Angiotensinogen modulating compositions and methods of use thereof

Abstract

Aspects of the present disclosure provide compounds, compositions and methods for modulating the expression or activity of angiotensinogen (AGT). In some aspects, the compounds, compositions, and methods of the present disclosure can be used to reduce expression of AGT mRNA in a cell or animal. In some aspects, the compounds, compositions, and methods of the present disclosure can be used to reduce expression of AGT protein in a cell or animal.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 326,733, filed on April 1, 2022, and U.S. Provisional Application No. 63 / 407,071, filed on September 15, 2022. The disclosure of each of the prior applications is considered part of the disclosure of the present application and is incorporated by reference in its entirety into the disclosure of the present application. Background Art

[0003] Angiotensinogen (AGT), also known as SERPINA8, is a member of the serine protease inhibitor (serpin) family. The encoded protein is angiotensinogen precursor, which is mainly expressed in the liver and is cleaved by the enzyme renin in response to reduced blood pressure. The product angiotensin I is then cleaved by angiotensin converting enzyme (ACE) to produce angiotensin II with physiological activity. Angiotensin II is the active peptide of the renin-angiotensin-aldosterone system (RAAS). Angiotensin II interacts with receptors to mediate vasoconstriction, thirst, release of vasopressin and aldosterone, renal sodium reabsorption, fibrosis, inflammation, angiogenesis, vascular aging and atherosclerosis. The release of aldosterone causes the kidneys to increase the reabsorption of sodium and water, resulting in an increase in the volume of fluid in the body, which in turn can increase blood pressure. Therefore, overstimulation or activity of the RAAS pathway can cause hypertension. High levels of angiotensin II are associated with chronic hypertension (systemic arterial hypertension, essential hypertension or hypertension), renal failure and cardiac fibrosis.

[0004] Hypertension is the most common risk factor for cardiovascular disease (CVD; including coronary heart disease, heart failure, stroke, myocardial infarction, atrial fibrillation and peripheral arterial disease), chronic kidney disease (CKD) and cognitive impairment, and is the main single contributing factor to all-cause mortality and disability worldwide (Forouzanfar et al., Lancet, 2016, 388: 1659-1724). The World Health Organization estimates that 1.28 billion adults aged 30-79 years suffer from hypertension worldwide. Less than half of the population is diagnosed and treated, and only about 20% of the population is able to control their hypertension via pharmacological treatment, diet and lifestyle changes.

[0005] The American Heart Association has defined refractory hypertension as uncontrolled blood pressure (BP) ≥ 130 / 80 mmHg, despite the simultaneous use of 3 antihypertensive drug categories including calcium channel blockers, blockers of the renin-angiotensin system, and thiazide diuretics (preferably chlorthalidone). Refractory hypertension can also be defined as treatment with ≥ 4 types of antihypertensive drugs regardless of BP. In the treated population, the global incidence of refractory hypertension is estimated to be approximately 14.7%. Currently approved therapies for the treatment of hypertension have significant limitations. Drugs such as ACE inhibitors and angiotensin receptor blockers are the main therapeutic drugs for hypertension. Such drugs are limited in their ability to inhibit RAAS pathways and have considerable adverse effects and contraindications in certain patient populations (Momoniat et al., Cleveland Clinic Journal of Medicine, 2019, 86: 601-607).

[0006] Factors such as increasing age and obesity predispose individuals to resistant hypertension. With the increasing aging and overweight populations and the lack of effective treatments, the incidence of hypertension, resistant hypertension, and related diseases is expected to continue to increase. Therefore, there is a need to find effective treatments for RAAS-related diseases. Summary of the invention

[0007] The present disclosure provides compounds, compositions and methods for regulating the expression or activity of AGT. In certain embodiments, the compounds, compositions and methods can be used to reduce the expression of AGT mRNA in cells or animals. In certain embodiments, the compounds, compositions and methods can be used to reduce the amount of AGT protein in cells or animals.

[0008] In certain embodiments, the animal suffers from a RAAS-related disease, disorder or condition. In certain embodiments, the disease, disorder or condition is hypertension, refractory hypertension, fibrosis, nephropathy, chronic kidney disease, cardiovascular disease (e.g., coronary heart disease, heart failure, stroke, myocardial infarction, atrial fibrillation, aneurysm and peripheral arterial disease), organ damage (e.g., heart, liver or kidney), inflammatory bowel disease or cognitive impairment. Certain compounds, compositions and methods provided herein relate to reducing RAAS-related diseases, disorders or conditions or their symptoms or hypertension, refractory hypertension, fibrosis, nephropathy, chronic kidney disease, cardiovascular disease (e.g., coronary heart disease, heart failure, stroke, myocardial infarction, atrial fibrillation, aneurysm and peripheral arterial disease), organ damage (e.g., heart, liver or kidney), inflammatory bowel disease or cognitive impairment in animals. In certain embodiments, the compounds and compositions provided herein are effective and tolerable and inhibit AGT expression, which can be used to treat, prevent, ameliorate or slow the progression of RAAS-related diseases, disorders or conditions or their symptoms or hypertension, resistant hypertension, fibrosis, renal disease, chronic kidney disease, cardiovascular disease (e.g., coronary heart disease, heart failure, stroke, myocardial infarction, atrial fibrillation, aneurysm and peripheral arterial disease), organ damage (e.g., heart, liver or kidney), inflammatory bowel disease or cognitive impairment.

[0009] In certain embodiments, the compounds and compositions comprise one or more features effective to increase potency. In certain embodiments, the compounds and compositions comprise one or more features effective to increase tolerability. In certain embodiments, the compounds and compositions comprise one or more features effective to target the compounds or compositions to cells or tissues. In certain embodiments, the compounds and compositions are more effective, have a longer duration of action, or have a higher therapeutic value than publicly disclosed compounds. DETAILED DESCRIPTION

[0010] It should be understood that the foregoing summary and the following detailed description are exemplary and explanatory only and do not limit the claimed embodiments.The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0011] All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, treatises, and GenBank, NCBI and other sequence reference records as of the filing date of the present application, are hereby expressly incorporated by reference in part and in their entirety as of the filing date of the present application.

[0012] It is understood that the sequence listed in each SEQ ID NO contained herein is independent of any modification to the sugar moiety, internucleoside linkage or nucleobase, even if shown as a modified compound in the context. Thus, the compound defined by the SEQ ID NO may independently comprise one or more modifications to the sugar moiety, internucleoside linkage or nucleobase. The oligomeric compounds referred to by the compound number or Ref ID NO indicate a combination of nucleobase sequence, chemical modification and motif.

[0013] In this article, unless otherwise specifically stated, the use of the singular includes the plural. For example, the articles "a" and "an" are used herein to refer to one or more than one (i.e., at least one) of the grammatical object of the article. For example, "element" means one element or more than one element, such as a plurality of elements. As used herein, the use of "or" means "and / or" unless otherwise stated. In addition, the use of the term "including" and other forms such as "includes" and "included" is not limiting and can be used interchangeably with the phrase "including but not limited to".

[0014] definition

[0015] Unless otherwise indicated, the following terms have the following meanings:

[0016] "Angiotensinogen", which can be used interchangeably with the term "AGT", refers to any nucleic acid or protein of AGT. Exemplary nucleotide and amino acid sequences of AGT can be found, for example, in GenBank Accession No. NM_000029.4 (incorporated herein with SEQ ID NO: 1), the complementary sequence of nucleotides 230702523 to 230745583 of NC_000001.11 (incorporated herein with SEQ ID NO: 2), NM_001382817.3 (incorporated herein with SEQ ID NO: 3), and nucleotides 5469 to 17068 of NG_008836.2 (incorporated herein with SEQ ID NO: 4). Other examples of AGT sequences are readily available via publicly available databases, such as GenBank, UniProt, and OMIM. Additional information about AGT can be found, for example, at www.ncbi.nlm.nih.gov / gene / ? term=AGT. As used herein, AGT also refers to variations of the AGT gene, including variants provided in the SNP database. Many sequence variations within the AGT gene have been identified and can be found, for example, in NCBI dbSNP and UniProt (see, for example, www.ncbi.nlm.nih.gov / snp / ?term=AGT). "AGT mRNA" means mRNA encoding the AGT protein. AGT can be referred to in uppercase or lowercase.

[0017] "AGT specific inhibitor" refers to any agent that can specifically inhibit AGT RNA and / or AGT protein expression or activity at the molecular level. For example, AGT specific inhibitors include nucleic acids (including oligonucleotide compounds), peptides, antibodies, small molecules and other agents that can inhibit the expression of AGT RNA and / or AGT protein.

[0018] "2'-O-methoxyethyl" or "2'-MOE" means 2'-O(CH 2 ) 2 -OCH 3 Modification. A 2'-O-methoxyethyl-modified sugar is a sugar having 2'-O(CH 2 ) 2 -OCH 3 A modified sugar replacing the 2'-OH group of the ribosyl ring.

[0019] "5' initiation site" means the nucleotide of a target nucleic acid or region to which the 3'-most nucleoside of an antisense oligonucleotide is aligned.

[0020] "3' termination site" means the nucleotide of the target nucleic acid or region to which the 5'-most nucleoside of the antisense oligonucleotide is aligned.

[0021] "About" means within ±10% of a value. For example, if it is stated that "the compound achieves about 70% inhibition of AGT," it implies that the AGT level is inhibited within the range of 60% and 80%. When about is present before a series of values ​​or ranges, it is understood that "about" can modify each of the values ​​in the series or range.

[0022] "Administer" or "administering" refers to the route by which a compound or composition provided herein is introduced into an individual to perform its intended function. For example, routes of administration that can be used include, but are not limited to, parenteral administration, such as subcutaneous, intravenous or intramuscular injection or infusion.

[0023] "Improvement" refers to the improvement or alleviation of at least one indicator, sign or symptom of a disease, disorder or condition of interest. In certain embodiments, improvement includes delaying or slowing the progression or severity of one or more indicators of a disorder or disease. The progression or severity of an indicator can be determined by subjective or objective measurements known to those skilled in the art.

[0024] "Animal" refers to human and non-human animals, including but not limited to mice, rats, rabbits, dogs, cats, pigs, and non-human primates, including but not limited to monkeys and chimpanzees.

[0025] "Antisense oligonucleotide" or "antisense strand" means an oligonucleotide that includes a region complementary to a target nucleic acid (eg, AGT RNA or a region thereof).

[0026] "Complementarity" about oligonucleotides means that the core base sequence of such oligonucleotides or one or more regions thereof are complementary to the core base sequence of another oligonucleotide or nucleic acid or one or more regions thereof when two core base sequences are aligned in relative directions. Unless otherwise specified, complementary core bases as described herein are limited to the following pairings: adenine (A) and thymine (T), adenine (A) and uracil (U), and cytosine (C) and guanine (G). Complementary oligonucleotides and / or nucleic acids do not need to have core base complementarity at each nucleoside and may include one or more core base mismatches. In contrast, "complete complementarity" or "100% complementary" about oligonucleotides means that such oligonucleotides have core base matches at each nucleoside without any core base mismatches.

[0027] "Composition" or "pharmaceutical composition" means a mixture of substances suitable for administration to an individual. For example, a composition may include one or more compounds or salts thereof and a sterile aqueous solution.

[0028] "Co-administration" means that two or more compounds are administered in any manner wherein their pharmacological effects are manifested in a patient. Co-administration does not require that the compounds are both in a single pharmaceutical composition, in the same dosage form, by the same route of administration, or administered simultaneously. The effects of the two compounds need not manifest simultaneously. The effects need only overlap for a period of time and need not extend together. Co-administration includes administration of one or more compounds in parallel or sequentially.

[0029] "Conjugate group" means a group that is attached to an atom of an oligonucleotide. A conjugate group is optionally attached to an oligonucleotide via a conjugate linker. A conjugate group may, for example, alter the distribution, targeting, or half-life of a compound into which it is incorporated. A conjugate group includes a targeting moiety.

[0030] "Conjugation linker" means a group of atoms comprising at least one bond that connects a linking moiety to an oligonucleotide.

[0031] "Identity" with respect to an oligonucleotide means that the nucleobase sequence of such oligonucleotide or one or more regions thereof matches the nucleobase sequence of another oligonucleotide or nucleic acid or one or more regions thereof. The identity of an oligonucleotide to another oligonucleotide or nucleic acid does not require that each nucleobase matches and may include one or more different nucleobases. In contrast, "complete identity" or "100% identity" with respect to an oligonucleotide means that such an oligonucleotide has the same nucleobase as the other oligonucleotide or nucleic acid at each relative position over its length.

[0032] "Subject" means a human or non-human animal selected for treatment or therapy.

[0033] "Inhibiting expression or activity" with respect to a target nucleic acid or protein means reducing or blocking the expression or activity of such target relative to expression or activity in an untreated or control sample, and does not necessarily indicate complete elimination of expression or activity.

[0034] As used herein, the term "internucleoside linkage" is a covalent linkage between adjacent nucleosides in an oligonucleotide. As used herein, "modified internucleoside linkage" means any internucleoside linkage other than a phosphodiester internucleoside linkage. A "phosphorothioate internucleoside linkage" is a modified internucleoside linkage in which one of the non-bridging oxygen atoms of the phosphodiester internucleoside linkage is replaced by a sulfur atom.

[0035] Representative internucleoside linkages with chiral centers include, but are not limited to, alkyl phosphonates and phosphorothioates. Modified oligonucleotides comprising internucleoside linkages with chiral centers can be prepared as a population of modified oligonucleotides comprising stereo-random internucleoside linkages, or as a population of modified oligonucleotides comprising phosphorothioate linkages of stereochemical configurations further described below. Unless otherwise indicated, the chiral internucleoside linkages of modified oligonucleotides described herein can be stereo-random or in a specific stereochemical configuration.

