US2010316615A1PendingUtilityA1

Antisense Oligonucleotides Against VR1

56
Assignee: GRUENENTHAL GMBHPriority: Sep 2, 2000Filed: Dec 23, 2009Published: Dec 16, 2010
Est. expirySep 2, 2020(expired)· nominal 20-yr term from priority
Inventors:Jens KurreckVolker Erdmann
A61P 35/00A61P 29/00A61P 25/02A61P 17/00C12N 15/1138A61P 17/04C12N 2310/121C12N 2310/12A61P 13/00A61P 13/06A61K 48/00A61K 38/00C12N 2310/3231C12N 2310/315
56
PatentIndex Score
0
Cited by
0
References
0
Claims

Abstract

Antisense oligodeoxynucleotides against VR1, corresponding nucleotide constructs, cells containing said nucleotide constructs, pharmaceutical and diagnostic substances, uses thereof in pain therapy, and methods for diagnosing symptoms related to VR1 and for identifying pain-modulating substances.

Claims

exact text as granted — not AI-modified
1 . An oligonucleotide comprising the sequence according to one of SEQ ID NOs 19-27, SEQ ID NOs 30-38, SEQ ID NOs 47-55, SEQ ID NOs 64-72, SEQ ID NOs 81-89, SEQ ID NOs 98-106, SEQ ID NOs 115-123, SEQ ID NOs 132-140, SEQ ID NOs 149-157, SEQ ID NOs 160-168, SEQ ID NOs 178-186, SEQ ID NOs 195-203, SEQ ID NOs 212-220, SEQ ID NOs 223-231 or SEQ ID NOs 240-248, wherein each of SEQ ID NOs 19-27 comprises a sequence domain of SEQ ID NO 18, each of SEQ ID NOs 30-38 comprises a sequence domain of SEQ ID NO 29, each of SEQ ID NOs 47-55 comprises a sequence domain of SEQ ID NO 46, each of SEQ ID NOs 64-72 comprises a sequence domain of SEQ ID NO 63, each of SEQ ID NOs 81-89 comprises a sequence domain of SEQ ID NO 80, each of SEQ ID NOs 98-106 comprises a sequence domain of SEQ ID NO 97, each of SEQ ID NOs 115-123 comprises a sequence domain of SEQ ID NO 114, each of SEQ ID NOs 132-140 comprises a sequence domain of SEQ ID NO 131, each of SEQ ID NOs 149-157 comprises a sequence domain of SEQ ID NO 148, each of SEQ ID NOs 160-168 comprises a sequence domain of SEQ ID NO 159, each of SEQ ID NOs 178-186 comprises a sequence domain of SEQ ID NO 177, each of SEQ ID NOs 195-203 comprises a sequence domain of SEQ ID NO 194, each of SEQ ID NOs 212-220 comprises a sequence domain of SEQ ID NO 211, each of SEQ ID NOs 223-231 comprises a sequence domain of SEQ ID NO 222, or each of SEQ ID NOs 240-248 comprises a sequence domain of SEQ ID NO 239. 
     
     
         2 . An oligonucleotide according to  claim 1 , comprising
 (1) a base sequence according to SEQ ID NOs 28, 56, 73, 90, 107, 124, 141, 158, 169, 187, 204, 221, 232, or 249, or   (2) a sequence differing from (1) by at most two different bases not located in the sequence according to SEQ ID NO 18, 46, 63, 80, 97, 114, 131, 148, 159, 177, 194, 211, 222, or 239, respectively.   
     
     
         3 . An anti-sense oligonucleotide 15 to 30 nucleotides in length and comprising
 (1) the sequence according to one of SEQ ID NOs 19-27, SEQ ID NOs 47-55, SEQ ID NOs 64-72, SEQ ID NOs 81-89, SEQ ID NOs 98-106, SEQ ID NOs 115-123, SEQ ID NOs 132-140, SEQ ID NOs 149-157, SEQ ID NOs 160-168, SEQ ID NOs 178-186, SEQ ID NOs 195-203, SEQ ID NOs 212-220, SEQ ID NOs 223-231 or SEQ ID NOs 240-248, or   (2) a sequence differing from (1) by one different base not located in the sequence according to SEQ ID NO 18, 46, 63, 80, 97, 114, 131, 148, 159, 177, 194, 211, 222 or 239, respectively.   
     
     
         4 . An anti-sense oligonucleotide according to  claim 2 , wherein the oligonucleotide is SEQ ID NO 28, 56, 73, 90, 107, 124, 141, 158, 169, 187, 204, 221, 232, or 249. 
     
