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Development of Next-Generation Muscle Gene Therapy AAV Vectors

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Muscle Gene Therapy

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Abstract

Recombinant adeno-associated virus (AAV)-based gene delivery is a promising approach to treat muscle diseases. However, body-wide muscle delivery and pre-existing immune responses pose significant challenges to AAV muscle gene therapy. While the determinants of tissue tropism and immunogenicity of AAV are amenable to traditional molecular engineering, the development of a muscle-specific, immunosilent AAV vector has remained elusive. Recent advances in understanding the relationship between capsid structural motifs and functional domains have created exciting developments in the search for a muscle-specific AAV. Novel approaches to generate unique AAV properties through forced evolution have resulted in capsids with improved immune properties and/or muscle-targeting efficiency. Optimization of the gene cassette to restrict expression to mature muscle fibers provides another level of control. These reengineered AAV vectors have the potential to greatly increase efficacy and reduce off-target effects for body-wide muscle gene therapy. In this chapter, we discuss recent advances in the development of a next-generation, muscle-specific AAV vector.

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References

  1. Mercuri E, Muntoni F (2013) Muscular dystrophies. Lancet 381(9869):845–860. https://doi.org/10.1016/S0140-6736(12)61897-2

    Article  CAS  PubMed  Google Scholar 

  2. Ertl HCJ, High KA (2017) Impact of AAV capsid-specific T-cell responses on design and outcome of clinical gene transfer trials with recombinant adeno-associated viral vectors: an evolving controversy. Hum Gene Ther 28(4):328–337. https://doi.org/10.1089/hum.2016.172

    Article  CAS  PubMed  Google Scholar 

  3. Muzyczka N (1992) Use of adeno-associated virus as a general transduction vector for mammalian cells. Curr Top Microbiol Immunol 158:97–129

    CAS  PubMed  Google Scholar 

  4. Muzyczka N, Berns KI (2015) AAV’s golden jubilee. Mol Ther 23(5):807–808. https://doi.org/10.1038/mt.2015.55

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hastie E, Samulski RJ (2015) Adeno-associated virus at 50: a golden anniversary of discovery, research, and gene therapy success--a personal perspective. Hum Gene Ther 26(5):257–265. https://doi.org/10.1089/hum.2015.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Carter BJ (2004) Adeno-associated virus and the development of adeno-associated virus vectors: a historical perspective. Mol Ther 10(6):981–989

    Article  CAS  Google Scholar 

  7. Gao G, Vandenberghe LH, Alvira MR, Lu Y, Calcedo R, Zhou X, Wilson JM (2004) Clades of adeno-associated viruses are widely disseminated in human tissues. J Virol 78(12):6381–6388. https://doi.org/10.1128/JVI.78.12.6381-6388.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gao GP, Alvira MR, Wang L, Calcedo R, Johnston J, Wilson JM (2002) Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy. Proc Natl Acad Sci U S A 99(18):11854–11859

    Article  CAS  Google Scholar 

  9. Weitzman MD, Linden RM (2011) Adeno-associated virus biology. Methods Mol Biol 807:1–23. https://doi.org/10.1007/978-1-61779-370-7_1

    Article  CAS  PubMed  Google Scholar 

  10. Sonntag F, Kother K, Schmidt K, Weghofer M, Raupp C, Nieto K, Kuck A, Gerlach B, Bottcher B, Muller OJ, Lux K, Horer M, Kleinschmidt JA (2011) The assembly-activating protein promotes capsid assembly of different adeno-associated virus serotypes. J Virol 85(23):12686–12697. https://doi.org/10.1128/JVI.05359-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Huang LY, Halder S, Agbandje-McKenna M (2014) Parvovirus glycan interactions. Curr Opin Virol 7:108–118. https://doi.org/10.1016/j.coviro.2014.05.007

    Article  CAS  PubMed  Google Scholar 

  12. Agbandje-McKenna M, Kleinschmidt J (2011) AAV capsid structure and cell interactions. Methods Mol Biol 807:47–92. https://doi.org/10.1007/978-1-61779-370-7_3

