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Therapeutic approaches for spinal muscular atrophy (SMA)

Gene Therapy volume 24, pages 514–519 (2017)Cite this article

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Abstract

Spinal muscular atrophy is an autosomal recessive neurodegenerative disorder characterized by progressive muscle wasting and loss of muscle function due to severe motor neuron dysfunction, secondary to mutations in the survival motor neuron 1 (SMN1) gene. A second neighboring centromeric gene, SMN2, is intact in all patients but contains a C-to-T variation in exon 7 that affects a splice enhancer and determines exclusion of exon 7 in the majority of its transcript, leading to an unstable protein that cannot substitute for mutant SMN1. Following successful studies on disease models and intensive studies on SMN functions in the past decade, SMN upregulation targeting SMN2, has been suggested as a possible therapeutic approach. Recently, we have witnessed an historical turning point with the first disease-modifying treatment receiving Food and Drug Administration approval and now being available to patients also outside the clinical trial. This innovative treatment is an antisense oligonucleotide, which, administered intrathecally, is able to increase exon 7 inclusion in the majority of the SMN2 mRNA and increase the production of fully functional SMN protein. Alternative advanced therapies, such as viral vector mediated gene therapy and orally available small molecules, are also showing promising results in early clinical trial phases.

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References

  1. Sugarman EA, Nagan N, Zhu H, Akmaev VR, Zhou Z, Rohlfs EM et al. Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72400 specimens. Eur J Hum Genet 2012; 20: 27–32.

    Article  PubMed  Google Scholar 

  2. MacDonald WK, Hamilton D, Kuhle S . SMA carrier testing: a meta-analysis of differences in test performance by ethnic group. Prenat Diagn 2014; 34: 1219–1226.

    Article  PubMed  Google Scholar 

  3. Wadman RI, Bosboom WM, van der Pol WL, van den Berg LH, Wokke JH, Iannaccone ST et al. Drug treatment for spinal muscular atrophy type I. Cochrane Database Syst Rev 2012: Cd006281.

  4. Wadman RI, Bosboom WM, van der Pol WL, van den Berg LH, Wokke JH, Iannaccone ST et al. Drug treatment for spinal muscular atrophy types II and III. Cochrane Database Syst Rev 2012: Cd006282.

  5. Hua Y, Sahashi K, Rigo F, Hung G, Horev G, Bennett CF et al. Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model. Nature 2011; 478: 123–126.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Porensky PN, Mitrpant C, McGovern VL, Bevan AK, Foust KD, Kaspar BK et al. A single administration of morpholino antisense oligomer rescues spinal muscular atrophy in mouse. Hum Mol Genet 2012; 21: 1625–1638.

    Article  CAS  PubMed  Google Scholar 

  7. Finkel RS, Chiriboga CA, Vajsar J, Day JW, Montes J, De Vivo DC et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet 2016; 388: 3017–3026.

    Article  CAS  PubMed  Google Scholar 

  8. Tsai LK, Tsai MS, Ting CH, Li H . Multiple therapeutic effects of valproic acid in spinal muscular atrophy model mice. J Mol Med (Berlin, Germany) 2008; 86: 1243–1254.

    Article  CAS  Google Scholar 

  9. Hastings ML, Berniac J, Liu YH, Abato P, Jodelka FM, Barthel L et al. Tetracyclines that promote SMN2 exon 7 splicing as therapeutics for spinal muscular atrophy. Sci Trans Med 2009; 1: 5ra12.

    Article  Google Scholar 

  10. Avila AM, Burnett BG, Taye AA, Gabanella F, Knight MA, Hartenstein P 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  CAS  PubMed  PubMed Central  Google Scholar 

  11. Narver HL, Kong L, Burnett BG, Choe DW, Bosch-Marce M, Taye AA 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 

  12. Garbes L, Riessland M, Holker I, Heller R, Hauke J, Trankle C et al. LBH589 induces up to 10-fold SMN protein levels by several independent mechanisms and is effective even in cells from SMA patients non-responsive to valproate. Hum Mol Genet 2009; 18: 3645–3658.

    Article  CAS  PubMed  Google Scholar 

  13. Riessland M, Ackermann B, Forster A, Jakubik M, Hauke J, Garbes L et al. SAHA ameliorates the SMA phenotype in two mouse models for spinal muscular atrophy. Hum Mol Genet 2010; 19: 1492–1506.

    Article  CAS  PubMed  Google Scholar 

  14. Mattis VB, Ebert AD, Fosso MY, Chang CW, Lorson CL . Delivery of a read-through inducing compound, TC007, lessens the severity of a spinal muscular atrophy animal model. Hum Mol Genet 2009; 18: 3906–3913.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Naryshkin NA, Weetall M, Dakka A, Narasimhan J, Zhao X, Feng Z et al. Motor neuron disease. SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy. Science (New York, NY) 2014; 345: 688–693.