[0036] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be treated with, for example, tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0037] The term "isotopic variant" refers to a therapeutic agent (e.g., a compound and / or modified oligonucleotide disclosed herein) that contains unnatural ratios of isotopes at one or more atoms that constitute such therapeutic agent. In certain embodiments, an "isotopic variant" of a therapeutic agent contains unnatural ratios of one or more isotopes, including but not limited to hydrogen (H), deuterium ( 2 H), tritium ( 3 H), carbon-11 ( 11 C), carbon-12 ( 12 C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-14 ( 14 N), nitrogen-15 ( 15 N), oxygen-14 ( 14 O), oxygen-15 (15 O), oxygen-16 ( 16 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), fluorine-17 ( 17 F), fluorine-18 ( 18 F), phosphorus-31 ( 31 P), phosphorus-32 ( 32 P), phosphorus-33 ( 33 P), sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 ( 34 S), sulfur-35 ( 35 S), sulfur-36 ( 36 S), chlorine-35 ( 35 Cl), chlorine-36 ( 36 Cl), chlorine-37( 37 Cl), bromine-79( 79 Br), bromine-81( 81 Br), iodine 123( 123 I), iodine-125( 125 I), iodine-127( 127 I), iodine-129( 129 I) and iodine-131( 131 I). In certain embodiments, an "isotopic variant" of a therapeutic agent contains unnatural proportions of one or more isotopes, including but not limited to hydrogen (H), deuterium ( 2 H), tritium ( 3 H), carbon-11 ( 11 C), carbon-12 ( 12 C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-14 ( 14 N), nitrogen-15 ( 15 N), oxygen-14 ( 14 O), oxygen-15 ( 15 O), oxygen-16 ( 16 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), fluorine-17 ( 17 F), fluorine-18 ( 18 F), phosphorus-31 ( 31 P), phosphorus-32 ( 32 P), phosphorus-33 ( 33 P), sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 (34 S), sulfur-35 ( 35 S), sulfur-36 ( 36 S), chlorine-35 ( 35 Cl), chlorine-36 ( 36 Cl), chlorine-37( 37 Cl), bromine-79( 79 Br), bromine-81( 81 Br), iodine 123( 123 I), iodine-125( 125 I), iodine-127( 127 I), iodine-129( 129 I) and iodine-131( 131 I).

[0038] It is understood that in a therapeutic agent (e.g., a compound and / or a modified oligonucleotide disclosed herein), any hydrogen may be, for example, 2 H, or any carbon may be, for example 13 C, or any nitrogen may be e.g. 15 N, or any oxygen may be 18 O. In certain embodiments, an "isotopic variant" of a therapeutic agent contains unnatural proportions of deuterium (D).

[0039] "Mismatch" or "non-complementary" means that when the first oligonucleotide / nucleic acid and the second oligonucleotide / nucleic acid are aligned in an antiparallel orientation, the nucleobase of the first oligonucleotide or nucleic acid is not complementary to the corresponding nucleobase of the second oligonucleotide or nucleic acid. For example, nucleobases including but not limited to universal nucleobases, inosine and hypoxanthine can hybridize with at least one nucleobase, but are still mismatched or non-complementary relative to the nucleobases hybridized thereto. As another example, when the first oligonucleotide and the second oligonucleotide are aligned in an antiparallel orientation, the nucleobase of the first oligonucleotide / nucleic acid that cannot hybridize with the corresponding nucleobase of the second oligonucleotide / nucleic acid is a mismatch or non-complementary nucleobase.

[0040] "Modified oligonucleotide" means an oligonucleotide in which at least one sugar, nucleobase or internucleoside linkage has been modified.

[0041] "Regulate" refers to changing or adjusting a characteristic in a cell, tissue, organ, or organism. For example, regulating AGT RNA can mean increasing or decreasing the level of AGT RNA and / or AGT protein in a cell, tissue, organ, or organism. A "modulator" affects a change in a cell, tissue, organ, or organism. For example, an AGT compound can be a modulator that decreases the amount of AGT RNA and / or AGT protein in a cell, tissue, organ, or organism.

[0042] "Motif" means the pattern of unmodified and modified sugar moieties, nucleobases and / or internucleoside linkages in an oligonucleotide.

[0043] "Nucleic acid" refers to a molecule composed of monomeric nucleotides. Nucleic acids include, but are not limited to, ribonucleic acid (RNA), deoxyribonucleic acid (DNA), single-stranded nucleic acid, and double-stranded nucleic acid.

[0044] "Nucleobase" means a heterocyclic moiety capable of pairing with the base of another nucleic acid. As used herein, "naturally occurring nucleobases" are adenine (A), thymine (T), cytosine (C), uracil (U), and guanine (G). "Modified nucleobases" are chemically modified naturally occurring nucleobases. "Universal bases" or "universal nucleobases" are nucleobases other than naturally occurring nucleobases and modified nucleobases, and are capable of pairing with any nucleobase.

[0045] "Nucleobase sequence" means the order of consecutive nucleobases in a nucleic acid or oligonucleotide independent of any sugar or internucleoside linkages.

[0046] "Nucleoside" means a compound comprising a nucleobase and a sugar moiety. The nucleobase and sugar moiety are each independently unmodified or modified. "Modified nucleoside" means a nucleoside comprising a modified nucleobase and / or a modified sugar moiety. Modified nucleosides include abasic nucleosides, which lack a nucleobase.

[0047] "Oligomeric compound" means a compound comprising one or more oligonucleotides and optionally one or more additional features, such as a conjugated group or a terminal group. Examples of oligomeric compounds include single-stranded and double-stranded compounds, such as oligonucleotides, antisense oligonucleotides, interfering RNA compounds (RNAi compounds), microRNA targeting oligonucleotides, occupancy-based compounds (e.g., mRNA processing or translation blocking compounds and splicing compounds). RNAi compounds include double-stranded compounds (e.g., short interfering RNA (siRNA) and double-stranded RNA (dsRNA)) and single-stranded compounds (e.g., single-stranded siRNA (ssRNA), single-stranded RNAi (ssRNAi), short hairpin RNA (shRNA) and microRNA mimics), which act at least in part via an RNA-induced silencing complex (RISC) pathway, thereby producing sequence-specific degradation and / or chelation of target nucleic acids via a process known as RNA interference (RNAi). The term "RNAi compound" is intended to be equivalent to other terms used to describe nucleic acid compounds that can modulate sequence-specific RNA interference, such as interfering RNA (iRNA), iRNA agents, RNAi agents, short interfering oligonucleotides, short interfering nucleic acids, short interfering modified oligonucleotides, chemically modified siRNA and others. In addition, the term "RNAi" is intended to be equivalent to other terms used to describe sequence-specific RNA interference.

[0048] The term "oligoduplex" means a duplex formed by two oligomeric compounds having complementary nucleobase sequences. Each oligomeric compound of an oligomeric duplex may be referred to as a "duplex oligomeric compound". The oligonucleotides of each oligomeric compound of an oligomeric duplex may include non-complementary overhanging nucleosides. In some embodiments, the terms "duplex oligomeric compound" and "modified oligonucleotide" are used interchangeably. In other embodiments, the terms "oligoduplex" and "compound" are used interchangeably.

[0049] "Oligonucleotide" means a polymer of linked nucleosides independently of each other, each of which may be modified or unmodified.

[0050] "Parenteral administration" means administration via injection or infusion. Parenteral administration includes subcutaneous administration, intravenous administration, intramuscular administration, intraarterial administration, intraperitoneal administration, or intracranial administration, such as intrathecal or intracerebroventricular administration.

[0051] "Pharmaceutically acceptable carrier or diluent" means any substance suitable for administration to an individual. In certain embodiments, a pharmaceutically acceptable carrier or diluent facilitates administration of the compound to an individual and facilitates absorption by the individual, and may be included in the compositions of the present disclosure without causing significant adverse toxicological effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, standard saline solution, and the like. For example, a pharmaceutically acceptable carrier may be a sterile aqueous solution, such as PBS or water for injection. Those skilled in the art will recognize that other pharmaceutical excipients are also suitable for use in the present disclosure.

[0052] "Pharmaceutically acceptable salt" means or refers to physiologically and pharmaceutically acceptable salts of compounds, such as oligomeric compounds or oligonucleotides, ie, salts that retain the desired biological activity of the parent compound and do not impart undesirable toxicological effects thereto.

[0053] As used herein, a pharmaceutically acceptable salt is any salt of a compound provided herein that retains its biological properties and is not toxic or otherwise undesirable for pharmaceutical use. Pharmaceutically acceptable salts of the therapeutic agents disclosed herein include salts prepared with relatively nontoxic acids or bases, depending on the specific substituents present on the compounds described herein or modified oligonucleotides.

[0054] When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.

[0055] When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.

[0056] Thus, the compounds of the present disclosure may exist in salt form, for example, with a pharmaceutically acceptable acid. Such salts may be derived from various organic and inorganic counterions well known in the art. Such salts include, but are not limited to: (1) acid addition salts formed from organic or inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, caproic acid, cyclopentylpropionic acid, glycolic acid, glutaric acid, pyruvic acid, lactic acid, malonic acid, succinic acid, sorbic acid, ascorbic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, bitter acid, cinnamic acid, mandelic acid, phthalic acid , lauric acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphoric acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, benzoic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylsulfamic acid, quinic acid, muconic acid and similar acids; or (2) when an acidic proton is present in the parent compound, a salt formed by: (a) replacement by: a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or an alkali metal or alkaline earth metal hydroxide, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminum hydroxide, lithium hydroxide, zinc hydroxide, and barium hydroxide; ammonia; or (b) coordination by: an organic base, such as an aliphatic, alicyclic, or aromatic organic amine, such as ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N,N'-dibenzhydrylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, N-methylglucosamine piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, and the like (see, e.g., Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19).

[0057] Pharmaceutically acceptable salts also include, by way of example only and without limitation, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like, and, when the compound contains a basic functional group, salts of non-toxic organic or inorganic acids such as hydrohalides (e.g., hydrochlorides and hydrobromides), sulfates, phosphates, sulfamates, nitrates, acetates, trifluoroacetates, trichloroacetates, propionates, hexanoates, cyclopentylpropionates, glycolates, glutarates, pyruvates, lactates, malonates, succinates, sorbates, ascorbates, malates, maleates, fumarates, tartrates, citrates, benzoates, 3-(4-hydroxybenzoyl)benzoate, picrates, cinnamates, mandelates, phthalates, The pharmaceutically acceptable salts of the compounds and modified oligonucleotides disclosed herein are sodium or potassium salts. In some embodiments, the pharmaceutically acceptable salts of the compounds and modified oligonucleotides disclosed herein are sodium salts or potassium salts. In some embodiments, the pharmaceutically acceptable salts of the compounds and modified oligonucleotides disclosed herein are sodium salts.

[0058] The neutral form of the compound is preferably regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The parent form of the compound may differ from various salt forms in certain physical properties, such as solubility in polar solvents. In an embodiment, the compound of the present disclosure contains both basic and acidic functional groups that allow the compound to be converted into a base addition salt or an acid addition salt. The neutral form of the compound may be regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The parent form of the compound may differ from various salt forms in certain physical properties such as solubility in polar solvents, but unless specifically indicated, for the purposes of the present disclosure, the salt disclosed herein is equivalent to the parent form of the compound.

[0059] "Pharmaceutical agent" means a chemical compound that provides a therapeutic benefit when administered to a subject.

[0060] "Phosphorothioate linkage" means a modified phosphate linkage in which one of the non-bridging oxygen atoms is replaced by a sulfur atom.

[0061] "Portion" means a defined number of adjacent (i.e., connected) core bases of a nucleic acid. In certain embodiments, a portion is a defined number of consecutive core bases of a target nucleic acid. In certain embodiments, a portion is a defined number of consecutive core bases of an oligonucleotide.

[0062] "Prevent" means to delay or forestall the onset, development or progression of a disease, disorder or condition for a period of time.

[0063] "RNA interference compound" or "RNAi compound" means a compound that acts at least in part via the RNA-induced silencing complex (RISC) pathway or Ago2 but not via RNase H to modulate a target nucleic acid and / or protein encoded by a target nucleic acid. RNAi compounds include, but are not limited to, double-stranded siRNA, single-stranded siRNA, and microRNA, including microRNA mimics.

[0064] "Sense oligonucleotide" or "sense strand" means the strand of a double-stranded compound that includes a region that is substantially complementary to a region of the antisense strand of the compound.

[0065] "Specific inhibition" with respect to a target nucleic acid or protein means reducing or blocking the expression or activity of the target nucleic acid or protein while minimizing or eliminating effects on non-target nucleic acids or proteins.

[0066] "Subunit" with respect to an oligonucleotide means a nucleotide, nucleoside, nucleobase or sugar or a modified nucleotide, nucleoside, nucleobase or sugar as provided herein.

[0067] "Target nucleic acid," "target RNA," and "nucleic acid target" all refer to a nucleic acid that can be targeted by the compounds described herein.

[0068] "Target region" means a portion of a target nucleic acid to which one or more compounds are targeted.

[0069] "Targeting moiety" means a conjugated group that provides enhanced affinity for a selected target (e.g., a molecule, cell or cell type, compartment (e.g., a cellular or organ compartment), tissue, organ or body region), e.g., compared to a compound in the absence of such moiety.

[0070] "Terminus group" means a chemical group or radical of atoms covalently attached to the terminus of an oligonucleotide.

[0071] "Therapeutically effective amount" or "effective amount" means the amount of a compound, pharmaceutical agent or composition that provides a therapeutic benefit to an individual. "Therapeutically effective amount" or "effective amount" is an amount of a compound sufficient to achieve the stated purpose (e.g., to achieve the effect of its administration, to treat, prevent or improve a disease or to alleviate one or more symptoms of a disease or disorder) relative to the absence of the compound. An example of a "therapeutically effective amount" or "effective amount" is an amount sufficient to promote the treatment, prevention, improvement or alleviation of one or more symptoms of a disease. "Relief" of one or more symptoms (and grammatical equivalents of this phrase) means reducing the severity or frequency of the symptoms or eliminating the symptoms. A "prophylactic effective amount" of a drug is an amount of a drug that will have the expected preventive effect when administered to a subject, such as preventing or delaying the onset (or recurrence) of an injury, disease, lesion or disorder, or reducing the likelihood of the onset (or recurrence) of an injury, disease, lesion or disorder or its symptoms. As used herein, the term "therapeutically effective amount" refers to an amount of a therapeutic agent sufficient to provide a therapeutic benefit to an individual, such as treating, preventing or improving a disease or disorder or its symptoms as described above. For example, a therapeutically effective amount will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100% for a given parameter. Therapeutic efficacy can also be expressed as a "-fold" increase or decrease. For example, a therapeutically effective amount can have an effect that is at least 1.2-fold, 1.5-fold, 2-fold, 5-fold, or greater than that of a control group.

[0072] The term "treating" or "treatment" refers to any mark of success in treating or ameliorating an injury, disease, lesion, or illness, including any objective or subjective parameter, such as alleviation of symptoms; relief; reducing symptoms or making an injury, lesion, or illness more tolerable to a patient; slowing the rate of degeneration or decline; making the end point of degeneration less debilitating; improving the patient's physical or mental health. Treatment or amelioration of symptoms may be based on objective or subjective parameters, including the results of a physical examination. The term "treat" and its verb conjugations may include prevention of an injury, lesion, illness, or disease. In an embodiment, treatment is prevention. In an embodiment, treatment does not include prevention.

