Liver-specific adenovirus expression vector

Details Liver-specific adenovirus expression vector Liver-specific adenovirus expression vector

1998-04-23

2000-02-15

Guzo, David

Chemistry: molecular biology and microbiology

Vector, per se

536 235, 536 241, C12N 1586, C07H 2104

Patent

active

060251956

DESCRIPTION:

BRIEF SUMMARY
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not applicable.


REFERENCE TO A "MICROFICHE APPENDIX"

Not applicable.


BACKGROUND OF THE INVENTION

The invention relates to an adenovirus vector for liver-specific gene therapy. Fields of application include medicine, the treatment of gene defects and tumour diseases of the liver, and molecular biology.
Numerous methods and vectors for gene therapy have been developed in recent years (survey in Mulligan/1993/Science 260, 920). Vectors derived from viruses are compared with those from non-viral transfer methods where the therapeutic gene is embedded in protein or lipid coats. The particles derived from the non-viral methods can preferentially bind to specific receptors once the particles are coupled to ligands for these receptors. This specificity works as an advantage to the gene therapeutic system in vivo. However, the therapeutic gene reaches only the tissue where its activity is desired.
Yet, viral vectors, notably the virus groups retrovirus and adenovirus have shown a higher efficiency in vivo. Both viruses allow the transfer of genes in liver cells. The retroviral infection leads to a stable integration of the genetic material into the cellular genome. This process depends on the proliferation of cells--a rare event for liver cells in vivo. Hepatocytes in culture are infected with retroviruses sufficiently. In the liver, however, either a partial liver resection is necessary to stimulate cell division (Ferry et al./1991/Proc. Natl. Acad. Sci. USA 88, 8377) or the application of methods which result in an acute decrease in the number of hepatocytes (Lieber et al. Proc. Natl. Acad. Sci. USA in press) is required to produce the same results.
Adenoviruses are by far more superior and more efficient to all other types of vectors. Even if administered intravenously, the virus may reach nearly 100 percent of the hepatocytes. Adenoviruses are available as episomes in the cell.
In contrast to retrovirus vectors, adenoviral vectors contain the biggest part of the viral genome. Originally, only the E1 region was transferred to the helper cell (HEK293) and used for the multiplication of viruses, thus preventing the virus from being replicated in the target tissue. As the adenovirus coat may receive up to 105 percent of the size of a genome (40 kb) the deletion of E1 was also essential for the insertion of new genes. To increase the capacity to a maximum of 8.3 kb, parts of the E3 region were additionally deleted (Bett et al./1994/Proc. Natl. Acad. Sci. USA 91, 8802). Although the most important transactivators of adenoviral genes--products of the E1 region--are lacking, other viral genes are expressed in addition to the therapeutic gene. The exposition of the respective proteins on the cell surface results in an activation of CD8 positive T-cells and an elimination of the infected cells. By eliminating further transactivators, e.g. E2A, it was functionally possible to reduce this effect farther (Yang et al./1994/Nature Genetics 7, 362).
An essential drawback of the existing adenovirus vectors is the lack of tissue specificity. Adenovirus receptors exist in a multitude of cell types, thereby explaining the lack of enthusiasm for methods calling for the additional coupling of the virus with ligands of specific receptors.
Liver specificity may also be achieved by using liver-specific promoters apart from the reception mode. Various cellular promoters (albumin and alphal antitrypsin promoters) active in hepatocytes were examined for gene therapy in retroviruses (Rettinger et al./1994/Proc. Natl. Acad. Sci. USA 91, 1460). Their size, however, makes them unsuitable in adenovirus vectors. Furthermore, the strong viral promoters (CMV and RSV promoters), frequently applied in the adenoviral context, are ubiquitously active and eliminated in the liver after a short time.


BRIEF SUMMARY OF THE INVENTION

This invention is aimed at constructing a vector that combines the advantages of an adenovirus vector with the property of liver-specific expression of

REFERENCES:
patent: 5895759 (1999-04-01), Strauss et al.
Chen et al., J. Virol., vol. 66, No. 12, pp. 7452-7460. Dec. 1992.

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