     
         5 . An anti-sense oligonucleotide selected from the group consisting of SEQ ID NOs 12-17, SEQ ID NOs 18-28, SEQ ID NOs 29-45, SEQ ID NOs 46-62, SEQ ID NOs 131-147, SEQ ID NOs 148-158, SEQ ID NOs 159-176, SEQ ID NOs 177-193, SEQ ID NOs 222-238, and SEQ ID NOs 239-249. 
     
     
         6 . An oligonucleotide according to  claim 5 , wherein the oligonucleotide is selected from the group consisting of SEQ ID NOs 12-17, SEQ ID NOs 18-28, SEQ ID NOs 29-45, SEQ ID NOs 46-62, SEQ ID NOs 159-176 and SEQ ID NOs 177-193. 
     
     
         7 . An oligonucleotide according to  claim 5 , wherein the oligonucleotide is selected from the group consisting of SEQ ID NOs 12-17, SEQ ID NOs 29-45 and SEQ ID NOs 159-176. 
     
     
         8 . An oligonucleotide according to  claim 5 , wherein the oligonucleotide is selected from the group consisting of SEQ ID NOs 12-17 and SEQ ID NOs 29-45. 
     
     
         9 . An oligonucleotide according to  claim 1 , wherein at least one of the nucleotides is a “locked nucleic acid” (LNA), and wherein more than 6 contiguous nucleotides in the oligonucleotide are not LNA's, and wherein the more than 6 contiguous nucleotides that are not LNAs are in the sequence domain of SEQ ID NO 18, 29, 46, 63, 80, 97, 114, 131, 148, 159, 177, 194, 211, 222 or 239. 
     
     
         10 . A polynucleotide construct comprising at least one oligonucleotide according to  claim 1 . 
     
     
         11 . A polynucleotide construct comprising, in two separate domains, Fragment I and Fragment III according to one of SEQ ID NOs 12-14, SEQ ID NOs 40-42, SEQ ID NOs 57-59, SEQ ID NOs 74-76, SEQ ID NOs 91-93, SEQ ID NOs 108-110, SEQ ID NOs 125-127, SEQ ID NOs 1452-144, SEQ ID NOs 170, 172 and 173, SEQ ID NOs 188-190, SEQ ID NOs 205-207, or SEQ ID NOs 233-235, or helix I and helix III according to one of SEQ ID NOs 15-17, SEQ ID NOs 43-45, SEQ ID NOs 60-62, SEQ ID NOs 77-79, SEQ ID NOs 94-96, SEQ ID NOs 11-113, SEQ ID NOs 128-130, SEQ ID NOs 145-147, SEQ ID NOs 174-176, SEQ ID NOs 191-193, SEQ ID NOs 208-210 or SEQ ID NOs 236-238. 
     
     
         12 . A ribozyme comprising an oligonucleotide of  claim 1 , comprising helix I and helix III according to one of SEQ ID NOs 15-17, SEQ ID NOs 43-45, SEQ ID NOs 60-62, SEQ ID NOs 77-79, SEQ ID NOs 94-96, SEQ ID NOs 128-130, SEQ ID NOs 174-176 or SEQ ID NOs 191-193. 
     
     
         13 . A ribozyme according to  claim 12 , comprising helix I and helix III according to SEQ ID NO 15, 43, 60, 77, 94, 128, 174 or 191. 
     
     
         14 . A ribozyme according to  claim 12 , comprising helix I and helix III according to one of SEQ ID NOs 15-17, SEQ ID NOs 43-45 or SEQ ID NOs 174-176. 
     
     
         15 . A ribozyme according to  claim 12 , comprising helix I and helix III according to one of SEQ ID NOs 60-62, SEQ ID NOs 94-96, SEQ ID NOs 128-130 or SEQ ID NOs 191-193. 
     
     
         16 . A DNA enzyme comprising an oligonucleotide of  claim 1 , comprising Fragment I and Fragment III according to one of SEQ ID NOs 12-14, SEQ ID NOs 40-42, SEQ ID NOs 57-59, SEQ ID NOs 74-76, SEQ ID NOs 91-93, SEQ ID NOs 108-110, SEQ ID NOs 125-127, SEQ ID NOs 1452-144, SEQ ID NOs 170, 172 and 173, SEQ ID NOs 188-190 or SEQ ID NOs 205-207. 
     
     
         17 . A DNA enzyme according to  claim 16 , comprising Fragment I and Fragment III according to one of SEQ ID NOs 12-14, SEQ ID NOs 40-42, SEQ ID NOs 108-110 or SEQ ID NOs 170, 172 and 173. 
     