[0073] "Treating" or "treatment" as used herein (and as fully understood in the art) also broadly includes any method for obtaining a beneficial or desired result (including a clinical result) for a subject's condition. Beneficial or desired clinical results may include, but are not limited to, alleviation or improvement of one or more symptoms or conditions, attenuation of the extent of the disease, stabilization of the disease state (i.e., not worsening), prevention of disease transmission or spread, delay or slowing of disease progression, improvement or slowing of the disease state, attenuation of disease recurrence, and alleviation (whether partial or complete and whether detectable or undetectable) of disease. In other words, "treatment" as used herein includes any cure, improvement, or prevention of a disease. Treatment may prevent the disease from occurring; inhibit the spread of the disease; alleviate the symptoms of the disease, completely or partially remove the underlying cause of the disease, shorten the duration of the disease, or a combination of these things.

[0074] As used herein, "treating" and "treatment" include preventive treatment. The method of treatment includes administering to a subject a therapeutically effective amount of a compound described herein. The administration step may consist of a single administration or may include a series of administrations. The length of the treatment period depends on a variety of factors, such as the severity of the disease, the age of the patient, the concentration of the compound, the activity of the composition used in the treatment, or a combination thereof. It should also be understood that the effective dose of the agent used for treatment or prevention may increase or decrease over the course of a particular treatment or prevention regimen. In some cases, long-term administration may be required. For example, a composition is administered to a subject in an amount and duration sufficient to treat the patient. "Treatment" refers to administering a compound or pharmaceutical composition to an animal so as to achieve a change or improvement in a disease, disorder or illness in the animal.

[0075] Certain compounds of the present disclosure have asymmetric carbon atoms (optical or chiral centers) or double bonds; enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms, and individual isomers that can be defined as (R)- or (S)- or as (D)- or (L)- for amino acids in terms of absolute stereochemistry are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include those compounds that are known in the art to be too unstable to synthesize and / or separate. The present disclosure is intended to include compounds in racemic and optically pure forms. Optically active (R)- and (S)- or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry and unless otherwise specified, it is contemplated that the compounds include E geometric isomers and Z geometric isomers.

[0076] As used herein, the term "isomers" refers to compounds that have the same number and kind of atoms, and therefore the same molecular weight, but differ in the arrangement or configuration of the atomic structure.

[0077] The term "tautomer" as used herein refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

[0078] It will be apparent to those skilled in the art that certain compounds of the present disclosure may exist in tautomeric forms and all such tautomeric forms of the compounds are within the scope of the present disclosure.

[0079] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structures (ie, R and S configurations for each asymmetric center). Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the disclosed compounds are within the scope of the present disclosure.

[0080] As used herein, "chiral enriched population" means a plurality of molecules of the same molecular formula, wherein if a particular chiral center is stereo-random, the number or percentage of molecules within the population containing a particular stereochemical configuration at a particular chiral center is greater than the number or percentage of molecules expected to contain the same particular stereochemical configuration at the same particular chiral center within the population. A chiral enriched population of molecules having multiple chiral centers within each molecule may contain one or more stereo-random chiral centers. In certain embodiments, the molecule is a modified oligonucleotide. In certain embodiments, the molecule is a compound comprising a modified oligonucleotide.

[0081] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 Compounds having the disclosed structures other than C-enriched carbon substitutions are within the scope of the present disclosure.

[0082] As used herein, in the case of a population of molecules of the same molecular formula, a "stereo-random chiral center" means a chiral center with a random stereochemical configuration. For example, in a population of molecules comprising a stereo-random chiral center, the number of molecules with the (S) configuration of the stereo-random chiral center may be, but not necessarily, the same as the number of molecules with the (R) configuration of the stereo-random chiral center. The stereochemical configuration of a chiral center is considered random when it is the result of a synthetic method that is not designed to control the stereochemical configuration. In certain embodiments, the stereo-random chiral center is a stereo-random phosphorothioate internucleoside linkage.

[0083] Certain embodiments

[0084] In certain aspects, the disclosure relates to methods, compounds and compositions for inhibiting AGT. In certain embodiments, AGT is specifically inhibited. In certain embodiments, AGT is specifically degraded. In certain embodiments, AGT expression is inhibited. In certain embodiments, AGT translation is inhibited. In certain embodiments, AGT activity is inhibited. In certain embodiments, AGT expression, translation or activity is reduced by at least 10% relative to expression, translation or activity in untreated or control samples. For example, in certain embodiments, AGT expression, translation or activity is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, 10-50%, 25-50%, 25-75%, 50-75%, 50-99% or 75-99% relative to expression, translation or activity in untreated or control samples. In certain embodiments, AGT expression, translation, or activity is reduced as measured by any suitable assay including, but not limited to, an immunoassay, a hybridization-based assay, or a sequencing-based assay (eg, RNA-Seq).

[0085] In certain aspects, the disclosure relates to compounds targeting AGT nucleic acids. In certain embodiments, the AGT nucleic acid has the sequence set forth below: GENBANK Accession No. NM_000029.4 (incorporated herein as SEQ ID NO: 1), the complementary sequence of nucleotides 230702523 to 230745583 of NC_000001.11 (incorporated herein as SEQ ID NO: 2), NM_001382817.3 (incorporated herein as SEQ ID NO: 3), and nucleotides 5469 to 17068 of NG_008836.2 (incorporated herein as SEQ ID NO: 4).

[0086] In certain embodiments, the compound is an oligomeric compound. In certain embodiments, the compound is single-stranded. In certain embodiments, the compound is double-stranded.

[0087] Certain embodiments provide a compound comprising a modified oligonucleotide (e.g., 14 to 30, e.g., 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 consecutive nucleobases of any one of the nucleobase sequences SEQ ID NOs: 11-20.

[0088] Certain embodiments provide a compound comprising a modified oligonucleotide (eg, 14 to 30, eg, 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising any one of the nucleobase sequences SEQ ID NOs: 11-20.

[0089] Certain embodiments provide a compound comprising a modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs: 11-20.

[0090] In certain embodiments, the modified oligonucleotide is at least 80%, at least 85%, at least 90%, or at least 95% complementary to SEQ ID NO: 1 or 3. In certain embodiments, the modified oligonucleotide comprises at least one modification selected from a modified internucleoside linkage, a modified sugar, and a modified nucleobase. In certain embodiments, the compound is double-stranded.

[0091] Certain embodiments provide a compound comprising a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length), wherein the first modified oligonucleotide has a nucleobase sequence of 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 consecutive nucleobases comprising the nucleobase sequence of any one of SEQ ID NOs: 11-20 or 31-42, and the second modified oligonucleotide has a region complementary to the first modified oligonucleotide.

[0092] In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 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 consecutive nucleobases of any one of the nucleobase sequences provided in Tables 2 to 25, Table 42, Table 45, Table 50, and Table 51, and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide.

[0093] Certain embodiments provide a compound comprising a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length), wherein the first modified oligonucleotide has a nucleobase sequence comprising any one of the nucleobase sequences SEQ ID NO: 11-20 or 31-42, and the second modified oligonucleotide has a region complementary to the first modified oligonucleotide.

[0094] Certain embodiments provide 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 having a length of 19 to 23 linked nucleosides and having a region complementary to the first modified oligonucleotide.

[0095] In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 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 consecutive nucleobases of any one of the nucleobase sequences SEQ ID NO: 16, 18, or 20. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 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 consecutive nucleobases of any one of the nucleobase sequences SEQ ID NO: 36, 39, or 42. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of a nucleobase sequence of SEQ ID NO: 16, SEQ ID NO: 18, and SEQ ID NO: 20. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of a nucleobase sequence of SEQ ID NO: 36, SEQ ID NO: 39, and SEQ ID NO: 42. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 16 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 36. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 18 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 39. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 20 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 42.

[0096] In certain embodiments, the modified oligonucleotide or the first modified oligonucleotide of any of the foregoing compounds has at least 80%, at least 85%, at least 90% or at least 95% complementarity or identity with SEQ ID NO: 1 or 3 over its length. In certain embodiments, the modified oligonucleotide or the first modified oligonucleotide has at least 1, at least 2, at least 3 mismatches with a region of SEQ ID NO: 1 or 3. In certain embodiments, the length of the complementary region between the first modified oligonucleotide or the first strand and the second modified oligonucleotide or the second strand is 14 to 30 linked nucleosides. In certain embodiments, the length of the complementary region between the first modified oligonucleotide or the first strand and the second modified oligonucleotide or the second strand is 14 to 23 linked nucleosides. In certain embodiments, the length of the complementary region between the first modified oligonucleotide or the first strand and the second modified oligonucleotide or the second strand is 19 to 23 linked nucleosides. In certain embodiments, the length of the complementary region between the first modified oligonucleotide or the first strand and the second modified oligonucleotide or the second strand is 21 to 23 linked nucleosides. In certain embodiments, the first modified oligonucleotide is fully complementary to the second modified oligonucleotide.

[0097] In certain embodiments, the modified oligonucleotide of any of the aforementioned compounds or the first modified oligonucleotide comprises at least one modification selected from modified internucleoside linkage, modified sugar and modified nucleobase. In certain embodiments, the second modified oligonucleotide of any of the aforementioned compounds comprises at least one modification selected from the group consisting of modified internucleoside linkage, modified sugar and modified nucleobase. In certain embodiments, the modified internucleoside linkage is a phosphorothioate internucleoside linkage or a methylphosphonate internucleoside linkage. In certain embodiments, the phosphorothioate internucleoside linkage or the methylphosphonate internucleoside linkage is at the 3' end of the first or second modified oligonucleotide or at the 5' end of the first modified oligonucleotide. In certain embodiments, the modified sugar comprises a modification selected from the group consisting of halogen, alkoxy and bicyclic sugar. In certain embodiments, the modified sugar comprises 2'-F modification. In certain embodiments, the modified sugar comprises 2'-OMe modification. In certain embodiments, each nucleoside of the first modified oligonucleotide comprises a modified sugar. In certain embodiments, each nucleoside of the second modified oligonucleotide comprises a modified sugar. In certain embodiments, the modified sugar comprises a modification selected from the group consisting of halogen, alkoxy and bicyclic sugar or a combination thereof. In certain embodiments, the modified sugar comprises a modification selected from the group consisting of 2'-MOE, 2'-F and 2'-OMe or a combination thereof. In certain embodiments, the first modified oligonucleotide comprises no more than ten 2'-F sugar modifications. In certain embodiments, the second modified oligonucleotide comprises no more than five 2'-F sugar modifications.

[0098] In certain embodiments, the compound of any of the foregoing embodiments comprises a conjugated group. In certain embodiments, the conjugated group is connected to the 5' end of the modified oligonucleotide. In certain embodiments, the conjugated group is a targeting moiety. In certain embodiments, the targeting moiety comprises one or more GalNAc. In certain embodiments, the modified oligonucleotide is a second modified oligonucleotide or a sense oligonucleotide. In certain embodiments, one or more GalNAc are connected to the 2' or 3' position of the ribose ring. In certain embodiments, one or more GalNAc are connected to the 5' nucleoside of the modified oligonucleotide. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is selected from the following formula or a salt, solvate or hydrate thereof, wherein R is a portion other than the 5' nucleoside of the modified oligonucleotide:

[0099]

[0100]

[0101]

[0102] In certain embodiments, R' is O. In certain embodiments, R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula I and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula I and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula II and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula II and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula III and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula III and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula IV and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula IV and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula V and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula V and R' is S.

[0103] In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula VI and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula VI and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula VII and R' is O.

[0104] In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula VII and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula VIII and R' is O.

[0105] In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula VIII and R' is S.

[0106] Certain embodiments provide a compound comprising a first modified oligonucleotide and a second modified oligonucleotide, wherein the first modified oligonucleotide is selected from the group consisting of any one of Ref ID NO: IA0500, IA1019, IA1022-1024, IA1027, IA1093-1095 and IA1103, and the second modified oligonucleotide has a length of 14 to 21 linked nucleosides and is fully complementary to the first modified oligonucleotide.

[0107] Certain embodiments provide a compound comprising a first modified oligonucleotide selected from the group consisting of any one of IA0500, IA1019, IA1022-1024, IA1027, IA1093-1095 and IA1103, and a second modified oligonucleotide selected from the group consisting of IS1255, IS1258, IS1259, IS1260, IS1279, IS1280, IS1372-1375, IS1381 and IS1382. In certain embodiments, the compound comprises a first modified oligonucleotide consisting of IA1024 and a second modified oligonucleotide consisting of IS1260. In certain embodiments, the compound comprises a first modified oligonucleotide consisting of IA1094 and a second modified oligonucleotide consisting of IS1374. In certain embodiments, the compound comprises a first modified oligonucleotide consisting of IA1103 and a second modified oligonucleotide consisting of IS1382.

[0108] In one aspect, provided herein is a modified oligonucleotide according to the following chemical structure:

[0109]

[0110] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, Ref ID NO: IA1094 is a modified oligonucleotide according to the aforementioned chemical structure or a pharmaceutically acceptable salt or stereoisomer thereof.

[0111] In one aspect, provided herein is a modified oligonucleotide according to the following chemical structure:

[0112]

[0113] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, Ref ID NO: IS1374 is a modified oligonucleotide according to the aforementioned chemical structure or a pharmaceutically acceptable salt or stereoisomer thereof.

[0114] In one aspect, provided herein is a modified oligonucleotide according to the following chemical structure:

[0115]

[0116] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, Ref ID NO: IA1103 is a modified oligonucleotide according to the aforementioned chemical structure or a pharmaceutically acceptable salt or stereoisomer thereof.

[0117] In one aspect, provided herein is a modified oligonucleotide according to the following chemical structure:

[0118]

[0119] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, Ref ID NO: IS1382 is a modified oligonucleotide according to the aforementioned chemical structure or a pharmaceutically acceptable salt or stereoisomer thereof.

[0120] In one aspect, provided herein is a compound according to the following chemical structure:

[0121]

[0122] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, compound No. RD3058 is a compound according to the aforementioned chemical structure or a pharmaceutically acceptable salt or stereoisomer thereof.

[0123] In one aspect, provided herein is a compound according to the following chemical structure:

[0124]

[0125] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, compound number RD3050 is a compound according to the aforementioned chemical structure or a pharmaceutically acceptable salt or stereoisomer thereof.

[0126] In certain embodiments, the pharmaceutically acceptable salts of the modified oligonucleotides provided herein are sodium or potassium salts. In certain embodiments, the pharmaceutically acceptable salts of the compounds provided herein are sodium or potassium salts.

