Selective antisense compounds and uses thereof

Abstract

The present invention provides oligomeric compounds. Certain such oligomeric compounds are useful for hybridizing to a complementary nucleic acid, including but not limited, to nucleic acids in a cell. In certain embodiments, hybridization results in modulation of the amount, activity, or expression of the target nucleic acid in a cell. In certain embodiments, hybridization results in selective modulation of the amount, activity, or expression of a target Huntingtin gene or Huntingtin transcript in a cell.

What is claimed is: 
     
         1 . A compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides, wherein the linked nucleosides comprise at least 8 contiguous nucleobases of a nucleobase sequence recited in SEQ ID NO: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, or 174-573. 
     
     
         2 . The compound of  claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is 90% complementary to SEQ ID NO. 1. 
     
     
         3 . The compound of  claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is 95% complementary to SEQ ID NO. 1. 
     
     
         4 . The compound of  claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is 100% complementary to SEQ ID NO. 1. 
     
     
         5 . The compound of any of  claims 1  to  4 , wherein the oligonucleotide has a sugar motif selected from among: eeedk-d7-keee; eeeedk-d7-eeee; eeeedk-d7-keee; eeeedk-d7-kkee; eeeee-d9-eeeee; eeeeedk-d7-eeeee; an eeeeeeeek-d7-eee; eeeeeeek-d7-eeee; eeeeek-d7-eee; eeeeek-d7-eeeeee; eeeeek-d7-kee; eeeeek-d7-kke; eeeek-d7-eeee; eeeek-d7-eeeeeee; eeeek-d7-keee; eeeek-d7-keeee; eeeek-d7-kke; eeeek-d7-kkee; eeeekk-d3-k-d3-keke; eeeekk-d7-kee; eeeekk-d7-keke; eeeekk-d7-kke; eeeekk-d7-kkee; eeek-d7-eeeeeeee; eeek-d7-keeeee; eeek-d7-kkee; eeek-d7-kkeee; eeek-d8-kee; eeek-d9-keee; eeek-d9-keke; eeekk-d7-eeee; eeekk-d7-keee; eeekk-d7-kke; eeekk-d7-kkee; eeekk-d7-kkeee; eek-d7-eeeeeeeee; eek-d7-keeeeee; eek-d7-kkeee; eek-d8-kkee; eekk-d8-kee; eekk-d8-kkee; eekk-d8-kkeee; ek-d7-eeeeeeeeee; ek-d8-kkeee; ek-d9-kkke; ekek-d6-k-dd-keke; ekek-d8-kkeke; ekek-d9-keee; ekek-d9-keke; ekekek-d7-keke; ekekk-d8-keke; ekk-d7-kkeee; ekk-d7-kkeeeee; ekk-d8-kkee; ekk-d8-kkeee; ekk-d8-kkeeee; ekk-d8-kkke; ekk-d9-kke; ekkdk-d7-kke; ekkk-d8-kke; ekkk-d9-ke; ekkkk-d7-kke; ekkkk-d7-kkke; kkekk-d9-kkekk; kkkkk-d7-kkkkk; ekkdk-d7-kke; ekek-d8-kekee; ekk-f-d8-kke; ekk-z-d8-kke; ekk-h-d8-kke; ekk-d2-h-d6-kke; ekk-d-h-d7-kke; ekk-d3-f-d5-kke; ekk-d3-z-d5-kke; ekk-d3-h-d5-kke; ekk-d4-h-d4-kke; ekk-d5-f-d3-kke; ekk-d5-z-d3-kke; ekk-d5-h-d3-kke; ekk-d6-f-d2-kke; ekk-d6-z-d2-kke; ekk-d6-h-d2-kke; ekk-d7-f-d-kke; ekk-d7-z-d-kke; ekk-d7-h-d-kke; ekk-d8-f-dkke; ekk-d8-z-kke; ekk-d8-h-kke; and ekk-d9-kke. 
     
