Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Genetically modified micro-organism – cell – or virus
Patent
1996-02-06
1998-05-26
Railey, II, Johnny F.
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Genetically modified micro-organism, cell, or virus
435 691, 4351723, 4353201, 536 234, 536 2372, C12N 1586, C12N 1562, C12N 1534, A61K 4800
Patent
active
057560862
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Adenovirus genomes are linear, double-stranded DNA molecules about 36 kilobase pairs long. Each extremity of the viral genome has a short sequence known as the inverted terminal repeat (or ITR), which is necessary for viral replication. The well-characterized molecular genetics of adenovirus render it an advantageous vector for gene transfer. The knowledge of the genetic organization of adenoviruses allows substitution of large fragments of viral DNA with foreign sequences. In addition, recombinant adenoviruses are structurally stable and no rearranged viruses are observed after extensive amplification.
Adenoviruses may be employed as delivery vehicles for introducing desired genes into eukaryotic cells. The adenovirus delivers such genes to eukaryotic cells by binding cellular receptors. The adenovirus fiber protein is responsible for such attachment. (Philipson, et al., J. Virol., Vol. 2, pgs. 1064-1075 (1968)). The fiber protein consists of two domains--a rod-like shaft portion and a globular head portion which contains the putative receptor binding region. The fiber spike is a homotrimer, and there are 12 spikes per virion. Human adenoviruses may bind to and infect a broad range of cultured cell lines and primary tissues from different species.
It is an object of the present invention to provide an adenovirus which can be targeted to a desired cell type.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with an aspect of the present invention, there is provided an adenovirus wherein the adenovirus fiber includes a ligand which is specific for a receptor located on a desired cell type.
In one embodiment, at least a portion of the adenovirus fiber protein is removed and replaced with a ligand which is specific for a receptor located on a desired cell type. In such embodiments the natural adenoviral ligand is removed and replaced with a ligand which is specific for a receptor located on a desired cell type.
As stated hereinabove, the adenovirus fiber protein includes a head portion and a shaft portion. In one embodiment, at least a portion of the head portion is removed and replaced with a ligand which is specific for a receptor located on a desired cell type. In one embodiment, a portion of the head portion is removed and replaced with a ligand which is specific for a receptor located on a desired cell type. In another embodiment, all of the head portion is removed and replaced with a ligand which is specific for a receptor located on a desired cell type.
In one embodiment, the adenovirus is Adenovirus 3, and amino acid residues 132 to 319 of the fiber (i.e., the fiber head region) of Adenovirus 3 are removed and are replaced with a ligand which is specific for a receptor located on a desired cell type. The DNA encoding the fiber protein of Adenovirus 3 is registered as Genbank accession #M12411, (incorporated herein by reference). In another embodiment, the adenovirus is Adenovirus 5, and amino acid residues 400 to 581 of the fiber (i.e., the fiber head region) of Adenovirus 5 are removed and are replaced with a ligand. The DNA encoding the fiber protein of Adenovirus 5 is registered as Genbank accession #M18369, (incorporated herein by reference). In yet another embodiment, the adenovirus is Adenovirus 41, and amino acid residues 387 to 563 of the long fiber (i.e., the fiber head region) of Adenovirus 41 are removed and replaced with a ligand. In a further embodiment, the adenovirus is Adenovirus 41, and amino acid residues 231 to 387 of the short fiber (i.e., the fiber head region) of Adenovirus 41 short are removed and replaced with a ligand. The DNA encoding the Adenovirus 41 long and short fibers is registered as Genbank accession #X17016, incorporated herein by reference.
Ligands which may replace a portion of the adenovirus fiber protein include, but are not limited to, the TNF superfamily of ligands which include tumor necrosis factors (or TNF's) such as, for example, TNF-alpha and TNF-beta, lymphotoxins (LT), such as LT-.alpha. and LT-.beta., Fas ligand which b
REFERENCES:
patent: 5559099 (1996-09-01), Wickham et al.
Bisbee, Genetic Engineering News 17(8):1 et seq (1997).
B.N. Fields et al., eds. Fundamental Virology, 2nd ed. New York: Raven Pres, 1991, p. 779.
"Report and Recommendations of the Panel to Assess the NIH Investment in Research on Gene Therapy," Orkin and Motulsky, Co-chairs, Dec. 7, 1995.
Levine et al., (1993) Am. J. Dis. Child 147(11):1167-1174.
Jolly, (1994) Cancer Gene Therapy 1(1):51-64.
McClelland Alan
Stevenson Susan C.
Genetic Therapy, Inc.
Lillie Raymond J.
Olstein Elliot M.
Railey II Johnny F.
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