| Autor: |
Robaczewska, M, Guerret, S, Remy, J-S, Chemin, I, Offensperger, W-B, Chevallier, M, Behr, J-P, Podhajska, A J, Blum, H E, Trepo, C, Cova, L |
| Předmět: |
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| Zdroj: |
Gene Therapy; Jun2001, Vol. 8 Issue 11, p874, 8p |
| Abstrakt: |
Antisense oligodeoxynucleotides (ODNs) appear as attractive anti-hepatitis B virus (HBV) agents. We investigated in vivo, in the duck HBV (DHBV) infection model, whether linear polyethylenimine (IPEI)-based intravenous delivery of the natural antisense phosphodiester ODNs (O-ODNs) can prevent their degradation and allow viral replication inhibition in the liver. DHBV-infected Pekin ducklings were injected with antisense O-ODNs covering the initiation codon of the DHBV large envelope protein, either in free form (O-ODNAS2) or coupled to IPEI (IPEI/O-ODN-AS2). Following optimization of IPEI/O-ODN complex formulation, complete OODN condensation into a homogenous population of small (20-60 nm) spherical particles was achieved. Flow cytometry analysis showed that IPEI-mediated transfer allowed the intrahepatic delivery of IPEI/O-ODN-AS2 to increase three-fold as compared with the O-ODN-AS2. Following 9-day therapy the intrahepatic levels of both DHBV DNA and RNA were significantly decreased in the IPEI/O-ODN-AS2-treated group as compared with the O-ODN-AS2-treated, control IPEI/O-ODN-treated, and untreated controls. In addition, inhibition of intrahepatic viral replication by IPEI/O-ODN-AS2 was not associated with toxicity and was comparable with that induced by the phosphorothioate S-ODN-AS2 at a fivefold higher dose. Taken together, our results demonstrate that phosphodiester antisense IPEI/O-ODN complexes specifically inhibit hepadnaviral replication. Therefore we provide here the first in vivo evidence that intravenous treatment with antisense phosphodiester ODNs coupled to IPEI can selectively block a viral disease-causing gene in the liver. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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