neurol 11, 90–101 (2009). https://doi.org/10.1007/s11940-009-0012-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11940-009-0012-x

Keywords

Navigation