US2003191080A1PendingUtilityA1

Antisense compositions targeted to beta1-adrenoceptor-specific mRNA and methods of use

53
Assignee: UNIV FLORIDAPriority: Sep 14, 1998Filed: Dec 3, 2002Published: Oct 9, 2003
Est. expirySep 14, 2018(expired)· nominal 20-yr term from priority
Inventors:M. PhillipsYuan Zhang
C12N 2310/111A61P 43/00A61K 38/00A61P 9/12A61P 9/00C12N 15/1138A61P 9/10C12N 2310/3181C12N 2310/315
53
PatentIndex Score
0
Cited by
0
References
0
Claims

Abstract

Disclosed are antisense oligonucleotide, polynucleotide, and peptide nucleic acid compounds that specifically bind to mammalian mRNA encoding a β 1 -adrenoceptor polypeptide and that are useful in the control and/or treatment of cardiac dysfunction, hypertension, hypertrophy, myocardial ischemia, and other cardiovascular diseases in an affected mammal, and preferably, in a human subject. The antisense compounds disclosed herein, and pharmaceutical formulations thereof, provide sustained control of β 1 -adrenoceptor expression over prolonged periods, and achieve therapeutic effects from as little as a single dose. Administration of these antisense compositions to approved animal models resulted in a decrease in blood pressure, but no significant change in heart rate. Use of such antisense compositions in the reduction of β 1 -adrenoceptor polypeptides in a host cell expressing β 1 -adrenoceptor-specific mRNA, and in the preparation of medicaments for treating human and animal diseases, and in particular, hypertension and other cardiac dysfunction is also disclosed.

Claims

exact text as granted — not AI-modified
What is claimed is:  
     
         1 . An isolated antisense oligonucleotide at least 9 to about 35 nucleotides in length, wherein said oligonucleotide specifically binds to a portion of an mRNA expressed from a gene encoding a mammalian β 1 -adrenoceptor polypeptide, and further wherein binding of said oligonucleotide to said mRNA is effective in altering the translation of said mRNA into said β 1 -adrenoceptor polypeptide in a host cell expressing said mRNA.  
     
     
         2 . The oligonucleotide of  claim 1 , comprising deoxyribonucleic acid, ribonucleic acid, or peptide-nucleic acid.  
     
     
         3 . The oligonucleotide of  claim 2 , comprising a derivatized deoxyribonucleic acid, ribonucleic acid, or peptide-nucleic acid.  
     
     
         4 . The oligonucleotide of  claim 3 , comprising a phosphorothioated deoxyribonucleic acid, ribonucleic acid, or peptide-nucleic acid derivative.  
     
     
         5 . The oligonucleotide of  claim 1 , comprising a sequence of at least nine contiguous bases from any one of SEQ ID NO:4 through SEQ ID NO: 186.  
     
     
         6 . The oligonucleotide of  claim 5 , comprising a sequence of at least ten contiguous bases from any one of SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID, NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, or any one of SEQ ID NO:93 through SEQ ID NO:186.  
     
     
         7 . The oligonucleotide of  claim 6 , comprising a sequence of at least thirteen contiguous bases from any one of SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:ll, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, or any one of SEQ ID NO:93 through SEQ ID NO: 186.  
     
     
         8 . The oligonucleotide of  claim 7 , comprising a sequence of at least sixteen contiguous bases from any one of SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:1, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, or any one of SEQ ID NO: 111 through SEQ ID NO: 186.  
     
     
         9 . The oligonucleotide of  claim 8 , comprising a sequence of at least eighteen contiguous bases from any one of SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:ll, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, or any one of SEQ ID NO:127 through SEQ ID NO:186.  
     
     
         10 . The oligonucleotide of  claim 9 , comprising a sequence of at least twenty contiguous bases from any one of SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:1, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, or any one of SEQ ID NO:147 through SEQ ID NO:186.  
     
     
         11 . The oligonucleotide of  claim 10 , comprising a sequence of at least twenty-two contiguous bases from any one of SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, or any one of SEQ ID NO:166 through SEQ ID NO:186.  
     
     
         12 . The oligonucleotide of  claim 11 , comprising a sequence of at least twenty-four contiguous bases from any one of SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:181, SEQ ID NO:182, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185 or SEQ ID NO:186.  
     
     
         13 . The oligonucleotide of  claim 12 , comprising a sequence of at least twenty-seven contiguous bases from any one of SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, or SEQ ID NO:28.  
     
