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| Stability of lentiviral vector-mediated transgene expression in the brain in the presence of systemic antivector immune responses |
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| Author(s): Abordo-Adesida E, Follenzi A, Barcia C, Sciascia S, Castro MG, Naldini L, Lowenstein PR |
| Source: HUMAN GENE THERAPY Volume: 16 Issue: 6 Pages: 741-751 Published: JUN 2005 |
| Times Cited: 26 References: 33 |
| Abstract: Lentiviral vectors are promising tools for gene therapy in the CNS. It is therefore important to characterize their interactions with the immune system in the CNS. This work characterizes transgene expression and brain inflammation in the presence or absence of immune responses generated after systemic immunization with lentiviral vectors. We characterized transduction with SIN-LV vectors in the CNS. A dose-response curve using SIN-LV-GFP demonstrated detectable transgene expression in the striatum at a dose of 10(2), and maximum expression at 10(6), transducing units of lentiviral vector, with minimal increase in inflammatory markers between the lowest and highest dose of vector injected. Our studies demonstrate that injection of a lentiviral vector into the CNS did not cause a measurable inflammatory response. Systemic immunization after CNS injection, with the lentiviral vector expressing the same transgene as a vector injected into the CNS, caused a decrease in transgene expression in the CNS, concomitantly with an infiltration of inflammatory cells into the CNS parenchyma at the injection site. However, peripheral immunization with a lentiviral vector carrying a different transgene did not diminish transgene expression, or cause CNS inflammation. Systemic immunization preceding injection of lentiviral vectors into the CNS determined that preexisting antilentiviral immunity, regardless of the transgene, did not affect transgene expression. Furthermore, we showed that the transgene, but not the virion or vector components, is responsible for providing antigenic epitopes to the activated immune system, on systemic immunization with lentivirus. Low immunogenicity and prolonged transgene expression in the presence of preexisting lentiviral immunity are encouraging data for the future use of lentiviral vectors in CNS gene therapy. In summary, the lentiviral vectors tested induced undetectable activation of innate immune responses, and stimulation of adaptive immune responses against lentiviral vectors was effective in causing a decrease in transgene expression only if the immune response was directed against the transgene. A systemic immune response against vector components alone did not cause brain inflammation, possibly because vector-derived epitopes were not being presented in the CNS. |
| Document Type: Article |
| Language: English |
| Reprint Address: Lowenstein, PR (reprint author), Cedars Sinai Med Ctr, Gene Therapeut Res Inst, 8700 Beverly Blvd,Davis Bldg,Res Pavil,Room 5090, Los Angeles, CA 90048 USA |
Addresses:
1. Cedars Sinai Med Ctr, Gene Therapeut Res Inst, Los Angeles, CA 90048 USA
2. Univ Manchester, Dept Med, Mol Med & Gene Therapy Unit, Manchester M13 9PL, Lancs England
3. Univ Milan, Vita Salute Raffaele Univ Med Sch, Telethon Inst Gene Therapy, I-20132 Milan, Italy
4. Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA
5. Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90095 USA |
| Publisher: MARY ANN LIEBERT INC, 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA |
| Subject Category: Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental |
| IDS Number: 938JG |
| ISSN: 1043-0342 |
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