Oligonucleotide-containing pharmacological compositions and their use

Abstract

The present invention relates to methods and compositions containing oligonucleotides suitable for administration to humans and other mammals.

We claim:  
     
         1 . A composition suitable for administration in a mammal comprising a modified oligonucleotide of about seven to seventy-five nucleotides containing seven or more contiguous ribose groups linked by achiral 5′ to 3′ internucleoside phosphate linkages, wherein the modified oligonucleotide is complementary to a region of a gene associated with a pathological disorder.  
     
     
         2 . The composition of  claim 1  wherein the mammal is a human.  
     
     
         3 . The composition of  claim 1  wherein the oligonucleotide is a ribonucleotide.  
     
     
         4 . The composition of  claim 1  wherein the oligonucleotide is a deoxyribonucleotide.  
     
     
         5 . The composition of  claim 1  wherein the modified oligonucleotide is complementary to a region of the gene selected from the group consisting of the 5′ UTR region, translational start site, the 3′ UTR, and translational termination site.  
     
     
         6 . The composition of  claim 1  wherein the gene is a gene selected from Table 1.  
     
     
         7 . The composition of  claim 1  wherein the pathological disorder is selected from the group consisting of abnormal appetite, hypertension, hypercholesteroremia, hyperlipidemia, erectile dysfunction, eczema, depression, anxiety, stress, inflammatory bowel syndrome, ulcerative colitis, Crohn's disease, renal stones, gall stones, constipation, migraine headache, seizure, multiple sclerosis, polymyositis, fiboromyalgia, Parkinson's disease, ALS, chronic pain, pre-menstrual syndrome, sinusitis, colds, trauma, carpal tunnel syndrome, chronic fatigue syndrome, rosacea, arthritis, psoriasis, prostatitis, inflammation, heartburn, infection, poison ivy, colon cancer, malignant melanoma and malignant nasal polyps.  
     
     
         8 . The composition of  claim 1  wherein the modified oligonucleotide is present at a concentration effective to reduce the expression of the gene.  
     
     
         9 . The composition of  claim 8  wherein the modified oligonucleotide is administered at a dose of less than 100 μg/kg.  
     
     
         10 . The composition of  claim 8  wherein the modified oligonucleotide is administered at a dose of less than 50 μg/kg.  
     
     
         11 . The composition of  claim 8  wherein the modified oligonucleotide is administered at a dose of less than 5.0 μg/kg.  
     
     
         12 . The composition of  claim 8  wherein the modified oligonucleotide is administered at a dose of less than 0.50 μg/kg.  
     
     
         13 . The composition of  claim 8  wherein the modified oligonucleotide is administered at a dose of less than 0.050 μg/kg.  
     
     
         14 . The composition of  claim 8  wherein the modified oligonucleotide is administered at a dose of less than 0.0050 μg/kg.  
     
     
         15 . The composition of  claim 1  wherein the modified oligonucleotide is suitable for oral administration.  
     
     
         16 . The composition of  claim 1  wherein the modified oligonucleotide has a Tm of about 75-115° C. at a concentration of 1 mM and a length of 10 to 26 bases, or a Tm of 40° C. to 85° C. at a concentration of 1 pM and a length of 10 to 26 bases.  
     
     
         17 . The composition of  claim 1  wherein the modified oligonucleotide is selected from the group consisting of SEQ ID NO: 1-81.  
     
     
         18 . The composition of  claim 1  wherein the ribose group has a modified 2′ substituent.  
     
     
         19 . The composition of  claim 18  wherein the 2′ substituent is selected from the group consisting of hydrogen, methoxy, propoxy, methoxy-ethoxy, flourine, chlorine, bromine and iodine.  
     
     
         20 . The composition of  claim 18  wherein the modified oligonucleotide is 3′ end-blocked.  
     
     
         21 . The composition of  claim 1  wherein the modified oligonucleotide is 3′ end-blocked.  
     
     
         22 . The composition of  claim 1  wherein the modified oligonucleotide is 5′ end-blocked.  
     
     
         23 . The composition of  claim 1  wherein the composition is a pharmaceutical composition.  
     
     
         24 . The composition of  claim 1  wherein the composition is a nutritional supplement composition.  
     
     
         25 . The composition of  claim 1  wherein the composition is a dietary supplement composition.  
     
     
         26 . The composition of  claim 1  wherein the composition is a cosmetic composition.  
     
