Phagocytosis-shielded lentiviral vectors improve liver gene therapy in nonhuman primates

Michela Milani, Andrea Annoni, Federica Moalli, Tongyao Liu, Daniela Cesana, Andrea Calabria, Sara Bartolaccini, Mauro Biffi, Fabio Russo, Ilaria Visigalli, Andrea Raimondi, Susannah Patarroyo-White, Douglas Drager, Patrizia Cristofori, Eduard Ayuso, Eugenio Montini, Robert Peters, Matteo Iannacone, Alessio Cantore, Luigi Naldini

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Abstract

Liver-directed gene therapy for the coagulation disorder hemophilia showed safe and effective results in clinical trials using adeno-associated viral vectors to replace a functional coagulation factor, although some unmet needs remain. Lentiviral vectors (LVs) may address some of these hurdles because of their potential for stable expression and the low prevalence of preexisting viral immunity in humans. However, systemic LV administration to hemophilic dogs was associated to mild acute toxicity and low efficacy at the administered doses. Here, exploiting intravital microscopy and LV surface engineering, we report a major role of the human phagocytosis inhibitor CD47, incorporated into LV cell membrane, in protecting LVs from uptake by professional phagocytes and innate immune sensing, thus favoring biodistribution to hepatocytes after systemic administration. By enforcing high CD47 surface content, we generated phagocytosis-shielded LVs which, upon intravenous administration to nonhuman primates, showed selective liver and spleen targeting and enhanced hepatocyte gene transfer compared to parental LV, reaching supraphysiological activity of human coagulation factor IX, the protein encoded by the transgene, without signs of toxicity or clonal expansion of transduced cells.

Original languageEnglish
JournalScience Translational Medicine
Volume11
Issue number493
DOIs
Publication statusPublished - Jan 1 2019

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ASJC Scopus subject areas

  • Medicine(all)

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