[0127] In one aspect, provided herein is a sodium salt of a modified oligonucleotide according to the following chemical structure:

[0128]

[0129] In certain embodiments, Ref ID NO: IA1094 is a modified oligonucleotide according to the aforementioned chemical structure or a stereoisomer thereof.

[0130] In one aspect, provided herein is a sodium salt of a modified oligonucleotide according to the following chemical structure:

[0131]

[0132] In certain embodiments, Ref ID NO: IS1374 is a modified oligonucleotide according to the aforementioned chemical structure or a stereoisomer thereof.

[0133] In one aspect, provided herein is a sodium salt of a modified oligonucleotide according to the following chemical structure:

[0134]

[0135] In certain embodiments, Ref ID NO: IA1103 is a modified oligonucleotide according to the aforementioned chemical structure or a stereoisomer thereof.

[0136] In one aspect, provided herein is a sodium salt of a modified oligonucleotide according to the following chemical structure:

[0137]

[0138] In certain embodiments, Ref ID NO: IS1382 is a modified oligonucleotide according to the aforementioned chemical structure or a stereoisomer thereof.

[0139] In one aspect, provided herein is a sodium salt of a compound according to the following chemical structure:

[0140]

[0141] In certain embodiments, compound No. RD3058 is a compound according to the aforementioned chemical structure or a stereoisomer thereof.

[0142] In one aspect, provided herein is a sodium salt of a compound according to the following chemical structure:

[0143]

[0144] In certain embodiments, compound No. RD3050 is a compound according to the aforementioned chemical structure or a stereoisomer thereof.

[0145] In certain embodiments, provided herein are populations of modified oligonucleotides, wherein all phosphorothioate internucleoside linkages of the modified oligonucleotides are stereo-random. In certain embodiments, provided herein are populations of compounds, wherein all phosphorothioate internucleoside linkages of the modified oligonucleotides are stereo-random.

[0146] In certain embodiments, the compound of any of the preceding embodiments is in the form of a pharmaceutically acceptable salt. In certain embodiments, the pharmaceutically acceptable salt is a sodium salt. In certain embodiments, the pharmaceutically acceptable salt is a potassium salt.

[0147] Certain embodiments provide a composition comprising a compound of any one of the preceding embodiments and a pharmaceutically acceptable carrier.

[0148] Certain embodiments provide a composition comprising a compound of any preceding embodiment for use in therapy.

[0149] Certain embodiments provide a method of treating, preventing or ameliorating a disease, disorder or condition associated with AGT in a subject, the method comprising administering to the subject a compound that targets AGT, thereby treating, preventing or ameliorating the disease.

[0150] In certain embodiments, a compound or composition of any of the preceding embodiments is administered to an individual. In certain embodiments, the disease, disorder or condition is a RAAS-related disease, disorder or condition or a symptom thereof or hypertension, resistant hypertension, fibrosis, renal disease, chronic kidney disease, cardiovascular disease (e.g., coronary heart disease, heart failure, stroke, myocardial infarction, atrial fibrillation, aneurysm, and peripheral arterial disease), organ damage (e.g., heart, liver, or kidney), inflammatory bowel disease, or cognitive impairment.

[0151] In certain embodiments, administration of the compound inhibits or reduces or ameliorates RAAS-related diseases, disorders or conditions or symptoms thereof or hypertension, resistant hypertension, fibrosis, renal disease, chronic kidney disease, cardiovascular disease (e.g., coronary heart disease, heart failure, stroke, myocardial infarction, atrial fibrillation, aneurysm and peripheral arterial disease), organ damage (e.g., heart, liver or kidney), inflammatory bowel disease or cognitive impairment.

[0152] In certain embodiments, a compound of any of the foregoing embodiments or a composition comprising a compound is administered to an individual in a therapeutically effective amount. In certain embodiments, a compound of any of the foregoing embodiments or a composition comprising a compound is administered to an individual in a dose sufficient to deliver about 1 to 100 mg / kg of individual body weight. In certain embodiments, a compound of any of the foregoing embodiments or a composition comprising a compound is administered to an individual at a fixed dose of about 25 mg to about 1,000 mg. In certain embodiments, a compound or composition is administered to an individual once or more in a day until the dose level or fixed dose is reached.

[0153] In certain embodiments, the compound of any of the foregoing embodiments or a composition comprising the compound is administered to an individual every day, every week, every month, every quarter, or every year. In certain embodiments, the compound of any of the foregoing embodiments or a composition comprising the compound is administered to an individual about once a quarter (i.e., once every three months) to about once a year. In certain embodiments, the compound of any of the foregoing embodiments or a composition comprising the compound is administered to an individual about once a quarter, about once every six months, or about once a year.

[0154] Certain embodiments provide a method of inhibiting the expression of AGT in a cell, the method comprising contacting the cell with a compound targeting AGT, thereby inhibiting the expression of AGT in the cell. In certain embodiments, the cell is in the liver of an individual. In certain embodiments, the individual suffers from or is at risk of suffering from a RAAS-related disease, disorder or illness or its symptoms or hypertension, refractory hypertension, fibrosis, nephropathy, chronic kidney disease, cardiovascular disease (e.g., coronary heart disease, heart failure, stroke, myocardial infarction, atrial fibrillation, aneurysm and peripheral arterial disease), organ damage (e.g., heart, liver or kidney), inflammatory bowel disease or cognitive impairment.

[0155] Certain embodiments provide a method for reducing or inhibiting a subject's RAAS-related disease, disorder or condition or its symptoms or hypertension, resistant hypertension, fibrosis, renal disease, chronic kidney disease, cardiovascular disease (e.g., coronary heart disease, heart failure, stroke, myocardial infarction, atrial fibrillation, aneurysm and peripheral arterial disease), organ damage (e.g., heart, liver or kidney), inflammatory bowel disease or cognitive impairment, the method comprising administering to the subject a compound targeting AGT, thereby reducing or inhibiting the subject's RAAS-related disease, disorder or condition or its symptoms or hypertension, resistant hypertension, fibrosis, renal disease, chronic kidney disease, cardiovascular disease (e.g., coronary heart disease, heart failure, stroke, myocardial infarction, atrial fibrillation, aneurysm and peripheral arterial disease), organ damage (e.g., heart, liver or kidney), inflammatory bowel disease or cognitive impairment. In certain embodiments, the individual suffers from or is at risk of RAAS-related diseases, disorders or illnesses or their symptoms or hypertension, refractory hypertension, fibrosis, nephropathy, chronic kidney disease, cardiovascular disease (e.g., coronary heart disease, heart failure, stroke, myocardial infarction, atrial fibrillation, aneurysm and peripheral arterial disease), organ damage (e.g., heart, liver or kidney), inflammatory bowel disease or cognitive impairment. In certain embodiments, the compound is a compound targeting AGT. In certain embodiments, the compound is any one of the aforementioned compounds. In certain embodiments, the compound or composition is administered parenterally.

[0156] Certain embodiments provide the use of a compound targeting AGT for treating, preventing or improving a disease, disorder or illness associated with AGT. In certain embodiments, the disease, disorder or illness is a RAAS-related disease, disorder or illness or its symptoms or hypertension, refractory hypertension, fibrosis, nephropathy, chronic kidney disease, cardiovascular disease (e.g., coronary heart disease, heart failure, stroke, myocardial infarction, atrial fibrillation, aneurysm and peripheral arterial disease), organ damage (e.g., heart, liver or kidney), inflammatory bowel disease or cognitive impairment. In certain embodiments, the compound is a compound targeting AGT. In certain embodiments, the compound is any one of the aforementioned compounds.

[0157] Certain embodiments provide the use of a compound targeting AGT for the manufacture of a medicament for treating, preventing or improving a disease, disorder or illness associated with AGT. In certain embodiments, the disease, disorder or illness is a RAAS-related disease, disorder or illness or its symptoms or hypertension, refractory hypertension, fibrosis, nephropathy, chronic kidney disease, cardiovascular disease (e.g., coronary heart disease, heart failure, stroke, myocardial infarction, atrial fibrillation, aneurysm and peripheral arterial disease), organ damage (e.g., heart, liver or kidney), inflammatory bowel disease or cognitive impairment. In certain embodiments, the compound is a compound targeting AGT. In certain embodiments, the compound is any one of the aforementioned compounds.

[0158] Certain indications

[0159] In certain aspects, the disclosure relates to methods of inhibiting AGT expression, which can be used to treat, prevent or improve an individual's AGT-related disease by administering a compound targeting AGT. In certain embodiments, the compound may be an AGT-specific inhibitor. In certain embodiments, the compound may be an antisense oligonucleotide, an oligomeric compound or an oligonucleotide targeting AGT.

[0160] In certain aspects, the disclosure relates to treating, preventing or ameliorating diseases, disorders or conditions associated with AGT. In certain embodiments, diseases, disorders or conditions associated with AGT that can be treated, prevented and / or improved using the methods provided herein include RAAS-related diseases, disorders or conditions or symptoms thereof or hypertension, refractory hypertension, fibrosis, nephropathy, chronic kidney disease, cardiovascular disease (e.g., coronary heart disease, heart failure, stroke, myocardial infarction, atrial fibrillation, aneurysm and peripheral arterial disease), organ damage (e.g., heart, liver or kidney), inflammatory bowel disease or cognitive impairment. Certain compounds provided herein relate to compounds and compositions that reduce RAAS-related diseases, disorders or conditions or symptoms thereof or hypertension, refractory hypertension, fibrosis, nephropathy, chronic kidney disease, cardiovascular disease (e.g., coronary heart disease, heart failure, stroke, myocardial infarction, atrial fibrillation, aneurysm and peripheral arterial disease), organ damage (e.g., heart, liver or kidney), inflammatory bowel disease or cognitive impairment in animals.

[0161] In certain embodiments, the method for treating, preventing or improving an individual's disease associated with AGT includes administering a compound comprising an AGT specific inhibitor to the individual, thereby treating, preventing or improving the disease. In certain embodiments, the individual is identified as suffering from a disease associated with AGT, or has the risk of suffering from the disease. In certain embodiments, the disease is a RAAS-related disease. In certain embodiments, the compound comprises an antisense oligonucleotide targeting AGT. In certain embodiments, the compound comprises an oligonucleotide targeting AGT. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a length of 14 to 30, e.g., 14 to 23 linked nucleosides), which has a core base sequence comprising any one of 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 continuous core bases of the core base sequence SEQ ID NO: 11-20. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising any one of the nucleobase sequences SEQ ID NOs: 11-20. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of a nucleobase sequence of any one of SEQ ID NOs: 11-20. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence of 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 consecutive nucleobases comprising any one of the nucleobase sequences SEQ ID NOs: 16, 18, or 20. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence of 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 consecutive nucleobases comprising any one of the nucleobase sequences SEQ ID NO: 36, 39, or 42. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequences of SEQ ID NO: 16, SEQ ID NO: 18, and SEQ ID NO: 20. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequences of SEQ ID NO: 36, SEQ ID NO: 39, and SEQ ID NO: 42. In certain embodiments, the compound comprises a first modified oligonucleotide having the nucleobase sequence of SEQ ID NO: 16 and a second modified oligonucleotide having the nucleobase sequence of SEQ ID NO: 36.In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 18 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 39. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 20 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 42. In any of the foregoing embodiments, the compound may be single-stranded or double-stranded. In certain embodiments, the length of the single-stranded compound may be 14 to 30, 14 to 23, 14 to 20, 16 to 20, or 14 to 16 linked nucleosides. In certain embodiments, the length of the single-stranded compound may be 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 linked nucleosides. In certain embodiments, the double-stranded compound may comprise two oligonucleotides of the same or different lengths, as described elsewhere herein. In any one of the aforementioned embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30 in length, e.g., 14 to 23 linkage nucleosides) and a second modified oligonucleotide (e.g., 14 to 30 in length, e.g., 14 to 23 linkage nucleosides), the first modified oligonucleotide having a core base sequence comprising any one of SEQ ID NO: 11-20 or 31-42 of 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 continuous core bases, the second modified oligonucleotide having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length), the first modified oligonucleotide having a nucleobase sequence comprising any one of the nucleobase sequences SEQ ID NO: 11-20 or 31-42, the second modified oligonucleotide having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NO: 11-20 and 31-42, the second modified oligonucleotide having a length of 19 to 23 linked nucleosides and having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound is administered parenterally to an individual.In certain embodiments, administration of the compound improves, maintains or prevents a RAAS-associated disease, disorder or condition or a symptom thereof, or hypertension, resistant hypertension, fibrosis, renal disease, chronic kidney disease, cardiovascular disease (e.g., coronary heart disease, heart failure, stroke, myocardial infarction, atrial fibrillation, aneurysm and peripheral arterial disease), organ damage (e.g., heart, liver or kidney), inflammatory bowel disease or cognitive impairment in an animal.

[0162] In certain embodiments, a method for treating, preventing or improving RAAS-related diseases, disorders or conditions or symptoms thereof or hypertension, refractory hypertension, fibrosis, nephropathy, chronic kidney disease, cardiovascular disease (e.g., coronary heart disease, heart failure, stroke, myocardial infarction, atrial fibrillation, aneurysm and peripheral arterial disease), organ damage (e.g., heart, liver or kidney), inflammatory bowel disease or cognitive impairment in an animal, the method comprising administering a compound comprising an AGT-specific inhibitor to an individual, thereby treating, preventing or improving RAAS-related diseases, disorders or conditions or symptoms thereof or hypertension, refractory hypertension, fibrosis, nephropathy, chronic kidney disease, cardiovascular disease (e.g., coronary heart disease, heart failure, stroke, myocardial infarction, atrial fibrillation, aneurysm and peripheral arterial disease), organ damage (e.g., heart, liver or kidney), inflammatory bowel disease or cognitive impairment. In certain embodiments, the compound comprises an antisense oligonucleotide targeting AGT. In certain embodiments, the compound comprises an oligonucleotide targeting AGT. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence of 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 consecutive nucleobases comprising the nucleobase sequence of any one of SEQ ID NOs: 11-20. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-20. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of any one of SEQ ID NOs: 11-20. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 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 consecutive nucleobases of any one of the nucleobase sequences SEQ ID NO: 16, 18, or 20. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 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 consecutive nucleobases of any one of the nucleobase sequences SEQ ID NO: 36, 39, or 42. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequences of SEQ ID NO:16, SEQ ID NO:18, and SEQ ID NO:20.In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of a nucleobase sequence of SEQ ID NO: 36, SEQ ID NO: 39, and SEQ ID NO: 42. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 16 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 36. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 18 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 39. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 20 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 42. In any of the foregoing embodiments, the compound may be single-stranded or double-stranded. In any of the foregoing embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence of 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 consecutive nucleobases comprising the nucleobase sequence of any one of SEQ ID NOs: 11-20 or 31-42, and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30 in length, e.g., 14 to 23 linked nucleosides) and a second modified oligonucleotide (e.g., 14 to 30 in length, e.g., 14 to 23 linked nucleosides), the first modified oligonucleotide having a nucleobase sequence comprising any one of the nucleobase sequences SEQ ID NO: 11-20 or 31-42, the second modified oligonucleotide having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NO: 11-20 and 31-42, the second modified oligonucleotide having a length of 19 to 23 linked nucleosides and having a region complementary to the first modified oligonucleotide.In certain embodiments, administration of the compound improves, maintains or prevents RAAS-related diseases, disorders or conditions or symptoms thereof or hypertension, resistant hypertension, fibrosis, renal disease, chronic kidney disease, cardiovascular disease (e.g., coronary heart disease, heart failure, stroke, myocardial infarction, atrial fibrillation, aneurysm and peripheral arterial disease), organ damage (e.g., heart, liver or kidney), inflammatory bowel disease or cognitive impairment in an animal. In certain embodiments, an individual is identified as having a disease associated with AGT, or as being at risk of developing the disease.

