Intravenous administration of lentiviral vectors expressing hyperfunctional factor IX converts severe into mild hemophilia B in a canine model

Lentiviral vectors (LVs) are attractive vehicles for liverdirected
gene therapy by virtue of their ability to stably integrate
in the genome of target cells and the lack of pre-existing
immunity against vector components in most humans. Over the
past years, we have developed a LV platform that can achieve
stable transgene expression in the liver and establish correction
of hemophilia in mouse models upon systemic administration.
This LV is designed to stringently target transgene expression to
hepatocytes through transcriptional and microRNA-mediated
regulation. We then investigated the efficacy and safety of
portal vein administration of LVs expressing wild-type, codonoptimized
(c.o.) or c.o. hyperfunctional canine factor IX (cFIX)
in a canine model of hemophilia B. We observed long-term
stable reconstitution of cFIX activity up to 1% of normal and
significant amelioration of the clinical phenotype in 3 treated
dogs (10 years cumulative follow up). In the perspective of
clinical translation and to increase therapeutic efficacy, we next
treated a hemophilia B dog by peripheral vein administration of
LVs expressing the c.o. hyperfunctional cFIX at a 5-fold higher
dose than those previously administered. At the current followup
(6 months after gene therapy) cFIX activity is 7–8% of
normal, suggesting comparable efficacy of LV by both portal
and peripheral vein administration Treatment of more hemophilia
B dogs is underway to extend these results. Overall our
studies position LV-mediated liver gene therapy for further preclinical
development and clinical translation. LVs may thus
complement other available vectors for liver gene therapy of
hemophilia.