Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1998-01-06
2001-07-17
McGarry, Sean (Department: 1635)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C435S006120, C435S455000, C435S375000, C435S377000, C536S024100, C536S024500
Reexamination Certificate
active
06262033
ABSTRACT:
TECHNICAL FIELD
The present invention relates to the prevention and treatment of various diseases associated with NF-&kgr;B which is known to be a regulatory factor in the transcription of cytokines and adhesion factors. More particularly, the invention relates to an NF-&kgr;B decoy, a composition comprising said decoy for the therapy and prophylaxis of NF-&kgr;B-associated diseases, and a method for said therapy and prophylaxis.
BACKGROUND ART
A variety of diseases including asthma, cancers, heart diseases, autoimmune diseases, and viral infections manifest varying symptoms and signs and yet it has been suggested that either an overexpression or underexpression of one or a few proteins is a major etiologic factor in many cases. Moreover, a variety of transcriptional regulatory factors such as transcription activators and transcription inhibitors are involved in the expression of proteins. NF-&kgr;B, a substance known to be one of such transcriptional regulatory factors, is a heterodimer of p65 and p50 proteins. In the cytoplasm, NF-&kgr;B is usually present as substance binding with I&kgr;B, an inhibition factor, and thereby prevented from migrating into the nucleus. However, when a cell is stimulated by cytokines, ischemia, or reperfusion for whatever reason, I&kgr;B is phosphorylated and decomposed so that the NF-&kgr;B is activated and penetrates into the nucleus. NF-&kgr;B attaches itself to the NF-&kgr;B binding site of the chromosome and then promotes transcription of the gene located at downstreams. The gene controlled by NF-&kgr;B includes cytokines such as IL-1, IL-6, IL-8, etc. and adhesion factors such as VCAM-1, ICAM-1, etc . . .
DISCLOSURE OF THE INVENTION
Predicting that stimulation of the production of those cytokines and adhesion factors is causative of various morbidities such as ischemic diseases, inflammatory diseases, autoimmune diseases, cancer metastasis and invasion, and cachexia, the inventors of this invention did much research and found that it is a rewarding therapeutic approach to suppress expression of those genes which are activated by NF-&kgr;B by administering a decoy of the NF-&kgr;B binding site of chromosome, that is to say a compound which specifically antagonizes the binding site of chromosome to which NF-&kgr;B is conjugated. The present invention has been developed on the basis of the above finding.
The present invention, therefore, provides a pharmaceutical composition comprising an NF-&kgr;B decoy as an active ingredient for the therapy and prophylaxis of various NF-&kgr;B-associated diseases and a method for said therapy and prophylaxis.
The diseases in which the therapeutic/prophylactic composition of the invention is indicated are NF-&kgr;B-associated diseases, that is to say diseases caused by the unwanted activation of genes under control of the transcriptional regulatory factor NF-&kgr;B, and among such diseases can be reckoned ischemic diseases, inflammatory diseases, autoimmune diseases, cancer metastasis and invasion, and cachexia. The ischemic disease includes ischemic diseases of organs (e.g. ischemic heart diseases such as myocardial infarction, acute heart failure, chronic heart failure, etc., ischemic brain diseases such as cerebral infarction, and ischemic lung diseases such as pulmonary infarction), aggravation of the prognosis of organ transplantation or organ surgery (e.g. aggravation of the prognosis of heart transplantation, cardiac surgery, kidney transplantation, renal surgery, liver transplantation, hepatic surgery, bone marrow transplantation, skin grafting, corneal transplantation, and lung transplantation), reperfusion disorders, and post-PTCA restenosis. The inflammatory disease mentioned above includes various inflammatory diseases such as nephritis, hepatitis, arthritis, etc., acute renal failure, chronic renal failure, and arteriosclerosis, among other diseases. The autoimmune disease mentioned above includes but is not limited to rheumatism, multiple sclerosis, and Hashimoto's thyroiditis. Particularly the pharmaceutical composition containing the NF-&kgr;B decoy according to the present invention as an active ingredient is very suited for the therapy and prophylaxis of reperfusion disorders in ischemic diseases, aggravation of the prognosis of organ transplantation or organ surgery, post-PTCA restenosis, cancer metastasis and invasion, and cachexia such as weight loss following the onset of a cancer.
The NF-&kgr;B decoy that can be used in the present invention may be any compound that specifically antagonizes the NF-&kgr;B binding site of the chromosome and includes but is not limited to nucleic acids and their analogs. As preferred examples of said NF-&kgr;B decoy, there can be mentioned oligonucleotides containing the nucleotide sequence of GGGATTTCCC (the sequence from the 8th through the 17th nucleotides from the 5′-end of SEQ ID NO:1 in Sequence Listing) or its complementary sequence, muteins thereof, and compounds containing any of them within the molecule. The oligonucleotides may be DNAs or RNAs, and may contain modified nucleotides and/or pseudonucleotides. Furthermore, those oligonucleotides, variants thereof, or compounds containing any of them may be single-stranded or double-stranded and linear or cyclic. The variants are those involving mutations such as substitution, addition and/or deletion of any part of the above-mentioned sequence, and mean nucleic acids specifically antagonizing the binding site of chromosome to which NF-&kgr;B is conjugated. The more preferred NF-&kgr;B decoy includes double-stranded oligonucleotides each containing one or a plurality of the above nucleotide sequence and variants thereof. The oligonucleotide which can be used in the present invention includes oligonucleotides modified so as to be less susceptible to biodegradation, such as those oligonucleotides containing the thiophosphoric diester bond available upon substitution of sulfur for the oxygen of the phosphoric diester moiety (S-oligo) and those oligonucleotides available upon substitution of a methyl phosphate group carrying no electric charge for the phosphoric diester moiety.
Regarding to a technology for producing the NF-&kgr;B decoy for use in the present invention, the conventional chemical or biochemical methods for synthesis can be utilized. When a nucleic acid, for instance, is to be used as the NF-&kgr;B decoy, the methods for nucleic acid synthesis which are commonly used in genetic engineering can be employed. For example, the objective decoy oligonucleotide can be directly synthesized on a DNA synthesizer. Or a nucleic acid or its fragments, each synthesized beforehand, can be amplified by PCR or using a cloning vector or the like. Furthermore, the desired nucleic acid can be obtained by such procedures as cleavage with restriction enzymes or the like and/or ligation by means of DNA ligase or the like. In order to obtain a decoy nucleotide which is more stable within cells, the base, sugar or/and phosphoric acid moieties of the nucleic acid may be alkylated, acylated, or otherwise chemically modified.
The pharmaceutical composition containing the NF-&kgr;B decoy as an active ingredient according to the present invention is not limited in form only if the active ingredient may be taken up by the cells in the affected site or the cells of the target tissue. Thus, the NF-&kgr;B decoy, either alone or in admixture with the common pharmaceutical carrier, can be administered orally, parenterally, topically or externally. The pharmaceutical composition may be provided in liquid dosage forms such as solutions, suspensions, syrups, liposomes, lotions, etc. or in solid dosage forms such as tablets, granules, powders, and capsules. Where necessary, those pharmaceutical compositions may be supplemented with various vehicles, excipients, stabilizers, lubricants, and/or other conventional pharmaceutical additives, such as lactose, citric acid, tartaric acid, stearic acid, magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, caccao butter, e
Chiba Toshiyuki
Kawamura Ikuo
Maeda Kazuhiro
Morishita Ryuichi
Ogiwara Toshio
Fujisawa Pharmaceutical Co. Ltd.
McGarry Sean
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
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