    Article  CAS  PubMed  Google Scholar 

  13. Ding W, Zhang L, Yan Z, Engelhardt JF (2005) Intracellular trafficking of adeno-associated viral vectors. Gene Ther 12(11):873–880. https://doi.org/10.1038/sj.gt.3302527

    Article  CAS  PubMed  Google Scholar 

  14. Nonnenmacher M, Weber T (2012) Intracellular transport of recombinant adeno-associated virus vectors. Gene Ther 19(6):649–658. https://doi.org/10.1038/gt.2012.6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Shen S, Bryant KD, Brown SM, Randell SH, Asokan A (2011) Terminal N-linked galactose is the primary receptor for adeno-associated virus 9. J Biol Chem 286(15):13532–13540. https://doi.org/10.1074/jbc.M110.210922

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Shen S, Bryant KD, Sun J, Brown SM, Troupes A, Pulicherla N, Asokan A (2012) Glycan binding avidity determines the systemic fate of adeno-associated virus type 9. J Virol 86(19):10408–10417. https://doi.org/10.1128/JVI.01155-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bell CL, Vandenberghe LH, Bell P, Limberis MP, Gao GP, Van Vliet K, Agbandje-McKenna M, Wilson JM (2011) The AAV9 receptor and its modification to improve in vivo lung gene transfer in mice. J Clin Invest 121(6):2427–2435. https://doi.org/10.1172/JCI57367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Bell CL, Gurda BL, Van Vliet K, Agbandje-McKenna M, Wilson JM (2012) Identification of the galactose binding domain of the adeno-associated virus serotype 9 capsid. J Virol 86(13):7326–7333. https://doi.org/10.1128/JVI.00448-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Bostick B, Ghosh A, Yue Y, Long C, Duan D (2007) Systemic AAV-9 transduction in mice is influenced by animal age but not by the route of administration. Gene Ther 14(22):1605–1609

    Article  CAS  Google Scholar 

  20. Pillay S, Meyer NL, Puschnik AS, Davulcu O, Diep J, Ishikawa Y, Jae LT, Wosen JE, Nagamine CM, Chapman MS, Carette JE (2016) An essential receptor for adeno-associated virus infection. Nature 530(7588):108–112. https://doi.org/10.1038/nature16465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Nonnenmacher M, Weber T (2011) Adeno-associated virus 2 infection requires endocytosis through the CLIC/GEEC pathway. Cell Host Microbe 10(6):563–576. https://doi.org/10.1016/j.chom.2011.10.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Xiao PJ, Samulski RJ (2012) Cytoplasmic trafficking, endosomal escape, and perinuclear accumulation of adeno-associated virus type 2 particles are facilitated by microtubule network. J Virol 86(19):10462–10473. https://doi.org/10.1128/JVI.00935-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sanlioglu S, Benson PK, Yang J, Atkinson EM, Reynolds T, Engelhardt JF (2000) Endocytosis and nuclear trafficking of adeno-associated virus type 2 are controlled by rac1 and phosphatidylinositol-3 kinase activation. J Virol 74(19):9184–9196

    Article  CAS  Google Scholar 

  24. Penaud-Budloo M, Le Guiner C, Nowrouzi A, Toromanoff A, Cherel Y, Chenuaud P, Schmidt M, von Kalle C, Rolling F, Moullier P, Snyder RO (2008) Adeno-associated virus vector genomes persist as episomal chromatin in primate muscle. J Virol 82(16):7875–7885. JVI.00649-08 [pii]. https://doi.org/10.1128/JVI.00649-08

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Duan D, Sharma P, Yang J, Yue Y, Dudus L, Zhang Y, Fisher KJ, Engelhardt JF (1998) Circular intermediates of recombinant adeno-associated virus have defined structural characteristics responsible for long term episomal persistence in muscle. J Virol 72(11):8568–8577

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Xiao PJ, Li C, Neumann A, Samulski RJ (2012) Quantitative 3D tracing of gene-delivery viral vectors in human cells and animal tissues. Mol Ther 20(2):317–328. https://doi.org/10.1038/mt.2011.250

