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AAV9 Vector: a Novel modality in gene therapy for spinal muscular atrophy

Gene Therapy volume 26, pages 287–295 (2019)Cite this article

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Abstract

Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, is characterized by the deterioration of alpha motor neurons in the brainstem and spinal cord. Currently, there is no cure for SMA, which calls for an urgent need to explore affordable and effective therapies and to maximize patients’ independence and quality of life. Adeno-associated virus (AAV) vector, one of the most promising and well-investigated vehicles for delivering transgenes, is a compelling candidate for gene therapy. Some of the hallmarks of AAVs are their nonpathogenicity, inability to incur an immune response, potential to achieve robust transgene expression, and varied tropism for several tissues of the body. Recently, these features were harnessed in a clinical trial conducted by AveXis in SMA patients, where AAV9 was employed as a vehicle for one-time administration of the SMN gene, the causative gene in SMA. The trial demonstrated remarkable improvements in motor milestones and rates of survival in the patients. This review focuses on the advent of SMA gene therapy and summarizes different preclinical studies that were conducted leading up to the AAV9–SMA trial in SMA patients.

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References

  1. Prior TW. Spinal muscular atrophy: a time for screening. Curr Opin Pediatr. 2010;22:696–702.

    Article  Google Scholar 

  2. Cherry JJ, Kobayashi DT, Lynes MM, Naryshkin NN, Tiziano FD, Zaworski PG, et al. Assays for the identification and prioritization of drug candidates for spinal muscular atrophy. Assay Drug Dev Technol. 2014;12:315–41.

    Article  CAS  Google Scholar 

  3. Farrar MA, Vucic S, Lin CS-Y, Park SB, Johnston HM, du Sart D, et al. Dysfunction of axonal membrane conductances in adolescents and young adults with spinal muscular atrophy. Brain 2011;134:3185–97.

    Article  Google Scholar 

  4. Finkel RS, McDermott MP, Kaufmann P, Darras BT, Chung WK, Sproule DM, et al. Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology 2014;83:810–7.

    Article  Google Scholar 

  5. 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 >72,400 specimens. Eur J Hum Genet. 2012;20:27–32.

    Article  Google Scholar 

  6. Prior TW, Nagan N, Sugarman EA, Batish SD, Braastad C. Technical standards and guidelines for spinal muscular atrophy testing. Genet Med. 2011;13:686–94.

    Article  Google Scholar 

  7. Lefebvre S, Bürglen L, Reboullet S, Clermont O, Burlet P, Viollet L, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell 1995;80:155–65.

    Article  CAS  Google Scholar 

  8. Kolb SJ, Kissel JT. Spinal muscular atrophy. Neurol Clin. 2015;33:831–46.

    Article  Google Scholar 

  9. Rochette CF, Gilbert N, Simard LR. SMN gene duplication and the emergence of the SMN2 gene occurred in distinct hominids: SMN2 is unique to Homo sapiens. Hum Genet. 2001;108:255–66.

    Article  CAS  Google Scholar 

  10. Monani UR, De Vivo DC. Neurodegeneration in spinal muscular atrophy: from disease phenotype and animal models to therapeutic strategies and beyond. Future Neurol. 2014;9:49–65.

    Article  CAS  Google Scholar 

  11. Burghes AHM, Beattie CE. Spinal muscular atrophy: why do low levels of survival motor neuron protein make motor neurons sick? Nat Rev Neurosci. 2009;10:597–609.

    Article  CAS  Google Scholar 

  12. Garcera A, Bahi N, Periyakaruppiah A, Arumugam S, Soler RM. Survival motor neuron protein reduction deregulates autophagy in spinal cord motoneurons in vitro. Cell Death Dis. 2013;4:e686.

    Article  CAS  Google Scholar 

  13. Stabley DL, Harris AW, Holbrook J, Chubbs NJ, Lozo KW, Crawford TO, et al. SMN1 and SMN2 copy numbers in cell lines derived from patients with spinal muscular atrophy as measured by array digital PCR. Mol Genet Genomic Med. 2015;3:248–57.