[0163] In certain embodiments, a method of suppressing the expression of AGT in an individual suffering from or at risk of suffering from a disease associated with AGT comprises administering a compound comprising an AGT-specific inhibitor to the individual, thereby suppressing the expression of AGT in the individual. In certain embodiments, administering a compound suppresses the expression of AGT in the liver. In certain embodiments, the disease is a RAAS-related disease. In certain embodiments, the individual suffers from or is at risk of suffering from a RAAS-related disease, disorder or illness or its symptoms or hypertension, refractory hypertension, fibrosis, nephropathy, chronic kidney disease, cardiovascular disease (e.g., coronary heart disease, heart failure, stroke, myocardial infarction, atrial fibrillation, aneurysm and peripheral arterial disease), organ damage (e.g., heart, liver or kidney), inflammatory bowel disease or cognitive impairment. In certain embodiments, the compound comprises an antisense oligonucleotide targeting AGT. In certain embodiments, the compound comprises an oligonucleotide targeting AGT. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence of 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 consecutive nucleobases comprising the nucleobase sequence of any one of SEQ ID NOs: 11-20. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-20. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of any one of SEQ ID NOs: 11-20. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 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 consecutive nucleobases of any one of the nucleobase sequences SEQ ID NO: 16, 18, or 20. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 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 consecutive nucleobases of any one of the nucleobase sequences SEQ ID NO: 36, 39, or 42. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequences of SEQ ID NO:16, SEQ ID NO:18, and SEQ ID NO:20.In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of a nucleobase sequence of SEQ ID NO: 36, SEQ ID NO: 39, and SEQ ID NO: 42. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 16 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 36. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 18 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 39. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 20 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 42. In any of the foregoing embodiments, the compound may be single-stranded or double-stranded. In any of the foregoing embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence of 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 consecutive nucleobases comprising the nucleobase sequence of any one of SEQ ID NOs: 11-20 or 31-42, and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length), the first modified oligonucleotide having a nucleobase sequence comprising any one of the nucleobase sequences SEQ ID NO: 11-20 or 31-42, the second modified oligonucleotide having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NO: 11-20 and 31-42, the second modified oligonucleotide having a length of 19 to 23 linked nucleosides and having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound is administered parenterally to an individual.In certain embodiments, administration of the compound improves, maintains or prevents a RAAS-associated disease, disorder or condition or symptoms thereof, hypertension, resistant hypertension, fibrosis, renal disease, chronic kidney disease, cardiovascular disease (e.g., coronary heart disease, heart failure, stroke, myocardial infarction, atrial fibrillation, aneurysm and peripheral arterial disease), organ damage (e.g., heart, liver or kidney), inflammatory bowel disease or cognitive impairment.

[0164] In certain embodiments, a method of inhibiting AGT expression in a cell includes contacting the cell with a compound comprising an AGT specific inhibitor, thereby inhibiting AGT expression in the cell. In certain embodiments, the cell is a hepatocyte. In certain embodiments, the cell is in the liver. In certain embodiments, the cell is in the liver of an individual suffering from or at risk of RAAS-related diseases, disorders or illnesses or their symptoms or hypertension, refractory hypertension, fibrosis, nephropathy, chronic kidney disease, cardiovascular disease (e.g., coronary heart disease, heart failure, stroke, myocardial infarction, atrial fibrillation, aneurysm and peripheral arterial disease), organ damage (e.g., heart, liver or kidney), inflammatory bowel disease or cognitive impairment. In certain embodiments, the compound comprises an antisense oligonucleotide targeting AGT. In certain embodiments, the compound comprises an oligonucleotide targeting AGT. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence of 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 consecutive nucleobases comprising the nucleobase sequence of any one of SEQ ID NOs: 11-20. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-20. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of any one of SEQ ID NOs: 11-20. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 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 consecutive nucleobases of any one of the nucleobase sequences SEQ ID NO: 16, 18, or 20. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 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 consecutive nucleobases of any one of the nucleobase sequences SEQ ID NO: 36, 39, or 42. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequences of SEQ ID NO:16, SEQ ID NO:18, and SEQ ID NO:20.In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of a nucleobase sequence of SEQ ID NO: 36, SEQ ID NO: 39, and SEQ ID NO: 42. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 16 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 36. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 18 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 39. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 20 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 42. In any of the foregoing embodiments, the compound may be single-stranded or double-stranded. In any of the foregoing embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence of 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 consecutive nucleobases comprising the nucleobase sequence of any one of SEQ ID NOs: 11-20 or 31-42, and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30 in length, e.g., 14 to 23 linked nucleosides) and a second modified oligonucleotide (e.g., 14 to 30 in length, e.g., 14 to 23 linked nucleosides), the first modified oligonucleotide having a nucleobase sequence comprising any one of the nucleobase sequences SEQ ID NO: 11-20 or 31-42, the second modified oligonucleotide having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NO: 11-20 and 31-42, the second modified oligonucleotide having a length of 19 to 23 linked nucleosides and having a region complementary to the first modified oligonucleotide.

[0165] In certain embodiments, a method of reducing or inhibiting a RAAS-related disease, disorder or condition or symptoms thereof, or hypertension, resistant hypertension, fibrosis, renal disease, chronic kidney disease, cardiovascular disease (e.g., coronary heart disease, heart failure, stroke, myocardial infarction, atrial fibrillation, aneurysm and peripheral arterial disease), organ damage (e.g., heart, liver or kidney), inflammatory bowel disease, or cognitive impairment in an individual suffering from or at risk of developing a disease associated with AGT, the method comprising administering to the individual a compound comprising an AGT-specific inhibitor, thereby reducing or inhibiting the individual's RAAS-related disease, disorder or condition or symptoms thereof, or hypertension, resistant hypertension, fibrosis, renal disease, chronic kidney disease, cardiovascular disease (e.g., coronary heart disease, heart failure, stroke, myocardial infarction, atrial fibrillation, aneurysm and peripheral arterial disease), organ damage (e.g., heart, liver or kidney), inflammatory bowel disease, or cognitive impairment. In certain embodiments, the individual suffers from or is at risk of developing a RAAS-related disease, disorder or condition or a symptom thereof, or hypertension, resistant hypertension, fibrosis, renal disease, chronic kidney disease, cardiovascular disease (e.g., coronary heart disease, heart failure, stroke, myocardial infarction, atrial fibrillation, aneurysm, and peripheral arterial disease), organ damage (e.g., heart, liver, or kidney), inflammatory bowel disease, or cognitive impairment. In certain embodiments, the compound comprises an antisense oligonucleotide targeting AGT. In certain embodiments, the compound comprises an oligonucleotide targeting AGT. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 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 consecutive nucleobases of any one of the nucleobase sequences SEQ ID NO: 11-20. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising any one of the nucleobase sequences SEQ ID NOs: 11-20. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of a nucleobase sequence of any one of SEQ ID NOs: 11-20. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence of 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 consecutive nucleobases comprising any one of the nucleobase sequences SEQ ID NOs: 16, 18, or 20.In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence of 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 consecutive nucleobases comprising any one of the nucleobase sequences SEQ ID NO: 36, 39, or 42. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequences of SEQ ID NO: 16, SEQ ID NO: 18, and SEQ ID NO: 20. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequences of SEQ ID NO: 36, SEQ ID NO: 39, and SEQ ID NO: 42. In certain embodiments, the compound comprises a first modified oligonucleotide having the nucleobase sequence of SEQ ID NO: 16 and a second modified oligonucleotide having the nucleobase sequence of SEQ ID NO: 36. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 18 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 39. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 20 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 42. In any of the foregoing embodiments, the compound may be single-stranded or double-stranded. In any of the foregoing embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence of 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 consecutive nucleobases comprising the nucleobase sequence of any one of SEQ ID NOs: 11-20 or 31-42, and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length), wherein the first modified oligonucleotide has a nucleobase sequence comprising any one of the nucleobase sequences SEQ ID NO: 11-20 or 31-42, and the second modified oligonucleotide has a region complementary to the first modified oligonucleotide.In certain embodiments, the compound comprises 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 having a length of 19 to 23 linked nucleosides and having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound is administered parenterally to an individual. In certain embodiments, the individual is identified as having a disease associated with AGT, or having a risk of developing the disease.

[0166] Certain embodiments relate to compounds comprising AGT specific inhibitors for the treatment of diseases, disorders or illnesses associated with AGT. In certain embodiments, the disease, disorder or illness is a RAAS-related disease, disorder or illness or its symptoms or hypertension, refractory hypertension, fibrosis, nephropathy, chronic kidney disease, cardiovascular disease (e.g., coronary heart disease, heart failure, stroke, myocardial infarction, atrial fibrillation, aneurysm and peripheral arterial disease), organ damage (e.g., heart, liver or kidney), inflammatory bowel disease or cognitive impairment. In certain embodiments, the compound comprises an antisense oligonucleotide targeting AGT. In certain embodiments, the compound comprises an oligonucleotide targeting AGT. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence of 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 consecutive nucleobases comprising the nucleobase sequence of any one of SEQ ID NOs: 11-20. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-20. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of any one of SEQ ID NOs: 11-20. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 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 consecutive nucleobases of any one of the nucleobase sequences SEQ ID NO: 16, 18, or 20. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 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 consecutive nucleobases of any one of the nucleobase sequences SEQ ID NO: 36, 39, or 42. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequences of SEQ ID NO: 16, SEQ ID NO: 18, and SEQ ID NO: 20. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequences of SEQ ID NO: 36, SEQ ID NO: 39, and SEQ ID NO: 42.In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 16 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 36. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 18 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 39. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 20 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 42. In any of the foregoing embodiments, the compound may be single-stranded or double-stranded. In any of the foregoing embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence of 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 consecutive nucleobases comprising the nucleobase sequence of any one of SEQ ID NOs: 11-20 or 31-42, and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length), the first modified oligonucleotide having a nucleobase sequence comprising any one of the nucleobase sequences SEQ ID NO: 11-20 or 31-42, the second modified oligonucleotide having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NO: 11-20 and 31-42, the second modified oligonucleotide having a length of 19 to 23 linked nucleosides and having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound is administered parenterally to an individual.

[0167] Certain embodiments relate to compounds comprising AGT-specific inhibitors for reducing or inhibiting RAAS-related diseases, disorders or conditions or symptoms thereof or hypertension, resistant hypertension, fibrosis, nephropathy, chronic kidney disease, cardiovascular disease (e.g., coronary heart disease, heart failure, stroke, myocardial infarction, atrial fibrillation, aneurysm and peripheral arterial disease), organ damage (e.g., heart, liver or kidney), inflammatory bowel disease or cognitive impairment. In certain embodiments, the compound comprises an antisense oligonucleotide targeting AGT. In certain embodiments, the compound comprises an oligonucleotide targeting AGT. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30 in length, e.g., 14 to 23 linked nucleosides) 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 consecutive nucleobases of any one of the nucleobase sequences SEQ ID NO: 11-20. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising any one of the nucleobase sequences SEQ ID NOs: 11-20. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of a nucleobase sequence of any one of SEQ ID NOs: 11-20. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence of 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 consecutive nucleobases comprising the nucleobase sequence of any one of SEQ ID NOs: 11-20 or 31-42, and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length), wherein the first modified oligonucleotide has a nucleobase sequence comprising any one of the nucleobase sequences SEQ ID NO: 11-20 or 31-42, and the second modified oligonucleotide has a region complementary to the first modified oligonucleotide.In certain embodiments, the compound comprises 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 having a length of 19 to 23 linked nucleosides and having a region complementary to the first modified oligonucleotide.

[0168] Certain embodiments relate to the use of a compound comprising an AGT specific inhibitor for the manufacture or preparation of a medicament for treating a disease associated with AGT. Certain embodiments relate to the use of a compound comprising an AGT specific inhibitor for the preparation of a medicament for treating a disease, disorder or illness associated with AGT. In certain embodiments, the disease, disorder or illness is a RAAS-related disease, disorder or illness or a symptom thereof. In certain embodiments, the disease, disorder or illness is hypertension, refractory hypertension, fibrosis, nephropathy, chronic kidney disease, cardiovascular disease (e.g., coronary heart disease, heart failure, stroke, myocardial infarction, atrial fibrillation, aneurysm and peripheral arterial disease), organ damage (e.g., heart, liver or kidney), inflammatory bowel disease or cognitive impairment. In certain embodiments, the compound comprises an antisense oligonucleotide targeting AGT. In certain embodiments, the compound comprises an oligonucleotide targeting AGT. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence of 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 consecutive nucleobases comprising the nucleobase sequence of any one of SEQ ID NOs: 11-20. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-20. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of any one of SEQ ID NOs: 11-20. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 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 consecutive nucleobases of any one of the nucleobase sequences SEQ ID NO: 16, 18, or 20. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 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 consecutive nucleobases of any one of the nucleobase sequences SEQ ID NO: 36, 39, or 42. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequences of SEQ ID NO:16, SEQ ID NO:18, and SEQ ID NO:20.In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of a nucleobase sequence of SEQ ID NO: 36, SEQ ID NO: 39, and SEQ ID NO: 42. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 16 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 36. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 18 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 39. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 20 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 42. In any of the foregoing embodiments, the compound may be single-stranded or double-stranded. In any of the foregoing embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence of 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 consecutive nucleobases comprising the nucleobase sequence of any one of SEQ ID NOs: 11-20 or 31-42, and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30 in length, e.g., 14 to 23 linked nucleosides) and a second modified oligonucleotide (e.g., 14 to 30 in length, e.g., 14 to 23 linked nucleosides), the first modified oligonucleotide having a nucleobase sequence comprising any one of the nucleobase sequences SEQ ID NO: 11-20 or 31-42, the second modified oligonucleotide having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NO: 11-20 and 31-42, the second modified oligonucleotide having a length of 19 to 23 linked nucleosides and having a region complementary to the first modified oligonucleotide.

