Abstract
Adenosine deaminase (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 (LVs). 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. Three separate doses administered to immune competent mice resulted in acute toxicity. Pegylation of the vesicular stomatitis virus G protein (VSV-G)-enveloped LVs 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 LVs as a potential therapeutic agent.
Highlights
Lentiviral vectors (LVs) have been described as an efficient delivery vehicle suitable for direct injection and gene delivery in vivo, owing mostly to the ability to achieve gene transfer in non-dividing cells.[1]
Biodistribution analyses demonstrated differences in the amount of LVs detected in AdaÀ/À mice treated as newborns compared to healthy infant rhesus monkeys treated at 1 month of age where no vector was detected in the rhesus thymus or brain.[16]
The initial focus of our studies with systemic LV administration centered on the specific disease model of adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID) and correction of the phenotype associated with knockout of the Ada gene
Summary
Lentiviral vectors (LVs) have been described as an efficient delivery vehicle suitable for direct injection and gene delivery in vivo, owing mostly to the ability to achieve gene transfer in non-dividing cells.[1]. ADA deficiency is an inborn error of metabolism that results in the accumulation of adenosine and deoxyadenosine metabolites resulting from absent or aberrant Ada gene expression. Patients are most notably stricken with severe combined immunodeficiency (SCID), as normal lymphocyte development is severely impaired by the accumulation of these metabolites.[11] Infants typically present with severe and persistent infections characterized by a failure-to-thrive and profound lymphopenia. In addition to SCID, affected ADA-deficient individuals may have hepatic, renal, pulmonary, skeletal, and/or neurological pathology associated with the accumulation of metabolites.[12]
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