    Article  CAS  PubMed  Google Scholar 

  27. Mueller C, Chulay JD, Trapnell BC, Humphries M, Carey B, Sandhaus RA, McElvaney NG, Messina L, Tang Q, Rouhani FN, Campbell-Thompson M, Fu AD, Yachnis A, Knop DR, Ye GJ, Brantly M, Calcedo R, Somanathan S, Richman LP, Vonderheide RH, Hulme MA, Brusko TM, Wilson JM, Flotte TR (2013) Human Treg responses allow sustained recombinant adeno-associated virus-mediated transgene expression. J Clin Invest 123(12):5310–5318. https://doi.org/10.1172/JCI70314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Jiang H, Pierce GF, Ozelo MC, de Paula EV, Vargas JA, Smith P, Sommer J, Luk A, Manno CS, High KA, Arruda VR (2006) Evidence of multiyear factor IX expression by AAV-mediated gene transfer to skeletal muscle in an individual with severe hemophilia B. Mol Ther 14(3):452–455

    Article  CAS  Google Scholar 

  29. Hawke TJ, Garry DJ (2001) Myogenic satellite cells: physiology to molecular biology. J Appl Physiol 91(2):534–551

    Article  CAS  Google Scholar 

  30. Arnett AL, Konieczny P, Ramos JN, Hall J, Odom G, Yablonka-Reuveni Z, Chamberlain JR, Chamberlain JS (2014) Adeno-associated viral (AAV) vectors do not efficiently target muscle satellite cells. Mol Ther Methods Clin Dev 1:14038. https://doi.org/10.1038/mtm.2014.38

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Stitelman DH, Brazelton T, Bora A, Traas J, Merianos D, Limberis M, Davey M, Flake AW (2014) Developmental stage determines efficiency of gene transfer to muscle satellite cells by in utero delivery of adeno-associated virus vector serotype 2/9. Mol Ther Methods Clin Dev 1:14040. https://doi.org/10.1038/mtm.2014.40

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Tabebordbar M, Zhu K, Cheng JK, Chew WL, Widrick JJ, Yan WX, Maesner C, Wu EY, Xiao R, Ran FA, Cong L, Zhang F, Vandenberghe LH, Church GM, Wagers AJ (2016) In vivo gene editing in dystrophic mouse muscle and muscle stem cells. Science 351(6271):407–411. https://doi.org/10.1126/science.aad5177

    Article  CAS  PubMed  Google Scholar 

  33. Wang D, Zhong L, Nahid MA, Gao G (2014) The potential of adeno-associated viral vectors for gene delivery to muscle tissue. Expert Opin Drug Deliv 11(3):345–364. https://doi.org/10.1517/17425247.2014.871258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Qiao C, Zhang W, Yuan Z, Shin JH, Li J, Jayandharan GR, Zhong L, Srivastava A, Xiao X, Duan D (2010) Adeno-associated virus serotype 6 capsid tyrosine-to-phenylalanine mutations improve gene transfer to skeletal muscle. Hum Gene Ther 21(10):1343–1348. https://doi.org/10.1089/hum.2010.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Duan D (2016) Systemic delivery of adeno-associated viral vectors. Curr Opin Virol 21:16–25. https://doi.org/10.1016/j.coviro.2016.07.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Duan D (2018) Micro-dystrophin gene therapy goes systemic in Duchenne muscular dystrophy patients. Hum Gene Ther 29(7):733–736. https://doi.org/10.1089/hum.2018.012

    Article  CAS  PubMed  Google Scholar 

  37. 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 (2017) Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med 377(18):1713–1722. https://doi.org/10.1056/NEJMoa1706198

    Article  CAS  PubMed  Google Scholar 

  38. Yu CY, Yuan Z, Cao Z, Wang B, Qiao C, Li J, Xiao X (2009) A muscle-targeting peptide displayed on AAV2 improves muscle tropism on systemic delivery. Gene Ther 16(8):953–962. https://doi.org/10.1038/gt.2009.59

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Work LM, Nicklin SA, Brain NJ, Dishart KL, Von Seggern DJ, Hallek M, Buning H, Baker AH (2004) Development of efficient viral vectors selective for vascular smooth muscle cells. Mol Ther 9(2):198–208

