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SR-A and SREC-I binding peptides increase HDAd-mediated liver transduction

Gene Therapy volume 21, pages 950–957 (2014)Cite this article

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Abstract

Helper-dependent adenoviral (HDAd) vectors can mediate long-term, high-level transgene expression from transduced hepatocytes without inducing chronic toxicity. However, vector therapeutic index is narrow because of a toxic acute response with potentially lethal consequences elicited by high vector doses. Kupffer cells (KCs) and liver sinusoidal endothelial cells (LSECs) are major barriers to efficient hepatocyte transduction. We investigated two small peptides (PP1 and PP2) developed by phage display to block scavenger receptor type A (SR-A) and scavenger receptor expressed on endothelial cells type I (SREC-I), respectively, for enhancement of HDAd-mediated hepatocyte transduction efficiency. Pre-incubation of J774A.1 macrophages with either PP1 or PP2 prior to HDAd infection significantly reduced viral vector uptake. In vivo, fluorochrome-conjugated PP1 and PP2 injected intravenously into mice co-localized with both CD68 and CD31 on KCs and LSECs, respectively. Compared with saline pre-treated animals, intravenous injections of both peptides prior to the injection of an HDAd resulted in up to 3.7- and 2.9-fold increase of hepatic transgene expression with PP1 and PP2, respectively. In addition to greater hepatocyte transduction, compared with control saline injected mice, pre-treatment with either peptide resulted in no increased levels of serum interleukin-6, the major marker of adenoviral vector acute toxicity. In summary, we developed small peptides that significantly increase hepatocyte transduction efficacy and improve HDAd therapeutic index with potential for clinical applications.

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Acknowledgements

We thank Annamaria Carissimo from TIGEM Bioinformatic Core for statistical analyses and Laura Pisapia from the CNR-IGB FACS facility for FACS analysis. This work was supported by the Fondazione Telethon, Italy (TCBP37TELC and TCBMT3TELD to N.B.-P.), by a research grant of The Hyperoxaluria and Oxalosis Foundation to N.B.-P., and by the Italian Ministry of Health (GR-2009-1594913 to N.B.-P.).

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Authors and Affiliations

  1. Telethon Institute of Genetics and Medicine, Naples, Italy

    P Piccolo, P Annunziata, P Mithbaokar & N Brunetti-Pierri

  2. Department of Translational Medicine, Federico II University of Naples, Naples, Italy

    N Brunetti-Pierri

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  1. P Piccolo
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Correspondence to N Brunetti-Pierri.

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Piccolo, P., Annunziata, P., Mithbaokar, P. et al. SR-A and SREC-I binding peptides increase HDAd-mediated liver transduction. Gene Ther 21, 950–957 (2014). https://doi.org/10.1038/gt.2014.71

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