     
         27 . The composition of  claim 1  comprising at least two different modified oligonucleotides.  
     
     
         28 . The composition of  claim 1  comprising at least three different modified oligonucleotides.  
     
     
         29 . A method of treating a patient with a pathological disorder comprising administering one or more modified oligonucleotides of about seven to seventy-five nucleotides, wherein the modified oligonucleotide contains seven or more contiguous ribose groups linked by achiral 5′ to 3′ internucleoside phosphate linkages.  
     
     
         30 . The method of  claim 29  wherein the modified oligonucleotide is complementary to a region of a gene associated with the pathological disorder.  
     
     
         31 . The method of  claim 29  wherein the gene is selected from Table 1.  
     
     
         32 . The method of  claim 29  wherein the modified oligonucleotide is complementary to a region of the gene selected from the group consisting of the 5′ UTR region, transitional start site and transitional termination site.  
     
     
         33 . The method of  claim 29  wherein the pathological disorder is selected from the group consisting of abnormal appetite, hypertension, hypercholesteroremia, hyperlipidemia, erectile dysfunction, eczema, depression, anxiety, stress, inflammatory bowel syndrome, ulcerative colitis, Crohn's disease, renal stones, gall stones, constipation, migraine headache, seizure, multiple sclerosis, polymyositis, fibromyalgia, Parkinson's disease, ALS, chronic pain, pre-menstrual syndrome, sinusitis, colds, trauma, carpal tunnel syndrome, chronic fatigue syndrome, rosacea, arthritis, psoriasis, prostatitis, inflammation, heart burn, infection, poison ivy, colon cancer, malignant melanoma and malignant nasal polyps.  
     
     
         34 . The method of  claim 29  wherein the modified oligonucleotide is administered at a dose effective to reduce the expression of the gene.  
     
     
         35 . The method of  claim 34  wherein the modified oligonucleotide is administered at a dose of less than 10.0 μg/kg.  
     
     
         36 . The method of  claim 29  wherein the modified oligonucleotide is administered at a dose of less than 5.0 μg/kg.  
     
     
         37 . The method of  claim 29  wherein the modified oligonucleotide is administered at a dose of less than 0.50 μg/kg.  
     
     
         38 . The method of  claim 29  wherein the modified oligonucleotide is administered at a dose of less than 0.050 μg/kg.  
     
     
         39 . The method of  claim 29  wherein the modified oligonucleotide is administered at a dose of less than 0.0050 μg/kg.  
     
     
         40 . The method of  claim 29  wherein the modified oligonucleotide is orally administered.  
     
     
         41 . The method of  claim 29  wherein the modified oligonucleotide has a Tm of about 75-90° C.  
     
     
         42 . The method of  claim 29  wherein wherein the modified oligonucleotide is selected from the group consisting of SEQ ID NO: 1-81.  
     
     
         43 . The method of  claim 29  wherein the ribose group has a modified 2′ substituent.  
     
     
         44 . The method of  claim 43  wherein the 2′ substituent is selected from the group consisting of hydrogen, methoxy, propoxy, methoxy-ethoxy, flourine, chlorine, bromine and iodine.  
     
     
         45 . The method of  claim 43  wherein the modified oligonucleotide is 3′ end-blocked.  
     
     
         46 . The method of  claim 29  wherein the modified oligonucleotide is 3′ end-blocked.  
     
     
         47 . The method of  claim 29  wherein the modified oligonucleotide is 5′ end-blocked.  
     
     
         48 . The method of  claim 29  wherein at least two different modified oligonucleotides are administered.  
     
     
         49 . The method of  claim 29  wherein at least three different modified oligonucleotides are administered.  
     
     
         50 . A nutritional supplement comprising a modified oligonucleotide of about seven to seventy-file nucleotides containing seven or more contiguous ribose groups linked by achiral 5′ to 3′ internucleoside phosphate linkages.  
     
     
         51 . A method of supplementing the diet of an individual comprising administering the nutritional supplement of  claim 50  wherein administration of the nutritional supplement improves the health of the individual.  
     
     
         52 . A cosmetic composition comprising a modified oligonucleotide of about seven to seventy-file nucleotides containing seven or more contiguous ribose groups linked by achiral 5′ to 3′ internucleoside phosphate linkages, wherein the modified oligonucleotide is complementary to a region of a gene associated with a skin disorder.  
     
     
         53 . A method of improving the appearance of the skin in an individual with a skin disorder comprising administering the cosmetic composition of  claim 44.