Antisense modulation of PTP1B expression

Abstract

Compounds, compositions and methods are provided for modulating the expression of PTP1B. The compositions comprise antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding PTP1B. Methods of using these compounds for modulation of PTP1B expression and for treatment of diseases associated with expression of PTP1B are provided.

1 . A compound 8 to 50 nucleobases in length targeted to a nucleic acid molecule encoding PTP1B (SEQ ID NO: 3 or 243), wherein said compound comprises a sense region and an antisense region, said antisense region comprising comprising a stretch of at least eight (8) consecutive nucleobases of SEQ ID NO: 18, 19, 20, 21, 22, 23, 24, 26, 27, 29, 30, 32, 33, 35, 36, 38, 39, 40, 42, 45, 46, 47, 48, 49, 50, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 72, 73, 75, 78, 79, 80, 81, 83, 84, 86, 87, 89, 90, 92, 93, 94, 95, 96, 97, 99, 100, 101, 102, 103, 104, 106, 107, 108, 109, 110, 112, 113, 114, 115, 117, 120, 121, 122, 123, 124, 126, 127, 128, 130, 131, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 144, 145, 146, 147, 148, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 191, 193, 195, 196, 198, 201, 202, 204, 205, 206, 211, 215, 217, 219, 223, 225, 226, 228, 229, 230, 232, 233, 235, 236, 237, 239, 240, 244, 245, 247, 248, 249, 250, 251, 252, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 267, 268, 269, 271, 275, 276, 277, 278, 279, 281, 282, 283, 288, 290, 291, 292, 294, 296, 297, 298, 299, 300, 302, 303, 307, 310, 311, 313, 315, 317, 318, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 337, 340, 341, 342, 343, 344, 345, 347, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 360, 361, 362, 363, 364, 365, 366, 368, 369, 371, 372, 373, 374, 375, 377, 378, 380, 381, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, or 398 wherein said compound specifically hybridizes with said nucleic acid molecule encoding PTP1B and inhibits the expression of PTP1B.  
     
     
         2 . The compound of  claim 1  wherein said antisense region comprises a stretch of at least eight (8) consecutive nucleobases of SEQ ID NO: 390, 391, 392, 393, 394, 395, 396, 397, or 398.  
     
     
         3 . The compound of  claim 2  wherein said sense region comprises a sequence complementary to said antisense region selected from sequences comprising a stretch of at least eight (8) consecutive nucleobases of SEQ ID NO: 403, 404, 405, 406, 407, 408, 409, 410, or 411  
     
     
         4 . The compound of  claim 1  wherein said antisense region comprises a stretch of at least eight (8) consecutive nucleobases of nucleobases 1 to 19 of SEQ ID NO: 390, 391, 392, 393, 394, or 395.  
     
     
         5 . The compound of  claim 4  wherein said sense region comprises a sequence complementary to said antisense region selected from sequences comprising a stretch of at least eight (8) consecutive nucleobases of nucleobases 1 to 19 of SEQ ID NO: 403, 404, 405, 406, 407, or 408  
     
     
         6 . The compound of  claim 1  wherein said antisense region comprises a stretch of at least eight (8) consecutive nucleobases of SEQ ID NO: 396, 397, or 398.  
     
     
         7 . The compound of  claim 6  wherein said sense region comprises a sequence complementary to said antisense region selected from sequences comprising a stretch of at least eight (8) consecutive nucleobases of SEQ ID NO: 409, 410, or 411.  
     
     
         8 . The compound of  claim 1  wherein the compound is a RNA oligonucleotide.  
     
     
         9 . The compound of  claim 2  wherein the compound is a RNA oligonucleotide.  
     
     
         10 . The compound of  claim 4  wherein the compound is a RNA oligonucleotide.  
     
     
         11 . The compound of  claim 6  wherein the compound is a RNA oligonucleotide.  
     
     
         12 . The compound of  claim 1  wherein said antisense strand further comprises an overhang of two deoxynucleotides at one or both termini.  
     
     
         13 . The compound of  claim 1  wherein said sense strand further comprises an overhang of two deoxynucleotides at one or both termini.  
     
     
         14 . The compound of  claim 2  wherein said antisense strand further comprises an overhang of two deoxynucleotides at one or both termini.  
     
     
         15 . The compound of  claim 2  wherein said sense strand further comprises an overhang of two deoxynucleotides at one or both termini.  
     
     
         16 . The compound of  claim 1  further comprising at least one modified internucleoside linkage.  
     
     
         17 . The compound of  claim 16  wherein the modified internucleoside linkage is a phosphorothioate linkage.  
     
     
         18 . The compound of  claim 1  further comprising at least one modified sugar moiety.  
     
     
         19 . The compound of  claim 1  further comprising at least one modified nucleobase.  
     
     
         20 . The compound of  claim 1 , wherein said compound is chimeric.  
     
     
         21 . The compound of  claim 1  wherein said antisense region and said sense region are part of a single molecule.  
     
     
         22 . The compound of  claim 1  wherein said antisense region and said sense region are on separate molecules.  
     
     
         23 . A composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier, diluent, enhancer or excipient.  
     
     
         24 . A method of inhibiting the expression of PTP1B in cells or tissues comprising contacting said cells or tissues with the compound of  claim 1  so that expression of PTP1B is inhibited.