TABLE 2.
Features of Liver-Directed Viral Gene Therapy Methods
| Method | Integration and persistence | In vivo gene transfer efficiency to liver | Liver-specificity | Immunological* and other issues |
|---|---|---|---|---|
|
| ||||
| RECOMBINANT VIRAL VECTORS: | ||||
| Murine leukemia-based retroviruses | Integration is required. | Requires mitosis. Low efficiency in quiescent cells types, e.g hepatocytes. | None | Non-immunogenic. Difficult to obtain very high titers. Envelope can be pseudotyped with other proteins to increase stability and broaden host range. |
| Lentivirus-based retroviruses | Integration is required. | Can infect non-dividing cells, but cell cycling may be needed. Low to intermediate efficiency for liver. |
None | Non-immunogenic. Difficult to obtain very high titers. Envelope can be pseudotyped with other proteins to increase stability and broaden host range. |
| Adeno-associated virus | Can exist in both episomal and integrated forms. | Can infect 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 type virus is lost in the absence of rep. Can undergo lytic cycle in the presence of helper proteins. Limited packaging space. |
| Adenovirus | Episomal. Can persist for several months in the absence of host immune response. |
Efficiently infects both dividing and non-dividing cells. Very high efficiency for liver. |
Liver targeted | Evokes both humoral and cell-mediated host immune response. Viral gene deletion reduces primary immunogenicity, but does not permit repeated injection. Host tolerization permits repeated gene transfer. |
| Hybrid viruses | Combines advantages of different viruses. | Efficiency of adenoviral vectors is combined with persistent nature of other viruses. | Liver targeted | Adenoviral proteins provided in trans may evoke immune response. Site-specific integration or episomal replication may be possible. |
| Simian virus 40 | Can exist in both episomal and integrated forms. | Infects both quiescent and dividing cells. High efficiency. |
None | No significant immune response. Can be grown at high titers. Limited packaging space. |
*
In all cases, an expressed transgene is potentially immunogenic in a mutant lacking the transgene product.