     
         18 . A DNA enzyme according to  claim 16 , comprising Fragment I and Fragment III according to one of SEQ ID NOs 57-59, SEQ ID NOs 91-93, SEQ ID NOs 125-127 or SEQ ID NOs 188-190. 
     
     
         19 . A DNA enzyme according to  claim 16 , comprising Fragment I and Fragment III according to SEQ ID NO 14, 42, 59, 76, 93, 110, 127, 144, 173, 190 or 207. 
     
     
         20 . A method for the treatment of pain, comprising administering an effective amount of a pharmaceutical composition comprising at least one oligonucleotide comprising the sequence according to one of SEQ ID NOs 2-10, SEQ ID NOs 19-27, SEQ ID NOs 30-38, SEQ ID NOs 47-55, SEQ ID NOs 64-72, SEQ ID NOs 81-89, SEQ ID NOs 98-106, SEQ ID NOs 115-123, SEQ ID NOs 132-140, SEQ ID NOs 149-157, SEQ ID NOs 160-168, SEQ ID NOs 178-186, SEQ ID NOs 195-203, SEQ ID NOs 212-220, SEQ ID NOs 223-231 or SEQ ID NOs 240-248, wherein each of SEQ ID NOs 2-10 comprises a sequence domain of SEQ ID NO 1, each of SEQ ID NOs 19-27 comprises a sequence domain of SEQ ID NO 18, each of SEQ ID NOs 30-38 comprises a sequence domain of SEQ ID NO 29, each of SEQ ID NOs 47-55 comprises a sequence domain of SEQ ID NO 46, each of SEQ ID NOs 64-72 comprises a sequence domain of SEQ ID NO 63, each of SEQ ID NOs 81-89 comprises a sequence domain of SEQ ID NO 80, each of SEQ ID NOs 98-106 comprises a sequence domain of SEQ ID NO 97, each of SEQ ID NOs 115-123 comprises a sequence domain of SEQ ID NO 114, each of SEQ ID NOs 132-140 comprises a sequence domain of SEQ ID NO 131, each of SEQ ID NOs 149-157 comprises a sequence domain of SEQ ID NO 148, each of SEQ ID NOs 160-168 comprises a sequence domain of SEQ ID NO 159, each of SEQ ID NOs 178-186 comprises a sequence domain of SEQ ID NO 177, each of SEQ ID NOs 195-203 comprises a sequence domain of SEQ ID NO 194, each of SEQ ID NOs 212-220 comprises a sequence domain of SEQ ID NO 211, each of SEQ ID NOs 223-231 comprises a sequence domain of SEQ ID NO 222, or each of SEQ ID NOs 240-248 comprises a sequence domain of SEQ ID NO 239, and a pharmaceutically acceptable carrier, to a patient in need thereof. 
     
     
         21 . A method according to  claim 20 , for the treatment of chronic pain selected from the group consisting of tactile allodynia, thermally induced pain and inflammatory pain. 
     
     
         22 . A method for the treatment of urinary incontinence, neurogenic bladder symptoms; pruritus; or tumors, comprising administering an effective amount of a pharmaceutical composition comprising at least one oligonucleotide comprising the sequence according to one of SEQ ID NOs 2-10, SEQ ID NOs 19-27, SEQ ID NOs 30-38, SEQ ID NOs 47-55, SEQ ID NOs 64-72, SEQ ID NOs 81-89, SEQ ID NOs 98-106, SEQ ID NOs 115-123, SEQ ID NOs 132-140, SEQ ID NOs 149-157, SEQ ID NOs 160-168, SEQ ID NOs 178-186, SEQ ID NOs 195-203, SEQ ID NOs 212-220, SEQ ID NOs 223-231 or SEQ ID NOs 240-248, wherein each of SEQ ID NOs 2-10 comprises a sequence domain of SEQ ID NO 1, each of SEQ ID NOs 19-27 comprises a sequence domain of SEQ ID NO 18, each of SEQ ID NOs 30-38 comprises a sequence domain of SEQ ID NO 29, each of SEQ ID NOs 47-55 comprises a sequence domain of SEQ ID NO 46, each of SEQ ID NOs 64-72 comprises a sequence domain of SEQ ID NO 63, each of SEQ ID NOs 81-89 comprises a sequence domain of SEQ ID NO 80, each of SEQ ID NOs 98-106 comprises a sequence domain of SEQ ID NO 97, each of SEQ ID NOs 115-123 comprises a sequence domain of SEQ ID NO 114, each of SEQ ID NOs 132-140 comprises a sequence domain of SEQ ID NO 131, each of SEQ ID NOs 149-157 comprises a sequence domain of SEQ ID NO 148, each of SEQ ID NOs 160-168 comprises a sequence domain of SEQ ID NO 159, each of SEQ ID NOs 178-186 comprises a sequence domain of SEQ ID NO 177, each of SEQ ID NOs 195-203 comprises a sequence domain of SEQ ID NO 194, each of SEQ ID NOs 212-220 comprises a sequence domain of SEQ ID NO 211, each of SEQ ID NOs 223-231 comprises a sequence domain of SEQ ID NO 222, or each of SEQ ID NOs 240-248 comprises a sequence domain of SEQ ID NO 239, and a pharmaceutically acceptable carrier, to a patient in need thereof. 
     