     
         6 . A compound comprising an oligonucleotide, wherein the oligonucleotide has a sugar motif selected from among: eeedk-d7-keee; eeeedk-d7-eeee; eeeedk-d7-keee; eeeedk-d7-kkee; eeeee-d9-eeeee; eeeeedk-d7-eeeee; an eeeeeeeek-d7-eee; eeeeeeek-d7-eeee; eeeeek-d7-eee; eeeeek-d7-eeeeee; eeeeek-d7-kee; eeeeek-d7-kke; eeeek-d7-eeee; eeeek-d7-eeeeeee; eeeek-d7-keee; eeeek-d7-keeee; eeeek-d7-kke; eeeek-d7-kkee; eeeekk-d3-k-d3-keke; eeeekk-d7-kee; eeeekk-d7-keke; eeeekk-d7-kke; eeeekk-d7-kkee; eeek-d7-eeeeeeee; eeek-d7-keeeee; eeek-d7-kkee; eeek-d7-kkeee; eeek-d8-kee; eeek-d9-keee; eeek-d9-keke; eeekk-d7-eeee; eeekk-d7-keee; eeekk-d7-kke; eeekk-d7-kkee; eeekk-d7-kkeee; eek-d7-eeeeeeeee; eek-d7-keeeeee; eek-d7-kkeee; eek-d8-kkee; eekk-d8-kee; eekk-d8-kkee; eekk-d8-kkeee; ek-d7-eeeeeeeeee; ek-d8-kkeee; ek-d9-kkke; ekek-d6-k-dd-keke; ekek-d8-kkeke; ekek-d9-keee; ekek-d9-keke; ekekek-d7-keke; ekekk-d8-keke; ekk-d7-kkeee; ekk-d7-kkeeeee; ekk-d8-kkee; ekk-d8-kkeee; ekk-d8-kkeeee; ekk-d8-kkke; ekk-d9-kke; ekkdk-d7-kke; ekkk-d8-kke; ekkk-d9-ke; ekkkk-d7-kke; ekkkk-d7-kkke; kkekk-d9-kkekk; kkkkk-d7-kkkkk; ekkdk-d7-kke; ekek-d8-kekee; ekk-f-d8-kke; ekk-z-d8-kke; ekk-h-d8-kke; ekk-d2-h-d6-kke; ekk-d-h-d7-kke; ekk-d3-f-d5-kke; ekk-d3-z-d5-kke; ekk-d3-h-d5-kke; ekk-d4-h-d4-kke; ekk-d5-f-d3-kke; ekk-d5-z-d3-kke; ekk-d5-h-d3-kke; ekk-d6-f-d2-kke; ekk-d6-z-d2-kke; ekk-d6-h-d2-kke; ekk-d7-f-d-kke; ekk-d7-z-d-kke; ekk-d7-h-d-kke; ekk-d8-f-dkke; ekk-d8-z-kke; ekk-d8-h-kke; and ekk-d9-kke. 
     
     
         7 . The oligomeric compound of any of  claims 1  to  6  comprising at least one modified internucleoside linkage. 
     
     
         8 . The oligomeric compound of  claim 7  comprising at least one phosphorothioate internucleoside linkage. 
     
     
         9 . The oligomeric compound of  claim 8  wherein each internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         10 . The oligomeric compound of any of  claims 1  to  8  comprising at least one methylphosphonate internucleoside linkage. 
     
     
         11 . The oligomeric compound of any of  claims 1  to  10  comprising at least one modified nucleobase. 
     
     
         12 . The oligomeric compound of  claim 11 , comprising at least one 2-thio-thymidine. 
     
     
         13 . An oligomeric compound having a sugar motif of: eeeekk-d7-kke motif and having a nucleobase sequence consisting of the nucleobase sequence of SEQ ID NO.: 24. 
     
     
         14 . The oligomeric compound of any of  claims 1  to  13  comprising at least one 5′-Me-DNA modification. 
     
     
         15 . The oligomeric compound of  claim 14 , comprising an S-5′-Me-DNA. 
     
     
         16 . The oligomeric compound of  claim 15 , comprising an R-5′-Me-DNA. 
     
     
         17 . The oligomeric compound of any of  claims 1 - 16 , having a nucleobase sequence consisting of the nucleobase sequence of SEQ ID NO.: 3. 
     
     
         18 . The oligomeric compound of any of  claims 1  to  17 , having an EC 50  for reduction of expression of target that is at least two-fold lower than its EC 50  for reduction of expression of a non-target that differs from the target in the target region by a single nucleobase, when measured in cells. 
     
     
         19 . The oligomeric compound of any of  claims 1  to  18 , having an ED 50  for reduction of expression of target that is at least two-fold lower than its ED 50  for reduction of expression of a non-target that differs from the target in the target region by a single nucleobase, when measured in an animal. 
     