    Article  CAS  Google Scholar 

  14. Coovert DD, Le TT, McAndrew PE, Strasswimmer J, Crawford TO, Mendell JR, et al. The survival motor neuron protein in spinal muscular atrophy. Hum Mol Genet. 1997;6:1205–14.

    Article  CAS  Google Scholar 

  15. Lefebvre S, Burlet P, Liu Q, Bertrandy S, Clermont O, Munnich A, et al. Correlation between severity and SMN protein level in spinal muscular atrophy. Nat Genet. 1997;16:265–9.

    Article  CAS  Google Scholar 

  16. Liu Q, Dreyfuss G. A novel nuclear structure containing the survival of motor neurons protein. EMBO J. 1996;15:3555–65.

    Article  CAS  Google Scholar 

  17. Faravelli I, Nizzardo M, Comi GP, Corti S. Spinal muscular atrophy—recent therapeutic advances for an old challenge. Nat Rev Neurol. 2015;11:351–9.

    Article  CAS  Google Scholar 

  18. Battle DJ, Kasim M, Yong J, Lotti F, Lau C-K, Mouaikel J, et al. The SMN complex: an assembly machine for RNPs. Cold Spring Harb Symp Quant Biol. 2006;71:313–20.

    Article  CAS  Google Scholar 

  19. Chari A, Golas MM, Klingenhäger M, Neuenkirchen N, Sander B, Englbrecht C, et al. An assembly chaperone collaborates with the SMN complex to generate spliceosomal SnRNPs. Cell 2008;135:497–509.

    Article  CAS  Google Scholar 

  20. Pellizzoni L. Chaperoning ribonucleoprotein biogenesis in health and disease. EMBO Rep. 2007;8:340–5.

    Article  CAS  Google Scholar 

  21. Boulisfane N, Choleza M, Rage F, Neel H, Soret J, Bordonné R. Impaired minor tri-snRNP assembly generates differential splicing defects of U12-type introns in lymphoblasts derived from a type I SMA patient. Hum Mol Genet. 2011;20:641–8.

    Article  CAS  Google Scholar 

  22. Gabanella F, Butchbach MER, Saieva L, Carissimi C, Burghes AHM, Pellizzoni L. Ribonucleoprotein assembly defects correlate with spinal muscular atrophy severity and preferentially affect a subset of spliceosomal snRNPs. PLoS ONE. 2007;2:e921.

    Article  Google Scholar 

  23. Li DK, Tisdale S, Lotti F, Pellizzoni L. SMN control of RNP assembly: from post-transcriptional gene regulation to motor neuron disease. Semin Cell Dev Biol. 2014;32:22–9.

    Article  CAS  Google Scholar 

  24. Zhang Z, Lotti F, Dittmar K, Younis I, Wan L, Kasim M, et al. SMN deficiency causes tissue-specific perturbations in the repertoire of snRNAs and widespread defects in splicing. Cell 2008;133:585–600.

    Article  CAS  Google Scholar 

  25. Boyer JG, Murray LM, Scott K, De Repentigny Y, Renaud J-M, Kothary R. Early onset muscle weakness and disruption of muscle proteins in mouse models of spinal muscular atrophy. Skelet Muscle. 2013;3:24.

    Article  Google Scholar 

  26. Fayzullina S, Martin LJ. Skeletal muscle DNA damage precedes spinal motor neuron DNA damage in a mouse model of spinal muscular atrophy (SMA). PLoS ONE. 2014;9:e93329.

    Article  Google Scholar 

  27. Goulet BB, Kothary R, Parks RJ. At the “junction” of spinal muscular atrophy pathogenesis: the role of neuromuscular junction dysfunction in SMA disease progression. Curr Mol Med. 2013;13:1160–74.

    Article  CAS  Google Scholar 

  28. Kariya S, Obis T, Garone C, Akay T, Sera F, Iwata S, et al. Requirement of enhanced survival motoneuron protein imposed during neuromuscular junction maturation. J Clin Investig. 2014;124:785–800.

    Article  CAS  Google Scholar 

  29. Martinez TL, Kong L, Wang X, Osborne MA, Crowder ME, Van Meerbeke JP, et al. Survival motor neuron protein in motor neurons determines synaptic integrity in spinal muscular atrophy. J Neurosci. 2012;32:8703–15.