     
         23 . A method for the treatment of vanilloid receptor subtype 1 (VR1)-associated disease, comprising administering an effective amount of a pharmaceutical composition comprising at least one oligonucleotide comprising the sequence according to one of SEQ ID NOs 2-10, SEQ ID NOs 19-27, SEQ ID NOs 30-38, SEQ ID NOs 47-55, SEQ ID NOs 64-72, SEQ ID NOs 81-89, SEQ ID NOs 98-106, SEQ ID NOs 115-123, SEQ ID NOs 132-140, SEQ ID NOs 149-157, SEQ ID NOs 160-168, SEQ ID NOs 178-186, SEQ ID NOs 195-203, SEQ ID NOs 212-220, SEQ ID NOs 223-231 or SEQ ID NOs 240-248, wherein each of SEQ ID NOs 2-10 comprises a sequence domain of SEQ ID NO 1, each of SEQ ID NOs 19-27 comprises a sequence domain of SEQ ID NO 18, each of SEQ ID NOs 30-38 comprises a sequence domain of SEQ ID NO 29, each of SEQ ID NOs 47-55 comprises a sequence domain of SEQ ID NO 46, each of SEQ ID NOs 64-72 comprises a sequence domain of SEQ ID NO 63, each of SEQ ID NOs 81-89 comprises a sequence domain of SEQ ID NO 80, each of SEQ ID NOs 98-106 comprises a sequence domain of SEQ ID NO 97, each of SEQ ID NOs 115-123 comprises a sequence domain of SEQ ID NO 114, each of SEQ ID NOs 132-140 comprises a sequence domain of SEQ ID NO 131, each of SEQ ID NOs 149-157 comprises a sequence domain of SEQ ID NO 148, each of SEQ ID NOs 160-168 comprises a sequence domain of SEQ ID NO 159, each of SEQ ID NOs 178-186 comprises a sequence domain of SEQ ID NO 177, each of SEQ ID NOs 195-203 comprises a sequence domain of SEQ ID NO 194, each of SEQ ID NOs 212-220 comprises a sequence domain of SEQ ID NO 211, each of SEQ ID NOs 223-231 comprises a sequence domain of SEQ ID NO 222, or each of SEQ ID NOs 240-248 comprises a sequence domain of SEQ ID NO 239, and a pharmaceutically acceptable carrier, to a patient in need thereof. 
     
     
         24 . A method according to  claim 23 , wherein the VR1 receptor-associated disease is inflammation. 
     
     
         25 . A gene therapy method comprising administering to a patient in need thereof an effective amount of an oligonucleotide comprising the sequence according to one of SEQ ID NOs 2-10, SEQ ID NOs 19-27, SEQ ID NOs 30-38, SEQ ID NOs 47-55, SEQ ID NOs 64-72, SEQ ID NOs 81-89, SEQ ID NOs 98-106, SEQ ID NOs 115-123, SEQ ID NOs 132-140, SEQ ID NOs 149-157, SEQ ID NOs 160-168, SEQ ID NOs 178-186, SEQ ID NOs 195-203, SEQ ID NOs 212-220, SEQ ID NOs 223-231 or SEQ ID NOs 240-248, wherein each of SEQ ID NOs 2-10 comprises a sequence domain of SEQ ID NO 1, each of SEQ ID NOs 19-27 comprises a sequence domain of SEQ ID NO 18, each of SEQ ID NOs 30-38 comprises a sequence domain of SEQ ID NO 29, each of SEQ ID NOs 47-55 comprises a sequence domain of SEQ ID NO 46, each of SEQ ID NOs 64-72 comprises a sequence domain of SEQ ID NO 63, each of SEQ ID NOs 81-89 comprises a sequence domain of SEQ ID NO 80, each of SEQ ID NOs 98-106 comprises a sequence domain of SEQ ID NO 97, each of SEQ ID NOs 115-123 comprises a sequence domain of SEQ ID NO 114, each of SEQ ID NOs 132-140 comprises a sequence domain of SEQ ID NO 131, each of SEQ ID NOs 149-157 comprises a sequence domain of SEQ ID NO 148, each of SEQ ID NOs 160-168 comprises a sequence domain of SEQ ID NO 159, each of SEQ ID NOs 178-186 comprises a sequence domain of SEQ ID NO 177, each of SEQ ID NOs 195-203 comprises a sequence domain of SEQ ID NO 194, each of SEQ ID NOs 212-220 comprises a sequence domain of SEQ ID NO 211, each of SEQ ID NOs 223-231 comprises a sequence domain of SEQ ID NO 222, or each of SEQ ID NOs 240-248 comprises a sequence domain of SEQ ID NO 239. 
     
