Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1995-03-09
2004-03-30
Priebe, Scott D. (Department: 1636)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S023100, C514S04400A
Reexamination Certificate
active
06713621
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to the field of oligonucleotide therapeutic compositions and methods. Modulation, especially down-regulation, of genes or gene portions associated with disease states is a particular object of the invention. The invention provides therapeutic and research compositions which interact with certain transcriptional regulatory factors to modulate transcription of vascular cell adhesion molecule genes. Chimeric compositions having multi-modalities are also provided which can affect a plurality of gene functions by interfering with splicing or translation as well as transcription. Treatment of inflammatory and vascular diseases is a preferred embodiment of the present invention.
BACKGROUND OF THE INVENTION
Certain cellular adhesion molecules have been implicated in inflammatory and vascular diseases. As an example, a major mediator of the atherosclerotic process is the expression of specific adhesion molecule proteins on the surface of vascular endothelial cells. These adhesion molecules bind to immune cells, termed leukocytes, and initiate and propagate the inflammatory response that is likely central to both atherosclerosis and post-angioplasty restenosis. One of these vascular cell adhesion molecules, VCAM-1, plays an especially important role in atherosclerosis by binding a specific class of leukocytes, termed mononuclear leukocytes. Multiple signals induce the expression of VCAM-1. ICAM-1 and E-selectin are other inducible vascular cell adhesion molecules that mediate other aspects of general inflammatory response.
It is greatly desired to achieve palliative, diagnostic and therapeutic regimes for inflammatory disorders, atherosclerosis, restenosis and other diseases through modulation of the production of vascular cell adhesion molecules by cells. Specificity of such therapy is also greatly desired.
Oligonucleotides have recently become accepted as therapeutic moieties in the treatment of disease states in animals and man. For example, workers in the field have now identified antisense, triplex and other oligonucleotide therapeutic compositions which are capable of modulating expression of genes implicated in viral, fungal and metabolic diseases. For example, PCT patent applications PCT/US90/ 07067 filed Dec. 3, 1990; PCT/US91/01327 filed Feb. 25, 1991; and PCT/US91/05815 filed Aug. 14, 1991 disclose therapeutic oligonucleotides for treatment of papillomavirus, herpesvirus and cytomegalovirus infections respectively.
PCT patent application PCT/US91/05802 Filed Aug. 15, 1991 discloses oligonucleotides for treatment of Candida infections. PCT patent application US91/02628 filed Apr. 17, 1991 and PCT/US91/05209 filed Jul. 23, 1991 are directed to modulation of genes regulating lipid metabolism and cell adhesion respectively employing oligonucleotides as therapeutic agents. U.S. Ser. No. 007,997 filed Jan. 21, 1993 now U.S. Pat. No. 5,591,623, U.S. Ser. No. 063,167 filed May 17, 1993 now U.S. Pat. No. 5,514,788 and PCT patent application PCT/US93/08101 are also directed to oligonucleotide therapeutics relating to cellular adhesion molecules.
U.S. Pat. No. 5,098,890, in the name of Gewirtz, et al., is directed to antisense oligonucleotide therapies for certain cancerous conditions, while U.S. Pat. No. 5,166,195 issued Nov. 24, 1992 provides oligonucleotide inhibitors of HIV. It is, thus, established that oligonucleotides can be useful therapeutic instrumentalities and that the same can be configured to be useful in treatment regimes for treatment of cells and animals, especially humans.
It is apparent that oligonucleotide therapeutics is an accepted modality for treatment of disease. Methods of drug delivery and of modification to permit therapeutically significant residencies are now known. Notwithstanding the acceptance of oligonucleotide therapeutics, additional, effective approaches to gene modulation, especially down-regulation, employing oligonucleotides are greatly desired. Moreover, mechanisms of action for oligonucleotide therapeutics different from classical antisense and triplex mechanisms are also greatly desired.
Transcriptional regulatory factors (transcription factors) are DNA binding proteins which transduce extracellular signals into nuclear regulatory signals. Normally, transcriptional regulatory factors are activated or synthesized, translocate to the nucleus of cells, and bind to specific DNA sequences called enhancer or regulatory elements. Once bound, the transcriptional regulatory factor modulates gene transcription.
Wu, et al. “Inhibition of in Vitro Transcription by Specific Double-Stranded Oligodeoxy-ribonucleotides,” Gene 89 203-209 (1990) used double stranded deoxyoligonucleotides to compete for binding of nuclear factors to specific promoter and enhancer elements. The authors tested the effect of oligonucleotide length, sequence and number of nuclear factor binding sites on in vitro transcription of adenovirus; potential therapeutic regimes were discussed. See also Holcenberg and Wu, WO 91/11535 which also discloses phosphorothioate derivatives in this context. Chu et al. “Binding of Hairpin and Dumbbell DNA to Transcription Factors”
Nucleic Acids Research
19 6958 (1991) discloses the use of single stranded DNA in hairpin loop and ligated circular (dumbbell) forms for binding to transcription factors. See also Chu and Orgel, WO 92/18522.
Others have approached therapeutics through oligonucleotide interaction with transcription regulatory factors. Taniguchi, T. U.S. Pat. No. 5,157,115 issued Oct. 20, 1992 discloses nucleic acid compositions which inhibit or control the IL-2 or IL-2a genes by competitively binding to their respective transcription factors.
Blumenfeld et al. in WO 92/19732 and WO 91/15114 disclose antisense or sense oligonucleotides which can have a protein binding sequence.
Androphy et al. in European Patent Application 302,758 disclose nucleic acids or proteins for inhibiting the growth of a virus, such as papillomavirus, by preventing binding of a stimulatory protein encoded by the DNA of the virus (which protein would, if bound, enhance viral transcription) to the DNA of the virus. See also Androphy, et al, Nature 325:70-73 (1987) and Androphy et al., WO 91/14790, relating to inhibitors of transcription activation activity of papilloma viruses. Clusel, et al., Nucleic Acids Research 21:3405-3411 (1993) disclose ex vivo regulation of specific gene expression by nanomolar concentration of double-stranded dumbbell oligonucleotides containing a hepatic nuclear factor-1 binding site.
Bielinska, et al., Science 250:997-1000 (1990) regulated gene expression with double-stranded phosphorothioate oligonucleotides. Inhibition of sequence-specific DNA-binding proteins with oligonucleotides containing octamer or kB consensus sequences, which bound specifically either octamer transcription factor or NF-kB, were disclosed to inhibit HIV enhancer activation or IL-2 secretion.
Eck et al., Molecular and Cellular Biology 13:6530-6536 (1993), used high doses (≧20 &mgr;M) of a double-stranded 38 mer phosphorothioate oligonucleotide containing three tandem repeats of the NF-kB consensus binding sequence to inhibit the expression of both ICAM-1 and CD11b, a leukocyte integrin, in human endothelial cells in culture.
While interaction with transcriptional regulatory factors by DNA oligonucleotides has been known heretofore, and while therapies have been predicted to be possible, there have been no specific oligonucleotides and no effective methods using oligonucleotides for interaction with transcriptional regulatory factors which can effectively and specifically target vascular cell adhesion molecules, particularly VCAM-1, and diseases for which such molecules are implicated. Such materials and methods are greatly desired.
It is an object of the invention to provide oligonucleotide diagnostic and therapeutic compositions and methods for modulating expression of genes associated with disease states implicating vascular cell adhesion molecules, particularly VCAM-1.
A further object is to provide suc
Bennett Clarence Frank
Medford Russell M.
ISIS Pharmaceuticals Inc.
Kaushal Sumesh
Priebe Scott D.
Woodcock & Washburn LLP
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