    Article  CAS  Google Scholar 

  30. McWhorter ML, Monani UR, Burghes AHM, Beattie CE. Knockdown of the survival motor neuron (Smn) protein in zebrafish causes defects in motor axon outgrowth and pathfinding. J Cell Biol. 2003;162:919–31.

    Article  CAS  Google Scholar 

  31. Akten B, Kye MJ, Hao LT, Wertz MH, Singh S, Nie D, et al. Interaction of survival of motor neuron (SMN) and HuD proteins with mRNA cpg15 rescues motor neuron axonal deficits. Proc Natl Acad Sci USA. 2011;108:10337–42.

    Article  CAS  Google Scholar 

  32. Hao LT, Duy PQ, An M, Talbot J, Iyer CC, Wolman M, et al. HuD and the survival motor neuron protein interact in motoneurons and are essential for motoneuron development, function and mRNA regulation. J Neurosci. 2017;37:1528–17.

    Google Scholar 

  33. Mulcahy PJ, Iremonger K, Karyka E, Herranz-Martín S, Shum K-T, Tam JKV, et al. Gene therapy: a promising approach to treating spinal muscular atrophy. Hum Gene Ther. 2014;25:575–86.

    Article  CAS  Google Scholar 

  34. Zanetta C, Nizzardo M, Simone C, Monguzzi E, Bresolin N, Comi GP, et al. Molecular therapeutic strategies for spinal muscular atrophies: current and future clinical trials. Clin Ther. 2014;36:128–40.

    Article  Google Scholar 

  35. DeVos SL, Miller TM. Antisense oligonucleotides: treating neurodegeneration at the level of RNA. Neurotherapeutics 2013;10:486–97.

    Article  CAS  Google Scholar 

  36. Groen EJN, Talbot K, Gillingwater TH. Advances in therapy for spinal muscular atrophy: promises and challenges. Nat Rev Neurol. 2018;14:214–24.

    Article  Google Scholar 

  37. Hua Y, Sahashi K, Hung G, Rigo F, Passini MA, Bennett CF, et al. Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model. Genes Dev. 2010;24:1634–44.

    Article  CAS  Google Scholar 

  38. Passini MA, Bu J, Richards AM, Kinnecom C, Sardi SP, Stanek LM, et al. Antisense oligonucleotides delivered to the mouse CNS ameliorate symptoms of severe spinal muscular atrophy. Sci Transl Med. 2011;3:72ra18.

    Article  Google Scholar 

  39. Williams JH, Schray RC, Patterson CA, Ayitey SO, Tallent MK, Lutz GJ. Oligonucleotide-mediated survival of motor neuron protein expression in CNS improves phenotype in a mouse model of spinal muscular atrophy. J Neurosci. 2009;29:7633–8.

    Article  CAS  Google Scholar 

  40. Hamilton G, Gillingwater TH. Spinal muscular atrophy: going beyond the motor neuron. Trends Mol Med. 2013;19:40–50.

    Article  CAS  Google Scholar 

  41. Shababi M, Lorson CL, Rudnik-Schöneborn SS. Spinal muscular atrophy: a motor neuron disorder or a multi-organ disease? J Anat. 2014;224:15–28.

    Article  CAS  Google Scholar 

  42. Chiriboga CA, Swoboda KJ, Darras BT, Iannaccone ST, Montes J, De Vivo DC, et al. Results from a phase 1 study of nusinersen (ISIS-SMNRx) in children with spinal muscular atrophy. Neurology 2016;86:890–7.

    Article  CAS  Google Scholar 

  43. Stein CA, Castanotto D. FDA-approved oligonucleotide therapies in 2017. Mol Ther. 2017;25:1069–75.

    Article  CAS  Google Scholar 

  44. Singh NN, Howell MD, Androphy EJ, Singh RN. How the discovery of ISS-N1 led to the first medical therapy for spinal muscular atrophy. Gene Ther. 2017;24:520–6.

