Research ArticleGene Therapy

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

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Science Translational Medicine  22 May 2019:
Vol. 11, Issue 493, eaav7325
DOI: 10.1126/scitranslmed.aav7325

Vectors in stealth mode

Gene therapy using adeno-associated viral vectors (AAVs) has shown safety and efficacy in patients with hemophilia. However, AAVs have limitations hindering their efficacy in a subgroup of patients. The use of lentiviral vectors (LVs) has been explored as possible alternative; however, preclinical data reported low transduction efficacy possibly due to fast clearance by phagocytes. Now, Milani et al. developed a shielded LV able to escape phagocytosis by increasing the content of the phagocytosis inhibitor CD47 on their surface. Upon intravenous administration in monkeys, the LVs showed high transduction efficacy without signs of toxicity. The results suggest that LV-mediated gene therapy might be an effective strategy for treating hemophilia and possibly other disorders.


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.

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