[0169] Certain embodiments relate to the use of a compound comprising an AGT-specific inhibitor for the manufacture or preparation of a medicament for reducing or inhibiting a RAAS-related disease, disorder or condition or its symptoms in an individual suffering from or at risk of suffering from a RAAS-related disease, disorder or condition or its symptoms associated with AGT. In certain embodiments, the RAAS-related disease, disorder or condition is hypertension, resistant hypertension, fibrosis, nephropathy, chronic kidney disease, cardiovascular disease (e.g., coronary heart disease, heart failure, stroke, myocardial infarction, atrial fibrillation, aneurysm and peripheral arterial disease), organ damage (e.g., heart, liver or kidney), inflammatory bowel disease or cognitive impairment. Certain embodiments relate to the use of a compound comprising an AGT-specific inhibitor for the preparation of a medicament for treating a disease, disorder or condition associated with AGT. In certain embodiments, the disease, disorder or condition is a RAAS-related disease, disorder or condition or a symptom thereof or hypertension, refractory hypertension, fibrosis, renal disease, chronic kidney disease, cardiovascular disease (e.g., coronary heart disease, heart failure, stroke, myocardial infarction, atrial fibrillation, aneurysm and peripheral arterial disease), organ damage (e.g., heart, liver or kidney), inflammatory bowel disease or cognitive impairment. In certain embodiments, the compound comprises an antisense oligonucleotide targeting AGT. In certain embodiments, the compound comprises an oligonucleotide targeting AGT. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30 in length, e.g., 14 to 23 linked nucleosides) 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 consecutive nucleobases of any one of the nucleobase sequences SEQ ID NO: 11-20. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising any one of the nucleobase sequences SEQ ID NOs: 11-20. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of a nucleobase sequence of any one of SEQ ID NOs: 11-20. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence of 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 consecutive nucleobases comprising any one of the nucleobase sequences SEQ ID NOs: 16, 18, or 20.In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence of 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 consecutive nucleobases comprising any one of the nucleobase sequences SEQ ID NO: 36, 39, or 42. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequences of SEQ ID NO: 16, SEQ ID NO: 18, and SEQ ID NO: 20. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequences of SEQ ID NO: 36, SEQ ID NO: 39, and SEQ ID NO: 42. In certain embodiments, the compound comprises a first modified oligonucleotide having the nucleobase sequence of SEQ ID NO: 16 and a second modified oligonucleotide having the nucleobase sequence of SEQ ID NO: 36. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 18 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 39. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 20 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 42. In any of the foregoing embodiments, the compound may be single-stranded or double-stranded. In any of the foregoing embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence of 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 consecutive nucleobases comprising the nucleobase sequence of any one of SEQ ID NOs: 11-20 or 31-42, and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length), wherein the first modified oligonucleotide has a nucleobase sequence comprising any one of the nucleobase sequences SEQ ID NO: 11-20 or 31-42, and the second modified oligonucleotide has a region complementary to the first modified oligonucleotide.In certain embodiments, the compound comprises 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 having a length of 19 to 23 linked nucleosides and having a region complementary to the first modified oligonucleotide.

[0170] In any of the aforementioned methods or uses, the compound may be an oligomeric compound. In any of the aforementioned methods or uses, the compound may be single-stranded or double-stranded. In any of the aforementioned methods or uses, the compound may target AGT. In certain embodiments, the compound comprises or consists of a modified oligonucleotide. In certain embodiments, the compound comprises one or more modified oligonucleotides. In certain embodiments, the compound comprises a first modified oligonucleotide and a second modified oligonucleotide. In certain embodiments, the length of the modified oligonucleotide is 8 to 80 linked nucleosides, a length of 10 to 30 linked nucleosides, a length of 14 to 30 linked nucleosides, a length of 14 to 23 linked nucleosides, or a length of 19 to 23 linked nucleosides. In certain embodiments, the modified oligonucleotide is at least 80%, at least 85%, at least 90%, at least 95%, or 100% complementary to any one of the nucleobase sequences described in SEQ ID NO: 1 and SEQ ID NO: 3 in its length. In certain embodiments, the modified oligonucleotide comprises at least one modified internucleoside linkage, at least one modified sugar and / or at least one modified nucleobase. In certain embodiments, the modified internucleoside linkage is a phosphorothioate internucleoside linkage. In certain embodiments, the modified sugar is a bicyclic sugar, 2'-MOE, 2'-F or 2'-OMe. In certain embodiments, the modified nucleobase is a 5-methylcytosine. In any one of the foregoing embodiments, the length of each modified oligonucleotide is independently 12 to 30, 14 to 30, 14 to 25, 14 to 24, 14 to 23, 16 to 23, 17 to 23, 18 to 23, 19 to 23, 19 to 22 or 19 to 20 bonded nucleosides. In certain embodiments, the modified oligonucleotide has at least 1, at least 2, at least 3 mismatches with the region of SEQ ID NO:1 and SEQ ID NO:3.

[0171] In any of the foregoing methods or uses, the compound comprises a first and a second modified oligonucleotide, wherein there is a complementary region between the first modified oligonucleotide and the second modified oligonucleotide. In certain embodiments, the length of the complementary region between the first oligonucleotide and the second oligonucleotide is 14 to 23, 19 to 23, or 21 to 23 bonded nucleosides. In certain embodiments, the first modified oligonucleotide is completely complementary to the second modified oligonucleotide. In certain embodiments, the first modified oligonucleotide comprises at least one modification selected from modified internucleoside linkages, modified sugars, and modified nucleobases. In certain embodiments, the second modified oligonucleotide comprises at least one modification selected from the group consisting of modified internucleoside linkages, modified sugars, and modified nucleobases. In certain embodiments, the modified internucleoside linkage is a phosphorothioate internucleoside linkage or a methylphosphonate internucleoside linkage. In certain embodiments, the modified internucleoside linkage is at the 3' end of the first or second modified oligonucleotide or the 5' end of the first or second modified oligonucleotide. In certain embodiments, the first or second modified oligonucleotide comprises one or more modified sugars. In certain embodiments, each nucleoside of the first or second modified oligonucleotide comprises a modified sugar. In certain embodiments, the modified sugar comprises a modification selected from the group consisting of halogen, alkoxy and bicyclic sugar. In certain embodiments, the modified sugar comprises a modification selected from the group consisting of 2'-MOE, 2'-F and 2'-OMe or a combination thereof. In certain embodiments, the first or second modified oligonucleotide comprises no more than ten 2'-F sugar modifications. In certain embodiments, the first or second modified oligonucleotide comprises no more than five 2'-F sugar modifications.

[0172] In any of the foregoing methods or uses, the compound comprises a conjugated group. In certain embodiments, the conjugated group is connected to the 5' end of the modified oligonucleotide. In certain embodiments, the conjugated group is a targeting moiety. In certain embodiments, the targeting moiety comprises one or more GalNAc. In certain embodiments, the one or more GalNAc is connected to the 2' or 3' position of the ribosyl ring. In certain embodiments, the one or more GalNAc is connected to the 5' nucleoside of the modified oligonucleotide. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is selected from Formula I to Formula VIII or a salt, solvate or hydrate thereof, wherein R is a modified oligonucleotide other than the 5' nucleoside. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula I and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula I and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula II and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula II and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula III and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula III and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula IV and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula IV and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula V and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula V and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula VI and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula VI and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula VII and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula VII and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula VIII and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula VIII and R' is S.

[0173] In any of the aforementioned methods or uses, the compound comprises a first modified oligonucleotide and a second modified oligonucleotide, wherein the first modified oligonucleotide is selected from the group consisting of any one of Ref ID NO: IA0500, IA1019, IA1022-1024, IA1027, IA1093-1095 and IA1103, and the second modified oligonucleotide has a length of 14 to 23 linked nucleosides and is fully complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide selected from the group consisting of IA0500, IA1019, IA1022-1024, IA1027, IA1093-1095, and IA1103, and a second modified oligonucleotide selected from the group consisting of IS1255, IS1258, IS1259, IS1260, IS1279, IS1280, IS1372-1375, IS1381, and IS1382. In certain embodiments, the compound comprises a first modified oligonucleotide consisting of IA1024 and a second modified oligonucleotide consisting of IS1260. In certain embodiments, the compound comprises a first modified oligonucleotide consisting of IA1094 and a second modified oligonucleotide consisting of IS1374. In certain embodiments, the compound comprises a first modified oligonucleotide consisting of IA1103 and a second modified oligonucleotide consisting of IS1382. In certain embodiments, the compound is in the form of a pharmaceutically acceptable salt. In certain embodiments, the pharmaceutically acceptable salt is a sodium salt. In certain embodiments, the pharmaceutically acceptable salt is a potassium salt. In certain embodiments, the composition comprises a compound of any one of the foregoing embodiments and a pharmaceutically acceptable carrier.

[0174] In any of the foregoing methods or uses, a compound of any of the foregoing embodiments or a composition comprising a compound is administered to an individual in a therapeutically effective amount. In certain embodiments, a compound of any of the foregoing embodiments or a composition comprising a compound is administered to an individual in a dose sufficient to deliver about 1 to 100 mg / kg of individual body weight. In certain embodiments, a compound of any of the foregoing embodiments or a composition comprising a compound is administered to an individual at a fixed dose of about 25 mg to about 1,000 mg. In certain embodiments, a composition is administered to an individual once or more in a day, up to the dose level or fixed dose.

[0175] In any of the foregoing methods or uses, the compound of any of the foregoing embodiments or a composition comprising the compound is administered to an individual every day, every week, every month, every quarter or every year. In certain embodiments, the compound of any of the foregoing embodiments or a composition comprising the compound is administered to an individual about once a quarter (i.e., once every three months) to about once a year. In certain embodiments, the compound of any of the foregoing embodiments or a composition comprising the compound is administered to an individual about once a quarter, about once every six months or about once a year.

[0176] Certain compounds

[0177] In certain aspects, the disclosure relates to a compound comprising or consisting of an oligomeric compound. In certain embodiments, the oligomeric compound comprises a nucleobase sequence that is complementary to a nucleobase sequence of a target nucleic acid.

[0178] In certain aspects, the disclosure relates to a compound comprising or consisting of a modified oligonucleotide. In certain embodiments, the modified oligonucleotide has a nucleobase sequence that is complementary to a nucleobase sequence of a target nucleic acid.

[0179] In certain aspects, the disclosure relates to a compound comprising or consisting of an antisense oligonucleotide. In certain embodiments, the antisense oligonucleotide has a nucleobase sequence that is complementary to a nucleobase sequence of a target nucleic acid.

[0180] In certain aspects, the disclosure relates to a compound, which is a single-stranded compound. In certain embodiments, the single-stranded compound comprises or consists of an oligomeric compound. In certain embodiments, such oligomeric compounds comprise or consist of an oligonucleotide and optionally a conjugated group. In certain embodiments, the oligonucleotide is a modified oligonucleotide. In certain embodiments, the oligonucleotide is an antisense oligonucleotide. In certain embodiments, the oligonucleotide or modified oligonucleotide of the single-stranded compound comprises a self-complementary nucleobase sequence.

[0181] In certain aspects, the disclosure relates to a compound, which is a double-stranded compound. In certain embodiments, the double-stranded compound comprises an oligomeric compound or consists of it. In certain embodiments, the double-stranded compound comprises a first oligonucleotide and a second oligonucleotide. In certain embodiments, the first oligonucleotide has regional complementarity with a target nucleic acid and the second oligonucleotide has regional complementarity with a first modified oligonucleotide. In certain embodiments, the double-stranded compound comprises a modified oligonucleotide. In certain embodiments, the modified oligonucleotide has regional complementarity with a target nucleic acid. In certain embodiments, the double-stranded compound comprises a first modified oligonucleotide and a second modified oligonucleotide. In certain embodiments, the first modified oligonucleotide has regional complementarity with a target nucleic acid and the second modified oligonucleotide has regional complementarity with the first modified oligonucleotide. In certain embodiments, the oligonucleotide or modified oligonucleotide of the double-stranded compound is an RNA oligonucleotide. In such embodiments, the thymine nucleobase in the modified oligonucleotide is replaced by a uracil nucleobase.

[0182] In certain embodiments, the compounds described herein include conjugated groups. In certain embodiments, the first oligonucleotide or the first modified oligonucleotide of the double-stranded compound includes a conjugated group. In certain embodiments, the second oligonucleotide or the second modified oligonucleotide of the double-stranded compound includes a conjugated group. In certain embodiments, the first oligonucleotide or the first modified oligonucleotide and the second oligonucleotide or the second modified oligonucleotide of the double-stranded compound each include a conjugated group.

[0183] In certain embodiments, the length of the compound is 14 to 30 linked nucleosides. In certain embodiments, the length of the first oligonucleotide or the first modified oligonucleotide of the double-stranded compound is 14 to 30 linked nucleosides. In certain embodiments, the length of the second oligonucleotide or the second modified oligonucleotide is 14 to 30 linked nucleosides. In certain embodiments, the oligonucleotide or the modified oligonucleotide of the double-stranded compound is blunt-ended at one or both ends of the compound. In certain embodiments, the oligonucleotide or the modified oligonucleotide of the double-stranded compound includes non-complementary overhanging nucleosides at one or both ends of the compound.

[0184] In certain embodiments, the compound has a nucleobase sequence comprising at least 14 consecutive nucleobases of any one of SEQ ID NOs: 11-20. In certain embodiments, one of the oligonucleotides or modified oligonucleotides of the double-stranded compound has a nucleobase sequence comprising at least 14 consecutive nucleobases of any one of SEQ ID NOs: 11-20.

[0185] Examples of single-stranded and double-stranded compounds include, but are not limited to, oligonucleotides, antisense oligonucleotides, siRNAs, microRNA targeting oligonucleotides, occupancy-based compounds (e.g., mRNA processing or translation blocking compounds and splicing compounds), and single-stranded RNAi compounds (e.g., small hairpin RNA (shRNA), single-stranded siRNA (ssRNA), and microRNA mimics).