    Article  CAS  Google Scholar 

  45. Bevan AK, Hutchinson KR, Foust KD, Braun L, McGovern VL, Schmelzer L, et al. Early heart failure in the SMNΔ7 model of spinal muscular atrophy and correction by postnatal scAAV9-SMN delivery. Hum Mol Genet. 2010;19:3895–905.

    Article  CAS  Google Scholar 

  46. Wijngaarde CA, Blank AC, Stam M, Wadman RI, van den Berg LH, van der Pol WL. Cardiac pathology in spinal muscular atrophy: a systematic review. Orphanet J Rare Dis. 2017;12. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5387385/.

  47. Azzouz M, Le T, Ralph GS, Walmsley L, Monani UR, Lee DCP, et al. Lentivector-mediated SMN replacement in a mouse model of spinal muscular atrophy. J Clin Investig. 2004;114:1726–31.

    Article  CAS  Google Scholar 

  48. Sinn PL, Sauter SL Jr, PBM. Gene therapy progress and prospects: development of improved lentiviral and retroviral vectors—design, biosafety, and production. Gene Ther. 2005;12:1089–98.

    Article  CAS  Google Scholar 

  49. Hacein-Bey-Abina S, Von Kalle C, Schmidt M, McCormack MP, Wulffraat N, Leboulch P, et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 2003;302:415–9.

    Article  CAS  Google Scholar 

  50. Hacein-Bey-Abina S, von Kalle C, Schmidt M, Le Deist F, Wulffraat N, McIntyre E, et al. A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. 2009. https://www.nejm.org/doi/10.1056/NEJM200301163480314?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dwww.ncbi.nlm.nih.gov.

  51. Gruber K. Europe gives gene therapy the green light. Lancet 2012;380:e10.

    Article  Google Scholar 

  52. Daya S, Berns KI. Gene therapy using adeno-associated virus vectors. Clin Microbiol Rev. 2008;21:583–93.

    Article  CAS  Google Scholar 

  53. Colella P, Ronzitti G, Mingozzi F. Emerging issues in AAV-mediated in vivo gene therapy. Mol Ther Methods Clin Dev. 2017;8:87–104.

    Article  Google Scholar 

  54. Cao L, During M, Xiao W. Replication competent helper functions for recombinant AAV vector generation. Gene Ther. 2002;9:1199–206.

    Article  CAS  Google Scholar 

  55. Drouin LM, Agbandje-McKenna M. Adeno-associated virus structural biology as a tool in vector development. Future Virol. 2013;8:1183–99.

    Article  CAS  Google Scholar 

  56. Zhang H-G, Wang YM, Xie JF, Liang X, Hsu H-C, Zhang X, et al. Recombinant adenovirus expressing adeno-associated virus cap and rep proteins supports production of high-titer recombinant adeno-associated virus. Gene Ther. 2001;8:704–12.

    Article  CAS  Google Scholar 

  57. Kantor B, Bailey RM, Wimberly K, Kalburgi SN, Gray SJ. Methods for gene transfer to the central nervous system. Adv Genet. 2014;87:125–97.

    Article  CAS  Google Scholar 

  58. Ferrari FK, Samulski T, Shenk T, Samulski RJ. Second-strand synthesis is a rate-limiting step for efficient transduction by recombinant adeno-associated virus vectors. J Virol. 1996;70:3227–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. McCarty DM. Self-complementary AAV vectors; advances and applications. Mol Ther. 2008;16:1648–56.

    Article  CAS  Google Scholar 

  60. Duque S, Joussemet B, Riviere C, Marais T, Dubreil L, Douar A-M, et al. Intravenous administration of self-complementary AAV9 enables transgene delivery to adult motor neurons. Mol Ther. 2009;17:1187–96.

    Article  CAS  Google Scholar 

  61. Foust KD, Nurre E, Montgomery CL, Hernandez A, Chan CM, Kaspar BK. Intravascular AAV9 preferentially targets neonatal-neurons and adult-astrocytes in CNS. Nat Biotechnol. 2009;27:59–65.

    Article  CAS  Google Scholar 

  62. 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;28:271–4.

