Dosing and re-administration of intravenous lentiviral vector for in vivo gene therapy: Studies in rhesus monkeys and ADA-deficient mice

Abstract ADA-deficient mice and healthy rhesus monkeys were studied to determine the impact of age at treatment, vector dosage, dosing schedule, repeat administration, biodistribution, and immunogenicity after systemic delivery of lentiviral vectors (LV). In Ada-/- mice, neonatal treatment resulted in broad vector marking across all tissues analyzed, whereas adult treatment resulted in marking restricted to the liver, spleen, and bone marrow. Intravenous administration to infant rhesus monkeys also resulted in dose-dependent marking in the liver, spleen, and bone marrow. Using an ELISA to monitor anti-vector antibody development, Ada-/- neonatal mice did not produce an antibody response, whereas Ada-/- adult mice produced a strong antibody response to vector administration. In mice and monkeys with repeat administration of LV, a strong anti-vector antibody response was shown in response to the second LV administration which resulted in LV inactivation. ADA-deficient mice administered three separate doses resulted in acute toxicity. PEGylation of the VSV-G enveloped LV showed a less robust anti-vector response but did not prevent the inactivation of the second LV administration. These studies identify important factors to consider related to age and timing of administration when implementing systemic delivery of LV as a potential therapeutic agent.