    Article  CAS  Google Scholar 

  16. Palacino J, Swalley SE, Song C, Cheung AK, Shu L, Zhang X et al. SMN2 splice modulators enhance U1-pre-mRNA association and rescue SMA mice. Nat Chem Biol 2015; 11: 511–517.

    Article  CAS  PubMed  Google Scholar 

  17. Foust KD, Wang X, McGovern VL, Braun L, Bevan AK, Haidet AM et al. Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN. Nat Biotechnol 2010; 28: 271–274.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Passini MA, Bu J, Roskelley EM, Richards AM, Sardi SP, O'Riordan CR et al. CNS-targeted gene therapy improves survival and motor function in a mouse model of spinal muscular atrophy. J Clin Invest 2010; 120: 1253–1264.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Valori CF, Ning K, Wyles M, Mead RJ, Grierson AJ, Shaw PJ et al. Systemic delivery of scAAV9 expressing SMN prolongs survival in a model of spinal muscular atrophy. Sci Trans Med 2010; 2: 35ra42.

    Article  Google Scholar 

  20. Duque SI, Arnold WD, Odermatt P, Li X, Porensky PN, Schmelzer L et al. A large animal model of spinal muscular atrophy and correction of phenotype. Ann Neurol 2015; 77: 399–414.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Duque S, Joussemet B, Riviere C, Marais T, Dubreil L, Douar AM et al. Intravenous administration of self-complementary AAV9 enables transgene delivery to adult motor neurons. Mol Ther 2009; 17: 1187–1196.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bordet T, Buisson B, Michaud M, Drouot C, Galea P, Delaage P et al. Identification and characterization of cholest-4-en-3-one, oxime (TRO19622), a novel drug candidate for amyotrophic lateral sclerosis. J Pharmacol Exp Ther 2007; 322: 709–720.

    Article  CAS  PubMed  Google Scholar 

  23. Calder AN, Androphy EJ, Hodgetts KJ . Small molecules in development for the treatment of spinal muscular atrophy. J Med Chem 2016; 59: 10067–10083.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kinali M, Mercuri E, Main M, De Biasia F, Karatza A, Higgins R et al. Pilot trial of albuterol in spinal muscular atrophy. Neurology 2002; 59: 609–610.

    Article  CAS  PubMed  Google Scholar 

  25. Pane M, Staccioli S, Messina S, D'Amico A, Pelliccioni M, Mazzone ES et al. Daily salbutamol in young patients with SMA type II. Neuromusc Disord 2008; 18: 536–540.

    Article  PubMed  Google Scholar 

  26. Angelozzi C, Borgo F, Tiziano FD, Martella A, Neri G, Brahe C . Salbutamol increases SMN mRNA and protein levels in spinal muscular atrophy cells. J Clin Genet 2008; 45: 29–31.

    Article  CAS  Google Scholar 

  27. Tiziano FD, Lomastro R, Pinto AM, Messina S, D'Amico A, Fiori S et al. Salbutamol increases survival motor neuron (SMN) transcript levels in leucocytes of spinal muscular atrophy (SMA) patients: relevance for clinical trial design. J Med Genet 2010; 47: 856–858.

    Article  CAS  PubMed  Google Scholar 

  28. Hedlund E, Hefferan MP, Marsala M, Isacson O . Cell therapy and stem cells in animal models of motor neuron disorders. Eur J Neurosci 2007; 26: 1721–1737.

    Article  PubMed  Google Scholar 

  29. Koliatsos VE, Xu L, Yan J . Human stem cell grafts as therapies for motor neuron disease. Expert Opin Biol Ther 2008; 8: 137–141.

    Article  CAS  PubMed  Google Scholar 

  30. Suzuki M, Svendsen CN . Combining growth factor and stem cell therapy for amyotrophic lateral sclerosis. Trends Neurosci 2008; 31: 192–198.

    Article  CAS  PubMed  Google Scholar 

  31. Corti S, Nizzardo M, Nardini M, Donadoni C, Salani S, Ronchi D 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  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wichterle H, Lieberam I, Porter JA, Jessell TM . Directed differentiation of embryonic stem cells into motor neurons. Cell 2002; 110: 385–397.

    Article  CAS  PubMed  Google Scholar 

  33. Li XJ, Du ZW, Zarnowska ED, Pankratz M, Hansen LO, Pearce RA et al. Specification of motoneurons from human embryonic stem cells. Nat Biotechnol 2005; 23: 215–221.