    Article  CAS  Google Scholar 

  63. Dominguez E, Marais T, Chatauret N, Benkhelifa-Ziyyat S, Duque S, Ravassard P, et al. Intravenous scAAV9 delivery of a codon-optimized SMN1 sequence rescues SMA mice. Hum Mol Genet. 2011;20:681–93.

    Article  CAS  Google Scholar 

  64. 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 Transl Med. 2010;2:35ra42–35ra42.

    Article  Google Scholar 

  65. Alrafiah A, Karyka E, Coldicott I, Iremonger K, Lewis KE, Ning K, et al. Plastin 3 promotes motor neuron axonal growth and extends survival in a mouse model of spinal muscular atrophy. Mol Ther Methods Clin Dev. 2018;9:81–9.

    Article  CAS  Google Scholar 

  66. Kaifer KA, VillalĂłn E, Osman EY, Glascock JJ, Arnold LL, Cornelison DDW, et al. Plastin-3 extends survival and reduces severity in mouse models of spinal muscular atrophy. JCI Insight. 2017;2. https://insight.jci.org/articles/view/89970.

  67. Powis RA, Karyka E, Boyd P, CĂ´me J, Jones RA, Zheng Y, et al. Systemic restoration of UBA1 ameliorates disease in spinal muscular atrophy. JCI Insight. 2016;1. https://insight.jci.org/articles/view/87908.

  68. Little D, Valori CF, Mutsaers CA, Bennett EJ, Wyles M, Sharrack B, et al. PTEN depletion decreases disease severity and modestly prolongs survival in a mouse model of spinal muscular atrophy. Mol Ther. 2015;23:270–7.

    Article  CAS  Google Scholar 

  69. Bevan AK, Duque S, Foust KD, Morales PR, Braun L, Schmelzer L, et al. Systemic gene delivery in large species for targeting spinal cord, brain, and peripheral tissues for pediatric disorders. Mol Ther. 2011;19:1971–80.

    Article  CAS  Google Scholar 

  70. Dehay B, Dalkara D, Dovero S, Li Q, Bezard E. Systemic scAAV9 variant mediates brain transduction in newborn rhesus macaques. Sci Rep. 2012;2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3275921/.

  71. Meyer K, Ferraiuolo L, Schmelzer L, Braun L, McGovern V, Likhite S, et al. Improving single injection CSF delivery of AAV9-mediated gene therapy for SMA: a dose–response study in mice and nonhuman primates. Mol Ther. 2015;23:477–87.

    Article  CAS  Google Scholar 

  72. Mendell JR, Al-Zaidy S, Shell R, Arnold WD, Rodino-Klapac LR, Prior TW, et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med. 2017;377:1713–22.

    Article  CAS  Google Scholar 

  73. Possible $4M Price for AVXS-101, “Foundational” SMA gene therapy, could be cost-effective, Novartis says. https://smanewstoday.com/2018/11/09/possible-4m-price-for-avxs-101-foundational-sma-gene-therapy-could-be-cost-effective-novartis-says/.

  74. Wu Z, Asokan A, Samulski RJ. Adeno-associated virus serotypes: vector toolkit for human gene therapy. Mol Ther. 2006;14:316–27.

    Article  CAS  Google Scholar 

  75. Chira S, Jackson CS, Oprea I, Ozturk F, Pepper MS, Diaconu I, et al. Progresses towards safe and efficient gene therapy vectors. Oncotarget 2015;6:30675.

    Article  Google Scholar 

  76. Finer M, Glorioso J. A brief account of viral vectors and their promise for gene therapy. Gene Ther. 2017;24:1–2.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the Blazer Foundation.

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  1. Department of Biomedical Sciences, University of Illinois College of Medicine Rockford, Rockford, IL, 61107, USA

    Rithu Pattali, Yongchao Mou & Xue-Jun Li

  2. Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, 60607, USA

    Yongchao Mou & Xue-Jun Li

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Pattali, R., Mou, Y. & Li, XJ. AAV9 Vector: a Novel modality in gene therapy for spinal muscular atrophy. Gene Ther 26, 287–295 (2019). https://doi.org/10.1038/s41434-019-0085-4

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