     
         14 . The oligonucleotide of  claim 13 , comprising a sequence of at least thirty contiguous bases from any one of SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:ll, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, or SEQ ID NO:28.  
     
     
         15 . The oligonucleotide of  claim 14 , comprising the sequence of any one of SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, or SEQ ID NO:13.  
     
     
         16 . The oligonucleotide of  claim 14 , comprising the sequence of any one of SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, or SEQ ID NO:23.  
     
     
         17 . The oligonucleotide of  claim 14 , comprising the sequence of any one of SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, or SEQ ID NO:28.  
     
     
         18 . The oligonucleotide of  claim 1 , wherein said oligonucleotide is at least 90% complementary to the portion of the mRNA sequence to which it specifically binds.  
     
     
         19 . The oligonucleotide of  claim 18 , wherein said oligonucleotide is at least 95% complementary to the portion of the mRNA sequence to which it specifically binds.  
     
     
         20 . The oligonucleotide of  claim 19 , wherein said oligonucleotide is at least 98% complementary to the portion of the mRNA sequence to which it specifically binds.  
     
     
         21 . The oligonucleotide of  claim 1 , wherein said oligonucleotide has no more than one nucleotide for every nine contiguous nucleotides that is non-complementary to the portion of the mRNA sequence to which it specifically binds.  
     
     
         22 . The oligonucleotide of  claim 21 , wherein said oligonucleotide has no more than one nucleotide for every ten contiguous nucleotides that is non-complementary to the portion of the mRNA sequence to which it specifically binds.  
     
     
         23 . The oligonucleotide of  claim 22 , wherein said oligonucleotide has no more than one nucleotide for every eleven contiguous nucleotides that is non-complementary to the portion of the mRNA sequence to which it specifically binds.  
     
     
         24 . The oligonucleotide of  claim 23 , wherein said oligonucleotide has no more than one nucleotide for every twelve contiguous nucleotides that is non-complementary to the portion of the mRNA sequence to which it specifically binds.  
     
     
         25 . The oligonucleotide of  claim 1 , wherein said host cell is a mammalian host cell.  
     
     
         26 . The oligonucleotide of  claim 25 , wherein said host cell is a human cell.  
     
     
         27 . The oligonucleotide of  claim 1 , wherein said host cell is comprised within a human.  
     
     
         28 . The oligonucleotide of  claim 1 , wherein said oligonucleotide is at least 9 to about 30 bases in length.  
     
     
         29 . The oligonucleotide of  claim 28 , wherein said oligonucleotide is at least 9 to about 25 bases in length.  
     
     
         30 . The oligonucleotide of  claim 29 , wherein said oligonucleotide is at least 9 to about 20 bases in length.  
     
     
         31 . The oligonucleotide of  claim 30 , wherein said oligonucleotide is at least 9 to about 15 bases in length.  
     
     
         32 . The oligonucleotide of  claim 31 , wherein said oligonucleotide is at least 9 to about 12 bases in length.  
     
     
         33 . The oligonucleotide of  claim 1 , wherein said oligonucleotide comprises the sequence of any one of SEQ ID NO:29 to SEQ ID NO: 186.  
     
     
         34 . The oligonucleotide of  claim 33 , wherein said oligonucleotide comprises the sequence of any one of SEQ ID NO:93 to SEQ ID NO: 186.  
     
     
         35 . The oligonucleotide of  claim 34 , wherein said oligonucleotide comprises the sequence of any one of SEQ ID NO:93 to SEQ ID NO: 166.  
     
     
         36 . The oligonucleotide of  claim 35 , wherein said oligonucleotide comprises the sequence of any one of SEQ ID NO:93 to SEQ ID NO:146.  
     
     
         37 . The oligonucleotide of  claim 36 , wherein said oligonucleotide comprises the sequence of any one of SEQ ID NO:93 to SEQ ID NO: 126.  
     
     
         38 . The oligonucleotide of  claim 36 , wherein said oligonucleotide comprises the sequence of any one of SEQ ID NO:96 to SEQ ID NO: 112.  
     
     
         39 . A recombinant vector comprising (a) the oligonucleotide of  claim 1 , or (b) a polynucleotide that comprises a sequence that is complementary to the sequence of from about position 87 to position 1520 of SEQ ID NO: 187.  
     