[0186] In certain embodiments, the compounds described herein have a nucleobase sequence that, when written in the 5' to 3' direction, comprises the reverse complement of a target region of a target nucleic acid to which it is targeted.

[0187] In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 12 to 30 linkage subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 12 to 23 linkage subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 14 to 30 linkage subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 14 to 23 linkage subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 15 to 30 linkage subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 15 to 23 linkage subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 16 to 30 linkage subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 16 to 23 linkage subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 17 to 30 linkage subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 17 to 23 linkage subunits. In certain embodiments, the compounds described herein include oligonucleotides having a length of 18 to 30 linkage subunits. In certain embodiments, the compounds described herein include oligonucleotides having a length of 18 to 23 linkage subunits. In certain embodiments, the compounds described herein include oligonucleotides having a length of 19 to 30 linkage subunits. In certain embodiments, the compounds described herein include oligonucleotides having a length of 19 to 23 linkage subunits. In other words, such oligonucleotides are 12 to 30 linkage subunits, 12 to 23 linkage subunits, 14 to 30 linkage subunits, 14 to 23 linkage subunits, 15 to 30 linkage subunits, 15 to 23 linkage subunits, 16 to 30 linkage subunits, 16 to 23 linkage subunits, 17 to 30 linkage subunits, 17 to 23 linkage subunits, 18 to 30 linkage subunits, 18 to 23 linkage subunits, 19 to 30 linkage subunits, or 19 to 23 linkage subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 14 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 16 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 17 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 18 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 19 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 20 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 21 linked subunits.In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 22 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 23 linked subunits. In other embodiments, the compounds described herein comprise oligonucleotides having a length of 8 to 80, 12 to 50, 13 to 30, 13 to 50, 14 to 30, 14 to 50, 15 to 30, 15 to 50, 16 to 30, 16 to 50, 17 to 30, 17 to 50, 18 to 23, 18 to 24, 18 to 25, 18 to 50, 19 to 23, 19 to 30, 19 to 50, 20 to 23, or 20 to 30 linked subunits. In certain such embodiments, the compounds described herein comprise oligonucleotides that are 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 linked subunits in length, or a range bounded by any two of the above values.

[0188] In certain embodiments, the compound may also include an additional portion, such as a conjugated group or a delivery portion. In certain embodiments, such compounds are oligomeric compounds, and the additional portion is connected to an oligonucleotide. In certain embodiments, the conjugated group is connected to the nucleoside of an oligonucleotide.

[0189] In certain embodiments, the compound may be shortened or truncated. For example, one or more subunits may be deleted from the 5' end of the oligonucleotide (5' truncation), or alternatively from the 3' end of the oligonucleotide (3' truncation).

[0190] In certain embodiments, the compound can be elongated. For example, one or more subunits can be connected to the 3' end or the 5' end of the oligonucleotide. In certain embodiments, at least one subunit (e.g., 1, 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 or more subunits) is connected to the 5' end of the oligonucleotide. In certain embodiments, at least one subunit (e.g., 1, 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 or more subunits) is attached to the 3' end of the oligonucleotide. In certain embodiments, at least one or more subunits may be attached to the 3' end or 5' end of the oligonucleotide of the double-stranded compound, thereby generating a 3' and / or 5' end overhang. In certain embodiments, at least one subunit (e.g., 1, 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 or more subunits) is attached to the 5' end of both oligonucleotides of the double-stranded compound. In certain embodiments, at least one subunit (e.g., 1, 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 or more subunits) is connected to the 3' end of the two oligonucleotides of the double-stranded compound. In certain embodiments, the subunit is connected to the two oligonucleotides of the double-stranded compound at the same end (e.g., the subunit is connected to the 3' end of one of the oligonucleotides and the subunit is connected to the 5' end of the other oligonucleotide). In certain embodiments, when the subunit is connected to the two oligonucleotides of the double-stranded compound at the same end, the number of subunits connected to each oligonucleotide may be the same or may be different.In certain embodiments, when a subunit is connected to two oligonucleotides of a double-stranded compound at the same end, the number of subunits connected to each oligonucleotide is the same. In certain embodiments, when a subunit is connected to two oligonucleotides of a double-stranded compound at the same end, the number of subunits connected to each oligonucleotide is different. This situation (wherein a subunit is connected to two oligonucleotides of a double-stranded compound at the same end) can occur at one or both ends of a double-stranded compound. In certain embodiments, the subunit connected to the 3' and / or 5' end is modified.

[0191] In certain embodiments, the compounds described herein are oligonucleotides. In certain embodiments, the compounds described herein are modified oligonucleotides. In certain embodiments, the compounds described herein are antisense oligonucleotides. In certain embodiments, the compounds described herein are oligomeric compounds. In certain embodiments, the compounds described herein are RNAi compounds. In certain embodiments, the compounds described herein are siRNA compounds.

[0192] In certain embodiments, the compounds described herein may comprise any of the oligonucleotide sequences targeting AGT described herein. In certain embodiments, the compounds may be double-stranded.

[0193] In certain embodiments, the compound comprises an oligonucleotide comprising at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleobase portions of any one of SEQ ID NOs: 11-20. In certain embodiments, the compound comprises an oligonucleotide comprising at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleobase portions of any one of SEQ ID NOs: 16, 18, or 20. In certain embodiments, the compound comprises a second oligonucleotide. In certain embodiments, the compound comprises an oligonucleotide comprising at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleobase portions of any one of SEQ ID NOs: 36, 39, or 42. In certain embodiments, the compound comprises a first oligonucleotide comprising at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleobase portions of SEQ ID NO: 16 and a second oligonucleotide comprising at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleobase portions of SEQ ID NO: 36. In certain embodiments, the compound comprises a first oligonucleotide comprising at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleobase portions of SEQ ID NO: 18 and a second oligonucleotide comprising at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleobase portions of SEQ ID NO: 39. In certain embodiments, the compound comprises a first oligonucleotide comprising at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleobase portions of SEQ ID NO:20 and a second oligonucleotide comprising at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleobase portions of SEQ ID NO:42.

[0194] In certain embodiments, the compound comprises ribonucleotides, wherein for any one of the sequences provided herein, the oligonucleotide has uracil (U) instead of thymine (T). In certain embodiments, the compound comprises deoxyribonucleotides, wherein for any one of the sequences provided herein, the oligonucleotide has thymine (T) instead of uracil (U).

[0195] Some mechanisms

[0196] In certain embodiments, the compounds described herein include modified oligonucleotides or consist of them. In certain embodiments, the compounds described herein include antisense oligonucleotides or consist of them. In certain embodiments, the compounds described herein include oligomeric compounds or consist of them. In certain embodiments, the compounds described herein can hybridize with target nucleic acids. In certain embodiments, the compounds described herein selectively affect one or more target nucleic acids. Such compounds include a core base sequence, which hybridizes with one or more target nucleic acids to produce one or more desired activities, and does not hybridize with one or more non-target nucleic acids or does not hybridize with one or more non-target nucleic acids in a manner that produces significant non-desired activities.

[0197] In certain embodiments, the hybridization of the compounds described herein with the target nucleic acid produces the recruitment of one or more proteins that cause the cracking of the target nucleic acid. For example, some compounds described herein or a portion of the compounds are loaded into the RNA-induced silencing complex (RISC), ultimately causing the cracking of the target nucleic acid. For example, some compounds described herein cause the target nucleic acid to be cracked by Argonaute. The compound loaded into RISC is an RNAi compound. The RNAi compound can be double-stranded (siRNA) or single-stranded (ssRNA).

[0198] In certain embodiments, the hybridization of the compound described herein with the target nucleic acid does not cause the recruitment of proteins that crack the target nucleic acid. In certain such embodiments, the hybridization of the compound with the target nucleic acid causes the splicing of the target nucleic acid to change. In certain embodiments, the hybridization of the compound with the target nucleic acid suppresses the binding interaction between the target nucleic acid and the protein or other nucleic acids. In certain such embodiments, the hybridization of the compound with the target nucleic acid causes RNA processing to change. In certain such embodiments, the hybridization of the compound with the target nucleic acid causes the translation of the target nucleic acid to change.

[0199] The activity produced by the hybridization of the compound to the target nucleic acid can be observed directly or indirectly. In certain embodiments, observing or detecting activity involves observing or detecting a change in the amount of a target nucleic acid or protein encoded by such target nucleic acid, a change in the ratio of a splicing variant of a nucleic acid or protein, and / or a phenotypic change in a cell or animal.

[0200] Some modifications

[0201] In certain aspects, the disclosure relates to compounds comprising or consisting of oligonucleotides. Oligonucleotides are composed of linked nucleosides. In certain embodiments, oligonucleotides may be unmodified RNA or DNA or may be modified. In certain embodiments, oligonucleotides are modified oligonucleotides. In certain embodiments, the modified oligonucleotides comprise at least one modified sugar, modified nucleobase or modified internucleoside linkage relative to unmodified RNA or DNA. In certain embodiments, oligonucleotides have modified nucleosides. Modified nucleosides may comprise modified sugars, modified nucleobases or both modified sugars and modified nucleobases. Modified oligonucleotides may also include end modifications, such as 5' end modifications and 3' end modifications.

[0202] Sugar modifications and motifs

[0203] In certain embodiments, the modified sugar is a substituted furanosyl sugar or a non-bicyclic modified sugar. In certain embodiments, the modified sugar is a bicyclic or tricyclic modified sugar. In certain embodiments, the modified sugar is a sugar surrogate. The sugar surrogate may comprise one or more substitutions described herein.

[0204] In certain embodiments, the modified sugar is a substituted furanosyl or non-bicyclic modified sugar. In certain embodiments, the furanosyl sugar is a ribosyl sugar. In certain embodiments, the furanosyl sugar comprises one or more substituents, including but not limited to substituents at the 2', 3', 4' and 5' positions.

[0205] In certain embodiments, the substituents at the 2' position include, but are not limited to, F and OCH 3 ("OMe", "O-methyl" or "methoxy"). In certain embodiments, suitable substituents for the 2' position of the non-bicyclic modified sugar include, but are not limited to, halo, allyl, amino, azido, SH, CN, OCN, CF 3 、OCF 3 、F、Cl、Br、SCH 3 、SOCH 3 、SO 2 CH 3 、ONO 2 、NO 2 、N 3 and NH 2 In certain embodiments, the substituent at the 2' position includes, but is not limited to, O-(C 1 -C 10) alkoxy, alkoxyalkyl, O-alkyl, S-alkyl, N-alkyl, O-alkenyl, S-alkenyl, N-alkenyl, O-alkynyl, S-alkynyl, N-alkynyl, O-alkyl-O-alkyl, alkynyl, wherein the alkyl, alkenyl and alkynyl groups may be substituted or unsubstituted C 1 To C 10 Alkyl or C 2 To C 10 In certain embodiments, the substituents at the 2' position include, but are not limited to, alkaryl, aralkyl, O-alkaryl, and O-aralkyl. In certain embodiments, these 2' substituents may be further substituted with one or more substituents independently selected from the following: hydroxyl, alkoxy, carboxyl, benzyl, phenyl, nitro (NO 2 ), thiol, thioalkoxy, thioalkyl, halogen, alkyl, aryl, alkenyl, and alkynyl. In certain embodiments, the substituent at the 2' position includes, but is not limited to, O[(CH 2 ) n O] m CH 3 、O(CH 2 ) n OCH 3 、O(CH 2 ) n CH 3 、O(CH2) n ONH 2 、O(CH 2 ) n NH 2 、O(CH 2 ) n SCH 3 and O(CH 2 ) n ON[(CH 2 ) n CH 3 )] 2 , wherein n and m are independently 1 to about 10. In certain embodiments, the substituent at the 2' position includes, but is not limited to, OCH 2 CH 2 OCH 3 ("MOE"), O(CH 2 ) 2 ON(CH 3 ) 2 ("DMAOE"), O(CH 2 ) 2 O(CH 2 ) 2 N(CH 3 ) 2 ("DMAEOE") and OCH2 C(=O)-N(H)CH 3 (“NMA”).

[0206] In certain embodiments, the substituents at the 4' position applicable to non-bicyclic modified sugars include, but are not limited to, alkoxy (e.g., methoxy), alkyl, and Manoharan et al., those described in WO2015 / 106128. In certain embodiments, the substituents at the 5' position applicable to non-bicyclic modified sugars include, but are not limited to, methyl ("Me") (R or S), vinyl, and methoxy. In certain embodiments, the substituents described herein for 2', 4', and 5' positions may be added to other specific positions on the sugar. In certain embodiments, such substituents may be added to the 3' position of the sugar on the 3' terminal nucleoside or the 5' position of the 5' terminal nucleoside. In certain embodiments, non-bicyclic modified sugars may include more than one non-bridging sugar substituent. In certain such embodiments, non-bicyclic modified sugar substituents include, but are not limited to, 5'-Me-2'-F, 5'-Me-2'-OMe (including both R and S isomers). In certain embodiments, modified sugar substituents include those described in Migawa et al., WO 2008 / 101157 and Rajeev et al., US 2013 / 0203836.

