Phagocytosis-shielded lentiviral vectors improve liver gene therapy in nonhuman primates.
Sci Transl Med
; 11(493)2019 05 22.
Article
in En
| MEDLINE
| ID: mdl-31118293
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Phagocytosis
/
Genetic Therapy
/
Lentivirus
/
Genetic Vectors
/
Liver
Type of study:
Risk_factors_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Sci Transl Med
Journal subject:
CIENCIA
/
MEDICINA
Year:
2019
Document type:
Article
Affiliation country:
Italy
Country of publication:
United States