    Article  CAS  Google Scholar 

  40. Ying Y, Muller OJ, Goehringer C, Leuchs B, Trepel M, Katus HA, Kleinschmidt JA (2010) Heart-targeted adeno-associated viral vectors selected by in vivo biopanning of a random viral display peptide library. Gene Ther 17(8):980–990. https://doi.org/10.1038/gt.2010.44

    Article  CAS  PubMed  Google Scholar 

  41. Asokan A, Conway JC, Phillips JL, Li C, Hegge J, Sinnott R, Yadav S, DiPrimio N, Nam HJ, Agbandje-McKenna M, McPhee S, Wolff J, Samulski RJ (2010) Reengineering a receptor footprint of adeno-associated virus enables selective and systemic gene transfer to muscle. Nat Biotechnol 28(1):79–82. https://doi.org/10.1038/nbt.1599

    Article  CAS  PubMed  Google Scholar 

  42. Adachi K, Enoki T, Kawano Y, Veraz M, Nakai H (2014) Drawing a high-resolution functional map of adeno-associated virus capsid by massively parallel sequencing. Nat Commun 5:3075. https://doi.org/10.1038/ncomms4075

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Stemmer WP (1994) DNA shuffling by random fragmentation and reassembly: in vitro recombination for molecular evolution. Proc Natl Acad Sci U S A 91(22):10747–10751

    Article  CAS  Google Scholar 

  44. Stemmer WP (1994) Rapid evolution of a protein in vitro by DNA shuffling. Nature 370(6488):389–391. https://doi.org/10.1038/370389a0

    Article  CAS  PubMed  Google Scholar 

  45. Nance ME, Duan D (2015) Perspective on adeno-associated virus capsid modification for Duchenne muscular dystrophy gene therapy. Hum Gene Ther 26(12):786–800. https://doi.org/10.1089/hum.2015.107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kotterman MA, Schaffer DV (2014) Engineering adeno-associated viruses for clinical gene therapy. Nat Rev Genet 15(7):445–451. https://doi.org/10.1038/nrg3742

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Marsic D, Govindasamy L, Currlin S, Markusic DM, Tseng YS, Herzog RW, Agbandje-McKenna M, Zolotukhin S (2014) Vector design Tour de Force: integrating combinatorial and rational approaches to derive novel adeno-associated virus variants. Mol Ther 22(11):1900–1909. https://doi.org/10.1038/mt.2014.139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Yang L, Jiang J, Drouin LM, Agbandje-McKenna M, Chen C, Qiao C, Pu D, Hu X, Wang DZ, Li J, Xiao X (2009) A myocardium tropic adeno-associated virus (AAV) evolved by DNA shuffling and in vivo selection. Proc Natl Acad Sci U S A 106(10):3946–3951. https://doi.org/10.1073/pnas.0813207106

    Article  PubMed  PubMed Central  Google Scholar 

  49. Pulicherla N, Shen S, Yadav S, Debbink K, Govindasamy L, Agbandje-McKenna M, Asokan A (2011) Engineering liver-detargeted AAV9 vectors for cardiac and musculoskeletal gene transfer. Mol Ther 19(6):1070–1078. https://doi.org/10.1038/mt.2011.22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Choudhury SR, Fitzpatrick Z, Harris AF, Maitland SA, Ferreira JS, Zhang Y, Ma S, Sharma RB, Gray-Edwards HL, Johnson JA, Johnson AK, Alonso LC, Punzo C, Wagner KR, Maguire CA, Kotin RM, Martin DR, Sena-Esteves M (2016) In vivo selection yields AAV-b1 capsid for central nervous system and muscle gene therapy. Mol Ther 24(7):1247–1257. https://doi.org/10.1038/mt.2016.84

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Calcedo R, Wilson JM (2013) Humoral immune response to AAV. Front Immunol 4:341. https://doi.org/10.3389/fimmu.2013.00341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Maheshri N, Koerber JT, Kaspar BK, Schaffer DV (2006) Directed evolution of adeno-associated virus yields enhanced gene delivery vectors. Nat Biotechnol 24(2):198–204. https://doi.org/10.1038/nbt1182

