| Method | Integration and Persistence | In vivo Gene Transfer Efficiency to Liver | Liver-Specificity | Immunological and Other Issues |
|---|---|---|---|---|
| VIRAL VECTORS: | ||||
| Leukemia type retroviruses | Integration is required. | Requires cell division. Low efficiency in quiescent cells, e.g., hepatocytes. | None | Non-immunogenic. Difficult to obtain very high titers. Envelope can be pseudotyped with other viral proteins to increase stability and broadenhost range. |
| Immunodeficiency type retroviruses | Integration is required. | Can infect non-dividing cells, but cell cycling may be needed for hepatocytes. Intermediate to high efficiency for liver. | None | Non-immunogenic. Difficult to obtain very high titers. Envelope can be pseudotyped with other viral proteins to increase stability and broaden host range. |
| Adeno-associated virus | Both episomal and integrated forms persist in the nucleus. | Can infect both quiescent and dividing cells. Low to intermediate efficiency for liver. | None | Causes humoral immune response. Can be grown at high titers. Site-specificity of integration of the wild typevirus is lost in the absence of rep. Can undergolytic cycle in the presence of helper proteins.Limited packaging space. |
| Simian virus 40 | Integrates into the host genome | Infects both quiescent and dividing cells. High efficiency. | None | No significant immune response. Can be grown at high titers. Limited packaging space. |
| Adenovirus | Episomal. Transgene is expressed for several months in the absence of host immune response. | Efficiently infects both dividing and non-dividing cells. Very high efficiency for liver upon systemic administration. | Liver targeted in rodents and mice, but not in humans. | Evokes both antibody and cell-mediated immune response. Deletion of viral genes reduces primary immunogenicity, but does not permit repeated injection. Host tolerization or coexpression of immunomodulatory genes permits repeated gene transfer. |
| Hybrid viruses | Combines the advantages of different viruses. | Efficiency of adenoviral vectors is combined with the integrating proprties of other viruses. | Can be liver targeted. | Adenoviral capsid proteins may evoke immune response. Site-specific integration or episomal replication may be possible. |
| NON-VIRAL VECTORS: | ||||
| Naked DNA or RNA injected into the liver or injected i.v. in a high volume to cause hepatic congestion | Transient | Intermediate efficiency | Can be liver targeted. | Immune response to the transfected DNA is possible. |
| Transposon-based integration | Permanent | Low to intermediate efficiency | Can be liver targeted. | Immune response to the transfected DNA is possible. |
| Receptor and/or liposome-mediated plasmid delivery | Transient | Intermediate efficiency | Can be liver targeted. | Probably non-immunogenic. |
| Oligonucleotides designed to correct mutations: triplex forming oligonucleotides, RNA-DNA chimera, single-stranded oligonucleotides. | Permanent | Low efficiency | Liver targeted | Non-immunogenic |
From: Hepatocyte Transplantation and Liver-Directed Gene Therapy
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