Angiotensinogen-modulating compositions and methods of use thereof

A compound comprising a modified oligonucleotide 14 to 23 linked nucleosides in length having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs:

• 11-20.

A compound comprising a modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs:

• 11-20.

A compound comprising a first modified oligonucleotide 14 to 23 linked nucleosides in length having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs:

• 11-20 or 31-42 and a second modified oligonucleotide 14 to 23 linked nucleosides in length having a region of complementarity to the first modified oligonucleotide.

A compound comprising a first modified oligonucleotide 14 to 23 linked nucleosides in length having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs:

• 11-20 or 31-42 and a second modified oligonucleotide 14 to 23 linked nucleosides in length having a region of complementarity to the first modified oligonucleotide.

A compound comprising a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs:

• 11-20 and 31-42 and a second modified oligonucleotide 19 to 23 linked nucleosides in length having a region of complementarity to the first modified oligonucleotide.

The compound of any preceding claim, comprising a conjugate group.

A compound comprising a first modified oligonucleotide selected from the group consisting of any one of Ref ID NOs:

• IA0500, IA1019, IA1022-1024, IA1027, IA1093-1095, and IA1103, and a second modified oligonucleotide 14 to 21 linked nucleosides in length fully complementary to the first modified oligonucleotide.

A compound comprising a first modified oligonucleotide selected from the group consisting of Ref ID NOs:

• IA0500, IA1019, IA1022-1024, IA1027, IA1093-1095, and IA1103 and a second modified oligonucleotide selected from the group consisting of Ref ID NOs:
• IS1255, IS1258, IS1259, IS1260, IS1279, IS1280, IS1372-1375, IS1381, and IS1382.

A compound comprising a first modified oligonucleotide selected from the group consisting of Ref ID NOs:

• IA1024, IA1094 and IA1103 and a second modified oligonucleotide selected from the group consisting of Ref ID NOs:
• IS1260, IS1374 and IS1382.

A modified oligonucleotide according to the following chemical structure:

• or a pharmaceutically acceptable salt or stereoisomer thereof.

A modified oligonucleotide according to the following chemical structure:

• or a pharmaceutically acceptable salt or stereoisomer thereof.

A modified oligonucleotide according to the following chemical structure:

• or a pharmaceutically acceptable salt or stereoisomer thereof.

A modified oligonucleotide according to the following chemical structure:

• or a pharmaceutically acceptable salt or stereoisomer thereof.

A compound according to the following chemical structure:

• or a pharmaceutically acceptable salt or stereoisomer thereof.

A compound according to the following chemical structure:

• or a pharmaceutically acceptable salt or stereoisomer thereof.

A composition comprising a compound or modified oligonucleotide of any preceding claim, for use in therapy.

A method of treating, preventing or ameliorating a disease, disorder or condition associated with AGT in an individual comprising administering to the individual a compound targeted to AGT, thereby treating, preventing, or ameliorating the disease, disorder or condition.

A method of inhibiting expression of AGT in a cell comprising contacting the cell with a compound targeted to AGT, thereby inhibiting expression of AGT in the cell.

A method of reducing or inhibiting RAAS related disease, disorder or condition or a symptom thereof, hypertension, resistant hypertension, fibrosis, kidney disease, chronic kidney disease, cardiovascular disease (e.g., coronary heart disease, heart failure, stroke, myocardial infarction, atrial fibrillation, aneurysm and peripheral artery disease), organ damage (e.g., heart, liver or kidney), inflammatory bowel disease or cognitive impairment in an individual, comprising administering a compound targeted to AGT to the individual, thereby reducing or inhibiting RAAS related disease, disorder or condition or a symptom thereof, hypertension, resistant hypertension, fibrosis, kidney disease, chronic kidney disease, cardiovascular disease (e.g., coronary heart disease, heart failure, stroke, myocardial infarction, atrial fibrillation, aneurysm and peripheral artery disease), organ damage (e.g., heart, liver or kidney), inflammatory bowel disease or cognitive impairment in the individual.

Use of a compound targeted to AGT for treating, preventing, or ameliorating a disease, disorder or condition associated with AGT.

Use of a compound targeted to AGT in the manufacture of a medicament for treating, preventing, or ameliorating a disease, disorder or condition associated with AGT.

The method or use of any preceding claim, wherein the compound or composition is administered to an individual about once every three months to about once every year.

The method or use of any preceding claim, wherein the compound or composition is administered to an individual about once every three months, about once every six months, or about once every year.