     
         20 . A pharmaceutical composition comprising an oligomeric compound of any of  claims 1 - 19  and a pharmaceutically acceptable carrier or diluent. 
     
     
         21 . A method comprising contacting a cell with an oligomeric compound of any of  claims 1 - 19 . 
     
     
         22 . The method of  claim 21 , wherein the cell is in vitro. 
     
     
         23 . The method of  claim 21 , wherein the cell is in an animal. 
     
     
         24 . The method of  claim 22 , wherein the animal is a human. 
     
     
         25 . The method of  claim 22 , wherein the animal is a mouse. 
     
     
         26 . A method of administering a pharmaceutical composition of  claim 20  to an animal. 
     
     
         27 . The method of  claim 26 , wherein the animal is a human. 
     
     
         28 . The method of  claim 26 , wherein the animal is a mouse. 
     
     
         29 . Use of an oligomeric compound of any of  claims 1 - 19  for the preparation of a medicament for the treatment or amelioration of Huntington's disease. 
     
     
         30 . A method of ameliorating a symptom of Huntington's disease, comprising administering an oligomeric compound of any of  claims 1 - 19  to an animal in need thereof. 
     
     
         31 . The method of  claim 30 , wherein the animal is a human. 
     
     
         32 . The method of  claim 30 , wherein the animal is a mouse. 
     
     
         33 . A method for reducing the rate of progression of a symptom associated with Huntington's Disease, comprising administering to a human in need thereof a compound of any of  claims 1 - 19 , and thereby reducing the rate of progression a symptom of Huntington's disease in the human. 
     
     
         34 . A method for reversing degeneration indicated by a symptom associated with Huntington's disease, comprising administering to a human in need thereof a compound of any of  claims 1 - 19 , and thereby reversing degeneration indicated by a symptom of Huntington's disease in the human. 
     
     
         35 . A method for treating a human with Huntington's disease comprising identifying the human with the disease and administering to the human a therapeutically effective amount of the compound of any of  claims 1 - 19 . 
     
     
         36 . The method of embodiment 35, wherein the treatment reduces at least one of restlessness, lack of coordination, unintentionally initiated motions, unintentionally uncompleted motions, unsteady gait, chorea, rigidity, writhing motions, abnormal posturing, instability, abnormal facial expressions, difficulty chewing, difficulty swallowing, difficulty speaking, seizure, sleep disturbances, impaired planning, impaired flexibility, impaired abstract thinking, impaired rule acquisition, impaired initiation of appropriate actions, impaired inhibition of inappropriate actions, impaired short-term memory, impaired long-term memory, paranoia, disorientation, confusion, hallucination, dementia, a anxiety, depression, blunted affect, egocentrisms, aggression, compulsive behavior, irritability, suicidal ideation, reduced brain mass, muscle atrophy, cardiac failure, impaired glucose tolerance, weight loss, osteoporosis, and testicular atrophy in the human. 
     
     
         37 . A method for reducing the rate of progression of a symptom associated with Huntington's Disease, comprising administering to a human in need thereof ISIS 572772, and thereby reducing the rate of progression a symptom of Huntington's disease in the human. 
     
     
         38 . A method for reversing degeneration indicated by a symptom associated with Huntington's disease, comprising administering to a human in need thereof ISIS 572772, and thereby reversing degeneration indicated by a symptom of Huntington's disease in the human. 
     
     
         39 . A method for treating a human with Huntington's disease comprising identifying the human with the disease and administering to the human a therapeutically effective amount of ISIS 572772. 
     
     
         40 . The method of embodiment 39, wherein the treatment reduces at least one of restlessness, lack of coordination, unintentionally initiated motions, unintentionally uncompleted motions, unsteady gait, chorea, rigidity, writhing motions, abnormal posturing, instability, abnormal facial expressions, difficulty chewing, difficulty swallowing, difficulty speaking, seizure, sleep disturbances, impaired planning, impaired flexibility, impaired abstract thinking, impaired rule acquisition, impaired initiation of appropriate actions, impaired inhibition of inappropriate actions, impaired short-term memory, impaired long-term memory, paranoia, disorientation, confusion, hallucination, dementia, a anxiety, depression, blunted affect, egocentrisms, aggression, compulsive behavior, irritability, suicidal ideation, reduced brain mass, muscle atrophy, cardiac failure, impaired glucose tolerance, weight loss, osteoporosis, and testicular atrophy in the human.