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• W2053649629 abstract "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 (1×1011 gc/kg) but not of a higher dose (3×1011 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. Van Dijk and colleagues show that macrophage scavenger receptor A (SR-A) can mediate nonspecific uptake of self-complementary AAV8 (scAAV8) vector; this process can be blocked by polyinosinic acid (PolyI:C) both in vitro and in vivo. Using a rat model of hyperbilirubinemia, they demonstrate that administration of Poly I:C prior to scAAV8 vector significantly increases the correction of serum bilirubin in male and female rats." @default.
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• W2053649629 date "2013-09-01" @default.
• W2053649629 modified "2023-10-18" @default.
• W2053649629 title "Polyinosinic Acid Blocks Adeno-Associated Virus Macrophage Endocytosis<i>In Vitro</i>and Enhances Adeno-Associated Virus Liver-Directed Gene Therapy<i>In Vivo</i>" @default.
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• W2053649629 doi "https://doi.org/10.1089/hum.2013.086" @default.
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