    Article  CAS  PubMed  Google Scholar 

  53. Tse LV, Klinc KA, Madigan VJ, Castellanos Rivera RM, Wells LF, Havlik LP, Smith JK, Agbandje-McKenna M, Asokan A (2017) Structure-guided evolution of antigenically distinct adeno-associated virus variants for immune evasion. Proc Natl Acad Sci U S A 114(24):E4812–E4821. https://doi.org/10.1073/pnas.1704766114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Li C, Wu S, Albright B, Hirsch M, Li W, Tseng YS, Agbandje-McKenna M, McPhee S, Asokan A, Samulski RJ (2016) Development of patient-specific AAV vectors after neutralizing antibody selection for enhanced muscle gene transfer. Mol Ther 24(1):53–65. https://doi.org/10.1038/mt.2015.134

    Article  CAS  PubMed  Google Scholar 

  55. Grieger JC, Samulski RJ (2005) Packaging capacity of adeno-associated virus serotypes: impact of larger genomes on infectivity and postentry steps. J Virol 79(15):9933–9944

    Article  CAS  Google Scholar 

  56. Dong B, Nakai H, Xiao W (2010) Characterization of genome integrity for oversized recombinant AAV vector. Mol Ther 18(1):87–92. mt2009258 [pii]. https://doi.org/10.1038/mt.2009.258

    Article  CAS  PubMed  Google Scholar 

  57. Wu Z, Yang H, Colosi P (2010) Effect of genome size on AAV vector packaging. Mol Ther 18(1):80–86. mt2009255 [pii]. https://doi.org/10.1038/mt.2009.255

    Article  CAS  PubMed  Google Scholar 

  58. Ponnazhagan S, Weigel KA, Raikwar SP, Mukherjee P, Yoder MC, Srivastava A (1998) Recombinant human parvovirus B19 vectors: erythroid cell-specific delivery and expression of transduced genes. J Virol 72(6):5224–5230

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Yan Z, Keiser NW, Song Y, Deng X, Cheng F, Qiu J, Engelhardt JF (2013) A novel chimeric adenoassociated virus 2/human bocavirus 1 parvovirus vector efficiently transduces human airway epithelia. Mol Ther 21(12):2181–2194. https://doi.org/10.1038/mt.2013.92

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Korbelin J, Trepel M (2017) How to successfully screen random Adeno-associated virus display peptide libraries in vivo. Hum Gene Ther Methods 28(3):109–123. https://doi.org/10.1089/hgtb.2016.177

    Article  CAS  PubMed  Google Scholar 

  61. Lisowski L, Dane AP, Chu K, Zhang Y, Cunningham SC, Wilson EM, Nygaard S, Grompe M, Alexander IE, Kay MA (2014) Selection and evaluation of clinically relevant AAV variants in a xenograft liver model. Nature 506(7488):382–386. https://doi.org/10.1038/nature12875

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO, USA

    Michael E. Nance & Dongsheng Duan

  2. Department of Neurology, School of Medicine, University of Missouri, Columbia, MO, USA

    Dongsheng Duan

  3. Department of Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA

    Dongsheng Duan

  4. Department of Bioengineering, University of Missouri, Columbia, MO, USA

    Dongsheng Duan

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  1. Michael E. Nance
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  2. Dongsheng Duan
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Correspondence to Michael E. Nance .

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Editors and Affiliations

  1. Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO, USA; Department of Neurology, School of Medicine, University of Missouri, Columbia, MO, USA, Department of Biomedical Sciences College of Veterinary Medicine, University of Missouri, Columbia, MO, USA; Department of Bioengineering, University of Missouri, Columbia, MO, USA

    Dongsheng Duan

  2. Department of Pediatrics Nationwide Children’s Hospital and Research Institute, Department of Neurology Nationwide Children’s Hospital and Research Institute, The Ohio State University, Columbus, OH, USA

    Jerry R. Mendell

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Nance, M.E., Duan, D. (2019). Development of Next-Generation Muscle Gene Therapy AAV Vectors. In: Duan, D., Mendell, J. (eds) Muscle Gene Therapy. Springer, Cham. https://doi.org/10.1007/978-3-030-03095-7_11

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