Liver-directed lentiviral gene therapy corrects hemophilia A mice and achieves normal-range factor VIII activity in non-human primates

Michela Milani, Cesare Canepari, Tongyao Liu, Mauro Biffi, Fabio Russo, Tiziana Plati, Rosalia Curto, Susannah Patarroyo-White, Douglas Drager, Ilaria Visigalli, Chiara Brombin, Paola Albertini, Antonia Follenzi, Eduard Ayuso, Christian Mueller, Andrea Annoni, Luigi Naldini () and Alessio Cantore ()
Additional contact information
Michela Milani: San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute
Cesare Canepari: San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute
Tongyao Liu: Sanofi
Mauro Biffi: San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute
Fabio Russo: San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute
Tiziana Plati: San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute
Rosalia Curto: San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute
Susannah Patarroyo-White: Sanofi
Douglas Drager: Sanofi
Ilaria Visigalli: San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute
Chiara Brombin: University Center for Statistics in the Biomedical Sciences, Vita-Salute San Raffaele University
Paola Albertini: San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute
Antonia Follenzi: University of Piemonte Orientale
Eduard Ayuso: INSERM UMR1089, University of Nantes, CHU de Nantes
Christian Mueller: Sanofi
Andrea Annoni: San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute
Luigi Naldini: San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute
Alessio Cantore: San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract Liver gene therapy with adeno-associated viral (AAV) vectors delivering clotting factor transgenes into hepatocytes has shown multiyear therapeutic benefit in adults with hemophilia. However, the mostly episomal nature of AAV vectors challenges their application to young pediatric patients. We developed lentiviral vectors, which integrate in the host cell genome, that achieve efficient liver gene transfer in mice, dogs and non-human primates, by intravenous delivery. Here we first compare engineered coagulation factor VIII transgenes and show that codon-usage optimization improved expression 10-20-fold in hemophilia A mice and that inclusion of an unstructured XTEN peptide, known to increase the half-life of the payload protein, provided an additional >10-fold increase in overall factor VIII output in mice and non-human primates. Stable nearly life-long normal and above-normal factor VIII activity was achieved in hemophilia A mouse models. Overall, we show long-term factor VIII activity and restoration of hemostasis, by lentiviral gene therapy to hemophilia A mice and normal-range factor VIII activity in non-human primate, paving the way for potential clinical application.

Date: 2022
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DOI: 10.1038/s41467-022-30102-3

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