     
         40 . The vector comprising a viral, retroviral, adenoviral, or adenoassociated viral vector.  
     
     
         41 . A host cell comprising the oligonucleotide of  claim 1  or the recombinant vector of  claim 39 .  
     
     
         42 . A composition comprising the oligonucleotide of  claim 1 .  
     
     
         43 . A kit comprising the oligonucleotide of  claim 1  or the composition of  claim 42 .  
     
     
         44 . The composition of  claim 42 , further comprising a pharmaceutical excipient.  
     
     
         45 . The composition of  claim 44 , further comprising a liposome, a lipid particle, a lipid vesicle, a nanoparticle, a microparticle, a nanocapsule, a nanosphere, or a sphingosome.  
     
     
         46 . The composition of  claim 42 , further comprising at least a second oligonucleotide of at least 9 to about 35 nucleotides in length, wherein said second oligonucleotide also specifically binds to a portion of an mRNA that encodes a β 1 -adrenoceptor polypeptide, and further wherein the nucleotide sequence of said second oligonucleotide is different from the nucleotide sequence of the first oligonucleotide in said composition.  
     
     
         47 . The composition of  claim 46 , wherein said second oligonucleotide is any one of SEQ ID NO:4 through SEQ ID NO:186.  
     
     
         48 . The composition of  claim 42 , further comprising at least a first anti-hypertensive agent.  
     
     
         49 . The composition of  claim 48 , wherein said anti-hypertensive agent is selected from the group consisting of captopril, enalapril, ramipril, cilazapril, fosinopril, and lisinopril.  
     
     
         50 . The composition of  claim 42 , further comprising at least a second antisense oligonucleotide specific for a mammalian transcription factor mRNA, a reninspecific mRNA, an angiotensin-specific mRNA, an angiotensinogen-specific mRNA, an AT-1 receptor-specific mRNA, or an angiotensin converting enzyme.  
     
     
         51 . The composition of  claim 50 , wherein said second antisense oligonucleotide is specific for a mammalian angiotensin converting enzyme mRNA.  
     
     
         52 . A method for reducing the level of β 1 -adrenoceptor polypeptide in a mammalian host cell, said method comprising providing to said cell, an amount of the oligonucleotide of  claim 1 , or the composition of  claim 42 , and for a time effective to reduce the level of said polypeptide in said host cell.  
     
     
         53 . A method for reducing the level of transcription of a β 1 -adrenoceptor polypeptide-specific mRNA in a mammalian host cell, said method comprising providing to said cell, an amount of the oligonucleotide of  claim 1 , or the composition of  claim 42 , and for a time effective to reduce the level of transcription of said mRNA in said host cell.  
     
     
         54 . The method of  claim 52  or  53 , wherein said host cell is comprised within a mammal.  
     
     
         55 . The method of  claim 54 , wherein said mammal is a human.  
     
     
         56 . A method for decreasing hypertension in a mammal, said method comprising administering to said mammal, an amount of the oligonucleotide of  claim 1  or the composition of  claim 42 , and for a time effective to decrease hypertension in said mammal.  
     
     
         57 . A method for reducing the symptoms of a disease or disorder associated with an elevated β 1 -adrenoceptor polypeptide level in a mammal, said method comprising administering to said mammal a therapeutically effective amount of the oligonucleotide of  claim 1 , SEQ ID NO:1, SEQ ID NO:2, or SEQ ID NO:3, or the composition of  claim 42 , for a time sufficient to decrease the level of said polypeptide in said mammal, thereby reducing the symptoms of said disease or disorder in said mammal.  
     
     
         58 . A method for treating myocardial ischemia or cardiac hypertrophy in an affected mammal, said method comprising administering to said mammal, a therapeutically effective amount of the oligonucleotide of  claim 1 , SEQ ID NO: 1, SEQ ID NO:2, or SEQ ID NO:3, or the composition of  claim 42 , for a time sufficient to treat said ischemia or said hypertrophy in said mammal.  
     
     
         59 . A method for reducing the level of β 1 -adrenoceptor polypeptide in a mammalian host cell, said method comprising expressing in said host cell, a selected genetic construct that comprises a full-length, or substantially full-length β 1 -adrenoceptor antisense polynucleotide operably linked to a promoter capable of expressing said polynucleotide in said cell.

Join the waitlist — get patent alerts

Track US2003191080A1 — get alerts on status changes and closely related new filings.

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