Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing compound containing saccharide radical
Patent
1995-06-22
1999-11-16
Elliott, George C.
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing compound containing saccharide radical
435 6, 435 911, 435 913, 435 9133, 4353201, 435440, 435455, 435471, 435325, 435243, 514 44, 536 231, 536 232, 536 245, C12P 1934, C07H 2104, C12N 1585, C12N 1563
Patent
active
059856203
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Throughout this application, various publications are referred by arabic numerals to within brackets. The disclosures for these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains.
The discovery of RNA molecules that possess enzymatic, self-cleaving activity (ribozymes) has provided a new way to artificially control gene expression (Foster & Symons, (1987) Cell, 49:585-591). Ribozymes have been designed that contain nearly all of the sequences required for cleavage. For the hammerhead type, the target RNA needs to contain only the sequence XUX with cleavage occurring 3' from XUX (Haseloff & Gerlach, (1988) Nature, (London) 334:585-591; Perriman et al., Gene (1992) 113: 157-163). The high specificity and limited target requirement give these catalytic RNA molecules the potential for inhibiting viral pathogens and for regulating specific gene expression by interfering with transcription in a highly specific manner (Uhlenbeck, (1987) Nature (London) 328:596-600; Haseloff & Gerlach, (1988) Nature, (London) 334:585-591).
Several reports indicate that the hammerhead type of ribozyme functions in living cells. Cotten & Birnstiel (1989, EMBO J., 8:3861-3866) and Cameron & Jennings (1989, Proc. Natl. Acad. Sci., USA 86:9139-9143) reported ribozyme-mediated destruction and lowering of specific gene expression in Xenopus laevis oocytes and monkey (COS1) cells, respectively. Sarver et al. (1990, Science, 247:1222-1225) showed that a ribozyme directed against HIV-1 gag RNA reduced p24 antigen expression in CD4.sup.+ HeLa cells. Recently, this line of study was extended to bacterial cells by showing that a ribozyme designed to cleave the integrase gene of HIV-1 is effective when transcribed from a plasmid in Escherichia coli. Integrase RNA was eliminated and integrase protein synthesis was blocked (Sioud & Drlica, (1991) Proc. Natl. Acad. Sci., USA 88:7303-7307). Since ribozymes are effective in vivo, problems of ribozyme stability and delivery may now be addressed.
To interfere with tumor necrosis factor .alpha. (TNF-.alpha.) gene expression we have used cationic liposome-mediated transfection (Malone et al., (1989) Proc. Natl. Acad. Sci., USA 86:6077-6081) to deliver a ribozyme directed against TNF-.alpha. into human promyelocytic leukaemia cells (HL60) and peripheral blood mononuclear cells (PBMNC). TNF-.alpha. plays an important role in many inflammatory rheumatic diseases (Shinmei et al., (1989) Sem. Arth. Rheum. 18 (suppl. 1) 27-32), and it modulates the expression of several proteins, including the class I antigens of the major histocompatibility complex (MHC) and cytokines such as interleukin 1 and interleukin 6 (Beutler & Cerami, (1988) Annu. Rev. Biochem. 57:505-518 and (1989) Annu. Rev. Immunol. 7:625-655). TNF-.alpha. also appears to be necessary for normal immune responses, but large quantities of it can produce destructive effects such as those seen in rheumatoid arthritis (Brennan et al., (1989) Lancet ii 244-247). In addition, TNF-.alpha. is the cytokine responsible for the induction of HIV-1 expression in ACH-2 cells (Rosenberg & Fauci, (1990) Immunol. Today 11:176-180). TNF-.alpha. induces the production of cellular factors that bind to the NF-KB enhancer elements within the viral long terminal repeat sequences and thereby activates HIV-1 expression.
The effectiveness of catalytic RNA molecules is dependent on the stability of the mRNA in vivo. In comparison with the knowledge of DNA structural elements, little is known about mRNA stability elements. m-RNA half-lives range from less than 30 minutes for fibroblast interferon and c-fos to greater than 17 hours for .beta. globin. Most eukaryotic mRNAs are protected in cells from exonuclease attack by the 5' cap structure and the 3'poly(A) tail and poly(A) binding proteins. In addition, eukaryotic mRNAs have both 5' and 3' non-coding regions on either side of the coding region. The 5' non-coding region is involve
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Elliott George C.
Gene Shears Pty. Limited
McGarry Sean
White John P.
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