     
         26 . A gene therapy method according to  claim 25 , which is an in vitro gene therapy. 
     
     
         27 . A gene therapy method according to  claim 25 , which is an in vivo gene therapy. 
     
     
         28 . A gene therapy method according to  claim 25 , wherein the oligonucleotide is comprised in an expression vector. 
     
     
         29 . A gene therapy method according to  claim 25 , wherein the expression vector is comprised in a cell. 
     
     
         30 . A process for the identification of pain-modulating substances comprising the following process steps:
 (a) providing a test cell which comprises at least one oligonucleotide comprising the sequence according to one of SEQ ID NOs 2-10, SEQ ID NOs 19-27, SEQ ID NOs 30-38, SEQ ID NOs 47-55, SEQ ID NOs 64-72, SEQ ID NOs 81-89, SEQ ID NOs 98-106, SEQ ID NOs 115-123, SEQ ID NOs 132-140, SEQ ID NOs 149-157, SEQ ID NOs 160-168, SEQ ID NOs 178-186, SEQ ID NOs 195-203, SEQ ID NOs 212-220, SEQ ID NOs 223-231 or SEQ ID NOs 240-248, wherein each of SEQ ID NOs 2-10 comprises a sequence domain of SEQ ID NO 1, each of SEQ ID NOs 19-27 comprises a sequence domain of SEQ ID NO 18, each of SEQ ID NOs 30-38 comprises a sequence domain of SEQ ID NO 29, each of SEQ ID NOs 47-55 comprises a sequence domain of SEQ ID NO 46, each of SEQ ID NOs 64-72 comprises a sequence domain of SEQ ID NO 63, each of SEQ ID NOs 81-89 comprises a sequence domain of SEQ ID NO 80, each of SEQ ID NOs 98-106 comprises a sequence domain of SEQ ID NO 97, each of SEQ ID NOs 115-123 comprises a sequence domain of SEQ ID NO 114, each of SEQ ID NOs 132-140 comprises a sequence domain of SEQ ID NO 131, each of SEQ ID NOs 149-157 comprises a sequence domain of SEQ ID NO 148, each of SEQ ID NOs 160-168 comprises a sequence domain of SEQ ID NO 159, each of SEQ ID NOs 178-186 comprises a sequence domain of SEQ ID NO 177, each of SEQ ID NOs 195-203 comprises a sequence domain of SEQ ID NO 194, each of SEQ ID NOs 212-220 comprises a sequence domain of SEQ ID NO 211, each of SEQ ID NOs 223-231 comprises a sequence domain of SEQ ID NO 222, or each of SEQ ID NOs 240-248 comprises a sequence domain of SEQ ID NO 239,   (b) providing a control cell that does not comprise said oligonucleotide,   (c) incubating a candidate substance under suitable conditions with the test cell, or a preparation made from the test cell, which has synthesized at least one vanilloid receptor,   (d) measuring the binding of the test substance to the receptor synthesized by the test cell, or measuring at least one functional parameter of the receptor modified by binding of the test substance onto the receptor,   (e) measuring the binding of the test substance to the receptor synthesized by the control cell, or measuring at least one functional parameter of the receptor modified by binding of the test substance onto the receptor,   (d) identifying a substance by a difference between the measured value for the test cell and that for the control cell.   
     
     
         31 . A method according to  claim 30 , wherein the vanilloid receptor is a VR-1 receptor.

Join the waitlist — get patent alerts

Track US2010316615A1 — get alerts on status changes and closely related new filings.

We store only your email — no account needed. See our privacy policy.