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An engineered serum albumin-binding AAV9 capsid achieves improved liver transduction after intravenous delivery in mice

Gene Therapy volume 27, pages 237–244 (2020)Cite this article

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Abstract

Recombinant adeno-associated viral (AAV) vectors are frequently used to deliver DNA into cells and are currently the leading platform for therapeutic gene delivery in humans. Presently, there is a need for optimized AAV vectors with improved transduction efficiencies in target tissues. In these studies, an engineered albumin-binding consensus domain (ABDCon) peptide was incorporated into the AAV9 capsid via fusion to the N-terminus of the AAV9 VP2 capsid protein to generate a variant AAV9 capsid with albumin-binding properties. The variant capsid, called AAV9-ABDCon, formed viable genome-containing vector particles and exhibited binding to human serum albumin. The AAV9 capsid, on the other hand, was not found to bind to human serum albumin by the methods used in this study. In C57BL/6J mice, AAV9-ABDCon achieved significantly higher levels of liver transduction compared with AAV9 following intravenous administration. These findings show that incorporation of the ABDCon peptide into the capsid VP2 N-terminus may be a potential method to augment AAV-mediated liver-directed gene delivery.

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References

  1. Wang D, Tai PWL, Gao G. Adeno-associated virus vector as a platform for gene therapy delivery. Nat Rev Drug Discov. 2019;18:358–78.

    Article  CAS  Google Scholar 

  2. Carpentier AC, Frisch F, Labbé SM, Gagnon R, de Wal J, Greentree S, et al. Effect of alipogene tiparvovec (AAV1-LPL(S447X)) on postprandial chylomicron metabolism in lipoprotein lipase-deficient patients. J Clin Endocrinol Metab. 2012;97:1635–44.

    Article  CAS  Google Scholar 

  3. Nathwani AC, Reiss UM, Tuddenham EGD, Rosales C, Chowdary P, McIntosh J, et al. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med. 2014;371:1994–2004.

    Article  Google Scholar 

  4. George LA, Sullivan SK, Giermasz A, Rasko JEJ, Samelson-Jones BJ, Ducore J, et al. Hemophilia B gene therapy with a high-specific-activity factor IX variant. N Engl J Med. 2017;377:2215–27.

    Article  CAS  Google Scholar 

  5. Rangarajan S, Walsh L, Lester W, Perry D, Madan B, Laffan M, et al. AAV5-factor VIII gene transfer in severe hemophilia A. N Engl J Med. 2017;377:2519–30.

    Article  CAS  Google Scholar 

  6. Lisowski L, Dane AP, Chu K, Zhang Y, Cunningham SC, Wilson EM, et al. Selection and evaluation of clinically relevant AAV variants in a xenograft liver model. Nature. 2014;506:382–6.

    Article  CAS  Google Scholar 

  7. Manno CS, Pierce GF, Arruda VR, Glader B, Ragni M, Rasko JJ, et al. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med. 2006;12:342–7.

    Article  CAS  Google Scholar 

  8. Mingozzi F, Maus MV, Hui DJ, Sabatino DE, Murphy SL, Rasko JEJ, et al. CD8(+) T-cell responses to adeno-associated virus capsid in humans. Nat Med. 2007;13:419–22.

    Article  CAS  Google Scholar 

  9. Mingozzi F, Meulenberg JJ, Hui DJ, Basner-Tschakarjan E, Hasbrouck NC, Edmonson SA, et al. AAV-1-mediated gene transfer to skeletal muscle in humans results in dose-dependent activation of capsid-specific T cells. Blood. 2009;114:2077–86.

    Article  CAS  Google Scholar 

  10. Wang M, Sun J, Crosby A, Woodard K, Hirsch ML, Samulski RJ, et al. Direct interaction of human serum proteins with AAV virions to enhance AAV transduction: immediate impact on clinical applications. Gene Ther. 2017;24:49–59.

    Article  CAS  Google Scholar 

  11. Pei X, He T, Hall NE, Gerber D, Samulski RJ, Li C. AAV8 virions hijack serum proteins to increase hepatocyte binding for transduction enhancement. Virology. 2018;518:95–102.

    Article  CAS  Google Scholar 

  12. Jacobs SA, Gibbs AC, Conk M, Yi F, Maguire D, Kane C, et al. Fusion to a highly stable consensus albumin binding domain allows for tunable pharmacokinetics. Protein Eng Des Sel. 2015;28:385–93.

    Article  CAS  Google Scholar 

  13. Warrington KH, Gorbatyuk OS, Harrison JK, Opie SR, Zolotukhin S, Muzyczka N. Adeno-associated virus type 2 VP2 capsid protein is nonessential and can tolerate large peptide insertions at its N terminus. J Virol. 2004;78:6595–609.

    Article  CAS  Google Scholar 

  14. Lux K, Goerlitz N, Schlemminger S, Perabo L, Goldnau D, Endell J, et al. Green fluorescent protein-tagged adeno-associated virus particles allow the study of cytosolic and nuclear trafficking. J Virol. 2005;79:11776–87.

    Article  CAS  Google Scholar 

  15. Rojas LA, Condezo GN, Moreno R, Fajardo CA, Arias-Badia M, San Martín C, et al. Albumin-binding adenoviruses circumvent pre-existing neutralizing antibodies upon systemic delivery. J Control Release. 2016;10:78–88.

