Modulation of SGLT2 expression

Abstract

Compounds, compositions and methods are provided for modulating the expression of SGLT2. The compositions comprise oligonucleotides, targeted to nucleic acid encoding SGLT2. Methods of using these compounds for modulation of SGLT2 expression and for diagnosis and treatment of diseases and conditions associated with expression of SGLT2 are provided.

1 . An oligomeric compound 8 to 80 nucleobases in length targeted to a nucleic acid molecule encoding SGLT2, wherein the compound is at least 70% complementary to the nucleic acid molecule encoding SGLT2, and wherein the compound inhibits the expression of SGLT2 mRNA by at least 10%.  
     
     
         2 . The compound of  claim 1  comprising 10 to 50 nucleobases in length.  
     
     
         3 . The compound of  claim 2  comprising 13 to 30 nucleobases in length.  
     
     
         4 . The compound of  claim 3  comprising 15 to 25 nucleobases in length.  
     
     
         5 . The compound of  claim 4  comprising 18 to 22 nucleobases in length.  
     
     
         6 . The compound of  claim 1  comprising an oligonucleotide.  
     
     
         7 . The compound of  claim 6  comprising a DNA oligonucleotide.  
     
     
         8 . The compound of  claim 6  comprising an RNA oligonucleotide.  
     
     
         9 . The compound of  claim 6  comprising a chimeric oligonucleotide.  
     
     
         10 . The compound of  claim 6  wherein at least a portion of the compound hybridizes with RNA to form an oligonucleotide-RNA duplex.  
     
     
         11 . The compound of  claim 1  comprising at least 80% complementarity with the nucleic acid molecule encoding SGLT2.  
     
     
         12 . The compound of  claim 1  comprising at least 90% complementarity with the nucleic acid molecule encoding SGLT2.  
     
     
         13 . The compound of  claim 1  comprising at least 95% complementarity with the nucleic acid molecule encoding SGLT2.  
     
     
         14 . The compound of  claim 1  comprising at least 99% complementarity with the nucleic acid molecule encoding SGLT2.  
     
     
         15 . The compound of  claim 1  comprising at least one modified internucleoside linkage, sugar moiety, or nucleobase.  
     
     
         16 . The compound of  claim 1  comprising at least one 2′-O-methoxyethyl sugar moiety.  
     
     
         17 . The compound of  claim 1  comprising at least one phosphorothioate internucleoside linkage.  
     
     
         18 . The compound of  claim 1  wherein at least one cytosine is a 5-methylcytosine.  
     
     
         19 . A method of inhibiting the expression of SGLT2 in a cell or tissue comprising contacting the cell or tissue with the compound of  claim 1  so that expression of SGLT2 is inhibited.  
     
     
         20 . A method of screening for a modulator of SGLT2 comprising: 
 contacting a target segment of a nucleic acid molecule encoding SGLT2 with one or more candidate modulators of SGLT2; and    identifying one or more modulators of SGLT2 expression which modulate the expression of SGLT2.    
     
     
         21 . The method of  claim 20  wherein the modulator of SGLT2 expression comprises an oligonucleotide, an antisense oligonucleotide, a DNA oligonucleotide, an RNA oligonucleotide, an RNA oligonucleotide having at least a portion of said RNA oligonucleotide capable of hybridizing with RNA to form an oligonucleotide-RNA duplex, or a chimeric oligonucleotide.  
     
     
         22 . A method for identifying a disease state comprising identifying the presence of SGLT2 in a sample using at least one primer comprising SEQ ID NO: 5 or SEQ ID NO: 6, or a probe comprising SEQ ID NO: 7.  
     
     
         23 . A kit or assay device comprising the compound of  claim 1 .  
     
     
         24 . A method of treating an animal having a disease or condition associated with SGLT2 comprising administering to the animal a therapeutically or prophylactically effective amount of the compound of  claim 1  so that expression of SGLT2 is inhibited.  
     
     
         25 . The method of  claim 24  wherein the disease or condition is a hyperproliferative or metabolic disorder.  
     
     
         26 . The compound of  claim 1  comprising at least an 8-nucleobase portion of SEQ ID NO: 19, 20, 21, 22, 23, 26, 27, 28, 29, 32, 33, 34, 35, 37, 38, 39, 40, 41, 43, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 61, 62, 63, 64, 66, 67, 68, 69, 70, 73, 74, 77, 79, 80, 82, 85, 88, 90, 91, 92, 93, 94, or 95.  
     
     
         27 . The compound of  claim 26  wherein the compound comprises SEQ ID NO: 19, 20, 21, 22, 23, 26, 27, 28, 29, 32, 33, 34, 35, 37, 38, 39, 40, 41, 43, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 61, 62, 63, 64, 66, 67, 68, 69, 70, 73, 74, 77, 79, 80, 82, 85, 88, 90, 91, 92, 93, 94, or 95.  
     
     
         28 . The compound of  claim 1  wherein the compound comprises at least an 8-nucleobase portion of SEQ ID NO: 99, 105, 107, 109, 110, 117, 121, 124, 125, 126, 130, 131, 132, 136, 138, 139, 142, 147, 148, 150, 153, 155, 162, 173, or 175.  
     