    Article  PubMed  Google Scholar 

  34. Dimos JT, Rodolfa KT, Niakan KK, Weisenthal LM, Mitsumoto H, Chung W et al. Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science (New York, NY) 2008; 321: 1218–1221.

    Article  CAS  Google Scholar 

  35. Corti S, Nizzardo M, Nardini M, Donadoni C, Salani S, Ronchi D et al. Embryonic stem cell-derived neural stem cells improve spinal muscular atrophy phenotype in mice. Brain 2010; 133 (Pt 2): 465–481.

    Article  PubMed  Google Scholar 

  36. Taylor JL, Lee FK, Yazdanpanah GK, Staropoli JF, Liu M, Carulli JP et al. Newborn blood spot screening test using multiplexed real-time PCR to simultaneously screen for spinal muscular atrophy and severe combined immunodeficiency. Clin Chem 2015; 61: 412–419.

    Article  CAS  PubMed  Google Scholar 

  37. Cifuentes-Diaz C, Faille L, Goudou D, Schachner M, Rieger F, Angaut-Petit D . Abnormal reinnervation of skeletal muscle in a tenascin-C-deficient mouse. J Neurosci Res 2002; 67: 93–99.

    Article  CAS  PubMed  Google Scholar 

  38. Kariya S, Mauricio R, Dai Y, Monani UR . The neuroprotective factor Wld(s) fails to mitigate distal axonal and neuromuscular junction (NMJ) defects in mouse models of spinal muscular atrophy. Neurosci Lett 2009; 449: 246–251.

    Article  CAS  PubMed  Google Scholar 

  39. Kariya S, Park GH, Maeno-Hikichi Y, Leykekhman O, Lutz C, Arkovitz MS et al. Reduced SMN protein impairs maturation of the neuromuscular junctions in mouse models of spinal muscular atrophy. Hum Mol Genet 2008; 17: 2552–2569.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Mentis GZ, Blivis D, Liu W, Drobac E, Crowder ME, Kong L et al. Early functional impairment of sensory-motor connectivity in a mouse model of spinal muscular atrophy. Neuron 2011; 69: 453–467.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Szunyogova E, Zhou H, Maxwell GK, Powis RA, Francesco M, Gillingwater TH et al. Survival Motor Neuron (SMN) protein is required for normal mouse liver development. Sci Rep 2016; 6: 34635.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Khairallah MT, Astroski J, Custer SK, Androphy EJ, Franklin CL, Lorson CL . SMN deficiency negatively impacts red pulp macrophages and spleen development in mouse models of Spinal muscular atrophy. Hum Mol Genet 2017; 26: 932–941.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

FM is supported by the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. The MRC Centre for Neuromuscular Diseases Biobank and the support of the MDUK and of the SMA Trust to the activities of the Dubowitz Neuromuscular Centre is also gratefully acknowledged.

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Authors and Affiliations

  1. The Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, London, UK

    M Scoto & F Muntoni

  2. Department of Pediatric Neurology, Nemours Children’s Hospital, College of Medicine, University of Central Florida, Orlando, FL, USA,

    R S Finkel

  3. Department of Pediatric Neurology, Catholic University and Centro Nemo, Policlinico Gemelli, Rome, Italy

    E Mercuri

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Correspondence to F Muntoni.

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Competing interests

FM is involved as principal investigator in the following clinical trials: nusinersen (SHINE, sponsored by Ionis and Biogen); olesoxime (OLEOS, sponsored by Roche). He has participated in scientific advisory board activities for Roche; Biogen and Avexis, and is also a member of the Pfizer rare disease scientific advisory board. MS is involved as sub-investigator in SHINE clinical trial and is principal investigator in OLEOS clinical trial. RFS is involved as principal investigator in the following SMA clinical trials: nusinersen (CS3A, ENDEAR, CHERISH, NURTURE and SHINE, sponsored by Ionis and Biogen) and CK-2127107 (CY 5021 study, sponsored by Cytokinetics and Astellas). He has participated in scientific advisory board activities for Ionis, Biogen, Roche, Novartis and AveXis; has served on the DSMB for the Roche RG7800 and AveXis AVXS-101 phase 1 study; and has served as an advisor to CureSMA (US), the SMA Foundation (US), SMA REACH (UK) and SMA Europe. EM is involved as principal investigator in the following clinical trials: nusinersen (SHINE, sponsored by Ionis and Biogen); olesoxime (OLEOS, sponsored by Roche). He has participated in scientific advisory board activities for Ionis, Roche; Biogen and Avexis.

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Scoto, M., Finkel, R., Mercuri, E. et al. Therapeutic approaches for spinal muscular atrophy (SMA). Gene Ther 24, 514–519 (2017). https://doi.org/10.1038/gt.2017.45

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