    Article  Google Scholar 

  16. Xiao X, Li J, Samulski RJ. Production of high-titer recombinant adeno-associated virus vectors in the absence of helper adenovirus. J Virol. 1998;72:2224–32.

    Article  CAS  Google Scholar 

  17. Choudhury SR, Harris AF, Cabral DJ, Keeler AM, Sapp E, Ferreira JS, et al. Widespread central nervous system gene transfer and silencing after systemic delivery of novel AAV-AS vector. Mol Ther. 2016;24:726–35.

    Article  CAS  Google Scholar 

  18. Lee S-J, Lee Y-S, Zimmers TA, Soleimani A, Matzuk MM, Tsuchida K, et al. Regulation of muscle mass by follistatin and activins. Mol Endocrinol. 2010;24:1998–2008.

    Article  CAS  Google Scholar 

  19. Kota J, Handy CR, Haidet AM, Montgomery CL, Eagle A, Rodino-Klapac LR, et al. Follistatin gene delivery enhances muscle growth and strength in nonhuman primates. Sci Transl Med. 2009;1:6ra15.

    Article  Google Scholar 

  20. Yan Z, Yan H, Ou H. Human thyroxine binding globulin (TBG) promoter directs efficient and sustaining transgene expression in liver-specific pattern. Gene. 2012;506:289–94.

    Article  CAS  Google Scholar 

  21. Denard J, Rouillon J, Leger T, Garcia C, Lambert MP, Griffith G, et al. AAV-8 and AAV-9 vectors cooperate with serum proteins differently than AAV-1 and AAV-6. Mol Ther Methods Clin Dev. 2018;10:291–302.

    Article  CAS  Google Scholar 

  22. Braun GA, Marsh JB, Drabkin DL. Synthesis of plasma albumin and tissue proteins in regenerating liver. Metab Clin Exp. 1962;11:957–66.

    CAS  PubMed  Google Scholar 

  23. Weisiger R, Gollan J, Ockner R. Receptor for albumin on the liver cell surface may mediate uptake of fatty acids and other albumin-bound substances. Science. 1981;211:1048–51.

    Article  CAS  Google Scholar 

  24. Ockner RK, Weisiger RA, Gollan JL. Hepatic uptake of albumin-bound substances: albumin receptor concept. Am J Physiol. 1983;245:G13–18.

    CAS  PubMed  Google Scholar 

  25. Chaudhury C, Mehnaz S, Robinson JM, Hayton WL, Pearl DK, Roopenian DC, et al. The major histocompatibility complex-related Fc receptor for IgG (FcRn) binds albumin and prolongs its lifespan. J Exp Med. 2003;197:315–22.

    Article  CAS  Google Scholar 

  26. Münch RC, Janicki H, Völker I, Rasbach A, Hallek M, Büning H, et al. Displaying high-affinity ligands on adeno-associated viral vectors enables tumor cell-specific and safe gene transfer. Mol Ther. 2013;21:109–18.

    Article  Google Scholar 

  27. Chen X, Zaro JL, Shen W-C. Fusion protein linkers: property, design and functionality. Adv Drug Deliv Rev. 2013;65:1357–69.

    Article  CAS  Google Scholar 

  28. Münch RC, Muth A, Muik A, Friedel T, Schmatz J, Dreier B, et al. Off-target-free gene delivery by affinity-purified receptor-targeted viral vectors. Nat Commun. 2015;6:6246.

    Article  Google Scholar 

  29. Rayaprolu V, Kruse S, Kant R, et al. Comparative analysis of adeno-associated virus capsid stability and dynamics. J Virol. 2013;87:13150–60.

    Article  CAS  Google Scholar 

  30. Hordeaux J, Wang Q, Katz N, Buza EL, Bell P, Wilson JM. The neurotropic properties of AAV-PHP.B are limited to C57BL/6J mice. Mol Ther. 2018;26:664–8.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Aravind Asokan for providing the capsid B1 antibody and Victoria Madden for assistance in planning, executing, and interpreting immuno-TEM experiments.

Funding

Funding

This work was funded by an award from the Eshelman Institute for Innovation (EII) to XX.

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Authors and Affiliations

  1. Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA

    Quan Jin, Chunping Qiao, Jianbin Li, Juan Li & Xiao Xiao

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  1. Quan Jin
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  2. Chunping Qiao
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  4. Juan Li
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Contributions

QJ and XX conceived and planned the experiments. QJ, CQ, and Jianbin Li carried out the experiments. QJ performed analysis of the data. QJ, Juan Li, and XX contributed to the interpretation of the results. QJ prepared figures and drafted the manuscript. XX procured funding support. All authors reviewed and provided critical feedback on the final manuscript.

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Correspondence to Quan Jin or Xiao Xiao.

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XX and QJ are co-inventors on a potential patent application related to the work. The remaining authors declare that they have no conflict of interest.

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Jin, Q., Qiao, C., Li, J. et al. An engineered serum albumin-binding AAV9 capsid achieves improved liver transduction after intravenous delivery in mice. Gene Ther 27, 237–244 (2020). https://doi.org/10.1038/s41434-019-0107-2

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