     
         29 . The compound of  claim 28  wherein the compound comprises SEQ ID NO: 99, 105, 107, 109, 110, 117, 121, 124, 125, 126, 130, 131, 132, 136, 138, 139, 142, 147, 148, 150, 153, 155, 162, 173, or 175.  
     
     
         30 . The compound of  claim 1  wherein the compound comprises an antisense nucleic acid molecule that is specifically hybridizable with a 5′-untranslated region of a nucleic acid molecule encoding SGLT2.  
     
     
         31 . The compound of  claim 1  wherein the compound comprises an antisense nucleic acid molecule that is specifically hybridizable with a start region of a nucleic acid molecule encoding SGLT2.  
     
     
         32 . The compound of  claim 1  wherein the compound comprises an antisense nucleic acid molecule that is specifically hybridizable with a coding region of a nucleic acid molecule encoding SGLT2.  
     
     
         33 . The compound of  claim 1  wherein the antisense compound comprises an antisense nucleic acid molecule that is specifically hybridizable with a stop region of a nucleic acid molecule encoding SGLT2.  
     
     
         34 . The compound of  claim 1  wherein the antisense compound comprises an antisense nucleic acid molecule that is specifically hybridizable with a 3′-untranslated region of a nucleic acid molecule encoding SGLT2.  
     
     
         35 . The compound of  claim 1  which comprises a first region consisting of at least 5 contiguous 2′-deoxy.nucleosides flanked by a second region and a third region, wherein each of the second and third regions, independently, comprises at least one 2′-O-methoxyethyl nucleoside, and wherein the internucleoside linkages of the first region are phosphorothioate linkages and the internucleoside linkages of the second and third regions are phosphodiester linkages.  
     
     
         36 . A method of inhibiting the expression of SGLT2 in a kidney cell or kidney tissue comprising contacting the kidney cell or kidney tissue with the compound of  claim 35 .  
     
     
         37 . A method of enhancing inhibition of expression of SGLT2 in a kidney cell or kidney tissue comprising contacting the kidney cell or kidney tissue with the compound of  claim 35  so that expression of SGLT2 is inhibited.  
     
     
         38 . The method of  claim 37  wherein the compound comprises SEQ ID NO: 106, 255, or 256.  
     
     
         39 . A method of preventing or delaying the onset of a disease or condition in an animal comprising administering to the animal an effective amount of the compound of  claim 35  so that expression of SGLT2 is inhibited, wherein the disease or condition is associated with expression of SGLT2 in the kidney.  
     
     
         40 . The method of  claim 39  wherein the compound comprises SEQ ID NO: 106, 255, or 256.  
     
     
         41 . A method of preventing or delaying the onset of type 2 diabetes in an animal comprising administering to the animal the compound of  claim 35  so that expression of SGLT2 is inhibited.  
     
     
         42 . The method of  claim 41  wherein said animal is a primate or a rodent.  
     
     
         43 . The method of  claim 41  wherein the compound comprises SEQ ID NO: 106, 255, or 256.  
     
     
         44 . A method of preventing or delaying the onset of an increase in blood glucose level in an animal comprising administering to the animal the compound of  claim 35  so that expression of SGLT2 is inhibited.  
     
     
         45 . The method of  claim 44  wherein the animal is a primate or a rodent.  
     
     
         46 . The method of  claim 44  wherein the blood glucose level is plasma glucose level or serum glucose level.  
     
     
         47 . The method of  claim 44  wherein the animal is a diabetic animal.  
     
     
         48 . The method of  claim 44  wherein the animal is insulin-resistant as compared to a normal animal.  
     
     
         49 . The method of  claim 44  wherein the compound comprises SEQ ID NO: 106, 255, or 256.  
     
     
         50 . A method of decreasing blood glucose level in an animal comprising administering to the animal the compound of  claim 35  so that expression of SGLT2 is inhibited.  
     
     
         51 . The method of  claim 50  wherein the animal is a primate or a rodent.  
     
     
         52 . The method of  claim 50  wherein the blood glucose level is plasma glucose level or serum glucose level.  
     
     
         53 . The method of  claim 50  wherein the animal is a diabetic animal.  
     
     
         54 . The method of  claim 50  wherein the animal is insulin-resistant as compared to a normal animal.  
     
     
         55 . The method of  claim 50  wherein the compound comprises SEQ ID NO: 106, 255, or 256.  
     
     
         56 . A method of enhancing inhibition of expression of SGLT2 in a kidney cell or kidney tissue comprising contacting the cell or tissue with an antisense compound comprising a first central region comprising at least 5 contiguous 2′-deoxy nucleosides flanked by a second 5′ region and a third 3′ region, wherein each of the second and third regions, independently, comprises at least one 2′-O-methoxyethyl nucleoside, and wherein the internucleoside linkages of the first region are phosphorothioate linkages and the internucleoside linkages of the second and third regions are phosphodiester linkages except one or both of the extreme 5′ linkage and the extreme 3′ linkage are phosphorothioate linkages, so that expression of the RNA target is inhibited.