From the Bench to the Clinic: Story and Lessons from VRX496, the First Lentivector Ever Tested in a Phase I Clinical Trial

Gene therapy for HIV-1 infection has been proposed as an alternative to antiretroviral drug regimens due to emerging drug resistance and toxicity that raises concerns about HAART as a long-term therapy. VIRxSYS has developed an HIV-based lentiviral vector platform for delivery of genetic therapies. For the first clinical application of the gene delivery technology, VIRxSYS created VRX496, a lentiviral vector expressing a 937-base long antisense against the HIV envelope gene. Along with the lentivector, a packaging vector, VIRPAC, was created based on a single plasmid approach for transient production. Many safety features were incorporated into VRX496 and VIRPAC. VRX496 pre-clinical efficacy was demonstrated in vitro by achieving high transduction efficiencies with stable gene transfer into human primary CD4+ T lymphocytes and by showing selective resistance to CD4 down regulation with over 4 logs (99.99%) of HIV replication inhibition in challenge assays using various X4, R5 or dual tropism strains of HIV. In December 2002, the US Food and Drug Administration approved the first ever Phase I clinical trial of lentiviral vectors in humans, testing the safety and tolerability of a single infusion of autologous HIV infected CD4+ T Cells transduced with VRX496. No adverse events due to the product were observed. Although the purpose of the Phase I clinical trial was to establish the safety of the 221 http://www.beilstein-institut.de/bozen2006/proceedings/Humeau/Humeau.pdf Bozen 2006, May 15 – 19, 2006, Bozen, Italy Beilstein-Institut