Polyinosinic Acid Blocks Adeno-Associated Virus Macrophage Endocytosis In Vitro and Enhances Adeno-Associated Virus Liver-Directed Gene Therapy In Vivo

van Dijk, R., Montenegro-Miranda, P. S., Riviere, C., Schilderink, R., ten Bloemendaal, L., van Gorp, J., Duijst, S., de Waart, D. R., Beuers, U., Haisma, H. J. & Bosma, P. J., 1-Sep-2013, In : Human Gene Therapy. 24, 9, p. 807-813 7 p.

Research output: Contribution to journalArticleAcademicpeer-review

  • Remco van Dijk
  • Paula S. Montenegro-Miranda
  • Christel Riviere
  • Ronald Schilderink
  • Lysbeth ten Bloemendaal
  • Jacqueline van Gorp
  • Suzanne Duijst
  • Dirk R. de Waart
  • Ulrich Beuers
  • Hidde J. Haisma
  • Piter J. Bosma

Adeno-associated virus serotype 8 (AAV8) has been demonstrated to be effective for liver-directed gene therapy in humans. Although hepatocytes are the main target cell for AAV8, there is a loss of the viral vector because of uptake by macrophages and Kupffer cells. Reducing this loss would increase the efficacy of viral gene therapy and allow a dose reduction. The receptor mediating this uptake has not been identified; a potential candidate seems the macrophage scavenger receptor A (SR-A) that is involved in the endocytosis of, for instance, adenovirus. In this study we show that SR-A can mediate scAAV8 endocytosis and that blocking it with polyinosinic acid (poly[i]) reduces endocytosis significantly in vitro. Subsequently, we demonstrate that blocking this receptor improves scAAV-mediated liver-directed gene therapy in a model for inherited hyperbilirubinemia, the uridine diphospho-glucuronyl transferase 1A1-deficient Gunn rat. In male rats, preadministration of poly[i] increases the efficacy of a low dose (1x10(11) gc/kg) but not of a higher dose (3x10(11) gc/kg) scAAV8-LP1-UT1A1. Administration of poly[i] just before the vector significantly increases the correction of serum bilirubin in female rats. In these, the effect of poly[i] is seen by both doses but is more pronounced in the females receiving the low vector, where it also results in a significant increase of bilirubin glucuronides in bile. In conclusion, this study shows that SR-A mediates the endocytosis of AAV8 in vitro and in vivo and that blocking this receptor can improve the efficacy of AAV-mediated liver-directed gene therapy.

Original languageEnglish
Pages (from-to)807-813
Number of pages7
JournalHuman Gene Therapy
Issue number9
Publication statusPublished - 1-Sep-2013



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