[0207] In certain embodiments, modified sugar is a bicyclic sugar. Bicyclic sugar is a modified sugar comprising two rings, wherein the second ring is formed via a bridge connecting two atoms in the first ring, thereby forming a bicyclic structure. In certain embodiments, bicyclic sugar comprises two atoms of a bridging furanose ring to form a bridging substituent of the second ring. In certain embodiments, bicyclic sugar does not comprise a furanose moiety. "Bicyclic nucleoside" ("BNA") is a nucleoside with a bicyclic sugar. In certain embodiments, the bicyclic sugar is included in a bridge between 4' furanose ring atoms and 2' furanose ring atoms. In certain embodiments, the bicyclic sugar is included in a bridge between 5' furanose ring atoms and 3' furanose ring atoms. In certain such embodiments, the furanose ring is a ribose ring. In certain embodiments, 4' to 2' bridging substituents include but are not limited to 4'-CH 2 -2', 4'-(CH 2 ) 2 -2', 4'-(CH 2 ) 3 -2', 4'-CH 2 -O-2'("LNA"), 4'-CH 2 -S-2', 4'-(CH 2 ) 2 -O-2'("ENA"), 4'-CH(CH 3)-O-2' ("constrained ethyl" or "cEt", when in the S configuration), 4'-CH2-O-CH 2 -2', 4'-CH 2 -N(R)-2', 4'-CH(CH 2 OCH 3 )-O-2' ("constrained MOE" or "cMOE") and its analogs (eg, U.S. Pat. No. 7,399,845), 4'-C(CH 3 )(CH 3 )-O-2' and its analogs (eg, U.S. Pat. No. 8,278,283), 4'-CH 2 -N(OCH 3 )-2' and its analogs (eg, U.S. Pat. No. 8,278,425), 4'-CH 2 -ON(CH 3 )-2' (eg, U.S. Patent Publication No. 2004 / 0171570), 4'-CH 2 -N(R)-O-2', where R is H, C 1 -C 12 Alkyl or protecting group (eg, U.S. Pat. No. 7,427,672), 4'-CH 2 -C(H)(CH 3 )-2' (eg, Chattopadhyaya et al., J. Org. Chem., 2009, 74, 118-134) and 4'-CH 2 -C(=CH 2)-2' and analogs thereof (e.g., U.S. Pat. No. 8,278,426). The entire contents of each of the foregoing are hereby incorporated herein by reference. Additional representative U.S. patents and U.S. patent publications that teach the preparation of bicyclic nucleic acid nucleotides include, but are not limited to, the following: U.S. Pat. Nos. 6,268,490; 6,525,191; 6,670,461; 6,770,748; 6,794,499; 6,998,484; 7,053,207; 7,034,133; 7,084,125; 7, No. 399,845; No. 7,427,672; No. 7,569,686; No. 7,741,457; No. 8,022,193; No. 8,030,467; No. 8,278,425; No. 8,278,426; No. 8,278,283; US2008 / 0039618; and US2009 / 0012281, US2013 / 0190383; and WO 2013 / 036868, the entire contents of each of which are hereby incorporated herein by reference. Any of the foregoing bicyclic nucleosides can be prepared to have one or more stereochemical sugar configurations, including, for example, α-L-ribofuranose and β-D-ribofuranose (see, for example, WO 99 / 14226). Unless otherwise specified, bicyclic nucleosides are designated herein as being in the β-D configuration.

[0208] In certain embodiments, modified sugar is a sugar substitute. In certain embodiments, sugar substitute has, for example, an oxygen atom replaced by a sulfur, carbon or nitrogen atom. In certain such embodiments, sugar substitutes may also include bridged and / or non-bridged substituents as described herein. In certain embodiments, sugar substitutes include rings with 5 atoms. In certain such embodiments, sugar substitutes include cyclobutyl moieties rather than pentofuranosyl sugars. In certain embodiments, sugar substitutes include six-membered rings rather than pentofuranosyl sugars. In certain embodiments, sugar substitutes include tetrahydropyran ("THP") rather than furanosyl sugars. In certain embodiments, sugar substitutes include morpholinyl rather than pentofuranosyl sugars. Representative U.S. patents that teach the preparation of such modified sugar structures include, but are not limited to, U.S. Patent Nos. 4,981,957; 5,118,800; 5,166,315; 5,185,444; 5,319,080; 5,359,044; 5,393,878; 5,446,137; 5,466,786; 5,514,785; 5,519,134; 5,567,811; 5,576,427; No. 5,591,722; No. 5,597,909; No. 5,610,300; No. 5,627,053; No. 5,639,873; No. 5,646,265; No. 5,658,873; No. 5,670,633; No. 5,700,920; No. 7,875,733; No. 7,939,677; No. 8,088,904; No. 8,440,803; and No. 9,005,906, the entire contents of each of the foregoing are hereby incorporated herein by reference.

[0209] In some embodiments, the sugar surrogate comprises a non-cyclic portion. In certain embodiments, the sugar surrogate is an unlocked nucleic acid ("UNA"). UNA is an unlocked non-cyclic nucleic acid in which any bond of the sugar has been removed, thereby forming an unlocked "sugar" residue. In one example, UNA also encompasses monomers in which the bond between C1'-C4' (i.e., the covalent carbon-oxygen-carbon bond between C1' carbon and C4' carbon) has been removed. In another example, the C2'-C3' bond of the sugar (i.e., the covalent carbon-carbon bond between C2' carbon and C3' carbon) has been removed. Representative U.S. disclosures of the preparation of teaching UNA include, but are not limited to, U.S. Patent No. 8,314,227; and U.S. Patent Publication No. 2013 / 0096289; No. 2013 / 0011922; and No. 2011 / 0313020, the entire contents of each of which are hereby incorporated herein by reference. In certain embodiments, sugar surrogates include peptide nucleic acids ("PNAs"), non-cyclobutyl nucleic acids (see, e.g., Kumar et al., Org. Biomol. Chem., 2013, 11, 5853-5865), and nucleosides and oligonucleotides described in Manoharan et al., US 2013 / 130378, the entire contents of which are hereby incorporated herein by reference. Many other bicyclic and tricyclic sugars and sugar surrogate ring systems that can be used in modified nucleosides are known in the art.

[0210] In some aspects, the disclosure relates to compounds comprising at least one oligonucleotide, wherein the nucleosides of such oligonucleotides comprise one or more types of modified sugars and / or unmodified sugars arranged along the oligonucleotide or its region in a defined pattern or "sugar motif" form. In some cases, such sugar motifs include, but are not limited to, any one of the sugar modification patterns described herein.

[0211] In certain embodiments, oligonucleotides include a spacer sugar motif. Spacer oligonucleotides include or consist of: a region with two external "wing" regions and a central or internal "gap" region. The gap and wing regions form a contiguous sequence of nucleosides, wherein the majority of nucleoside sugars of each of the wings are different from the majority of nucleoside sugars of the gap. In certain embodiments, the wing region includes a majority of modified sugars, and the gap includes a majority of unmodified sugars. In certain embodiments, the nucleoside of the gap is a deoxynucleoside. Compounds with a spacer sugar motif are described in, for example, U.S. Patent No. 8,790,919, the entire contents of which are hereby incorporated herein by reference.

[0212] In certain embodiments, one or two oligonucleotides of the double-stranded compound include a triplet sugar motif. An oligonucleotide with a triplet sugar motif includes three identical sugar modifications on three consecutive nucleosides. In certain embodiments, the triplet is at or near the cleavage site of the oligonucleotide. In certain embodiments, the oligonucleotide of the double-stranded compound may contain more than one triplet sugar motif. In certain embodiments, the identical sugar modification of the triplet sugar motif is a 2'-F modification. Compounds with triplet sugar motifs are disclosed in, for example, U.S. Patent No. 10,668,170, the entire contents of which are incorporated herein by reference.

[0213] In certain embodiments, one or two oligonucleotides of the double-stranded compound include a quadruplex sugar motif. Oligonucleotides with a quadruplex sugar motif include four identical sugar modifications on four consecutive nucleosides. In certain embodiments, the quadruplex is at or near a cleavage site. In certain embodiments, the oligonucleotides of the double-stranded compound may contain more than one quadruplex sugar motif. In certain embodiments, the same sugar modification of the quadruplex sugar motif is a 2'-F modification. For double-stranded compounds with a duplex region of 19 to 23 nucleotides in length, the cleavage site of the antisense oligonucleotide is generally about 10, 11, and 12 positions at the 5' end. In certain embodiments, the quadruplex sugar motif is at position 8, 9, 10, 11; 9, 10, 11, 12; 10, 11, 12, 13; 11, 12, 13, 14; or 12, 13, 14, 15 of the sense oligonucleotide, counting from the first nucleoside at the 5' end of the sense oligonucleotide, or counting from the first paired nucleotide in the duplex region at the 5' end of the sense oligonucleotide. In certain embodiments, the quadruplex sugar motif is at position 8, 9, 10, 11; 9, 10, 11, 12; 10, 11, 12, 13; 11, 12, 13, 14; or 12, 13, 14, 15 of the antisense oligonucleotide, counting from the first nucleoside at the 5' end of the antisense oligonucleotide, or counting from the first paired nucleotide in the duplex region at the 5' end of the antisense oligonucleotide. The cleavage site may vary depending on the length of the duplex region of the double-stranded compound and the position of the quadruplex may be altered accordingly.

[0214] In certain embodiments, the oligonucleotide comprises an alternating sugar motif. In certain embodiments, one or two oligonucleotides of the double-stranded compound comprise an alternating sugar motif. The oligonucleotide with an alternating sugar motif comprises at least two different sugar modifications, wherein one or more consecutive nucleosides comprising a first sugar modification are alternating with one or more consecutive nucleosides comprising a second sugar modification and one or more consecutive nucleosides comprising a third sugar modification. For example, if A, B, and C each represent a modification to a nucleoside, the alternating motif may be "ABABABABABAB...", "AABBAABBAABB...", "AABAABAABAAB...", "AAABAAABAAA B...", "AAABBBAAABBB..." or "ABCABCABCABC...", etc. In certain embodiments, the alternating sugar motif is repeated along the oligonucleotide for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleobases. In certain embodiments, the alternating sugar motif comprises two different sugar modifications. In certain embodiments, the alternating sugar motif comprises 2'-OMe and 2'-F sugar modifications.

[0215] In certain embodiments, each nucleoside of an oligonucleotide is independently modified with one or more sugar modifications provided herein. In certain embodiments, each oligonucleotide of a double-stranded compound independently has one or more sugar motifs provided herein. In certain embodiments, the oligonucleotide containing the sugar motif is fully modified because each nucleoside except the nucleoside containing the sugar motif contains a sugar modification.

[0216] Nucleobase modifications and motifs

[0217] In certain embodiments, the compounds described herein comprise modified oligonucleotides. In certain embodiments, modified oligonucleotides comprise one or more nucleosides comprising modified nucleobases. In certain embodiments, modified oligonucleotides comprise one or more nucleosides that do not comprise nucleobases, referred to as abasic nucleosides.

[0218] In certain embodiments, the modified nucleobase is selected from the group consisting of: 5-substituted pyrimidines, 6-azapyrimidines, pyrimidines substituted by alkyl or alkynyl groups, purines substituted by alkyl groups, and purines substituted by N-2, N-6, and O-6. In certain embodiments, the modified nucleobase is selected from the group consisting of: 2-aminopropyladenine, 5-hydroxymethylcytosine, 5-methylcytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-N-methylguanine, 6-N-methyladenine, 2-propyladenine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-propynyl (C≡C-CH 3)uracil, 5-propynylcytosine, 6-azauracil, 6-azacytosine, 6-azathymine, 5-ribosyluracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxy, 8-aza and other 8-substituted purines, 5-halo (especially 5-bromo, 5-trifluoromethyl, 5-halouracil and 5-halocytosine), 7-methylguanine, 7-methyladenine, 2- F-adenine, 2-aminoadenine, 7-deazaguanine, 7-deazaadenine, 3-deazaguanine, 3-deazaadenine, 6-N-benzoyladenine, 2-N-isobutyrylguanine, 4-N-benzoylcytosine, 4-N-benzoyluracil, 5-methyl4-N-benzoylcytosine, 5-methyl4-N-benzoyluracil, universal bases, hydrophobic bases, promiscuous bases, size-extended bases, and fluorinated bases. Other modified nucleobases include tricyclic pyrimidines such as 1,3-diazaphenoxazin-2-one, 1,3-diazaphenathiazin-2-one, and 9-(2-aminoethoxy)-1,3-diazaphenoxazin-2-one (G-clamp). Modified nucleobases may also include those in which the purine or pyrimidine base is replaced by other heterocycles, such as 7-deaza-adenine, 7-deazaguanosine, 2-aminopyridine, and 2-pyridone.

[0219] Other nucleobases include those disclosed in U.S. Pat. No. 3,687,808; Modified Nucleosides in Biochemistry, Biotechnology and Medicine, Herdewijn, P., ed., Wiley-VCH, 2008; The Concise Encyclopedia Of Polymer Science And Engineering, pp. 858-859; Kroschwitz, JL, ed., John Wiley & Sons, 1990, 858-859; Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613; Sanghvi, YS, Chapter 15, dsRNA Research and Applications, pp. 289-302; Antisense Research and Applications, Crooke, ST and Lebleu, B., eds., CRC Press, 1993, 273-288; Antisense Drug Technology, Crooke ST, ed., CRC Press, 2008, 163-166 and 442-443 (Chapters 6 and 15), each of which is hereby incorporated herein by reference.

[0220] Disclosures teaching the preparation of some of the modified nucleobases noted above, as well as other modified nucleobases, include, but are not limited to, U.S. Application Nos. 2003 / 0158403 and 2003 / 0175906; U.S. Patent Nos. 4,845,205; 5,130,302; 5,134,066; 5,175,273; 5,367,066; 5,432,272; 5,434,257; 5,457,187; 5,459,255; 5,484,908; 5,502,177; 5,525,711; 5,552,540; 5,587,469; 5,594,121; 5,596,091; 5,614,617; 5,645,985 ; 5,681,941; 5,811,534; 5,750,692; 5,948,903; 5,587,470; 5,457,191; 5,763,588; 5,830,653; 5,808,027; 6,005,096; 6,015,886; 6,147,200; 6,166 ,197; 6,166,199; 6,222,025; 6,235,887; 6,380,368; 6,528,640; 6,639,062; 6,617,438; 7,045,610; 7,427,672; and 7,495,088, the entire contents of each of which are hereby incorporated herein by reference.

[0221] In certain embodiments, the compounds described herein comprise oligonucleotides. In certain embodiments, oligonucleotides comprise modified and / or unmodified nucleobases configured in a defined pattern or motif along an oligonucleotide or its region. In certain embodiments, each nucleobase is modified. In certain embodiments, nucleobases are unmodified. In certain embodiments, each purine or each pyrimidine is modified. In certain embodiments, each adenine is modified. In certain embodiments, each guanine is modified. In certain embodiments, each thymine is modified. In certain embodiments, each uracil is modified. In certain embodiments, each cytosine is modified. In certain embodiments, some or all of the cytosine nucleobases in the modified oligonucleotides are 5-methylcytosine.

[0222] In certain embodiments, the modified oligonucleotide comprises a block of modified nucleobases. In certain such embodiments, the block is at the 3' end of the oligonucleotide. In certain embodiments, the block is within 3 nucleosides at the 3' end of the oligonucleotide. In certain embodiments, the block is at the 5' end of the oligonucleotide. In certain embodiments, the block is within 3 nucleosides at the 5' end of the oligonucleotide.

[0223] Internucleoside linkage modifications and motifs

[0224] The 3' to 5' phosphodiester linkage is a naturally occurring internucleoside linkage of RNA and DNA. In certain embodiments, the compounds described herein have one or more modified, i.e., non-naturally occurring, internucleoside linkages. Certain non-naturally occurring internucleoside linkages can impart desirable properties, such as enhanced cellular uptake, enhanced affinity for target nucleic acids, and increased stability in the presence of nucleases. Representative phosphorus-modified internucleoside linkages include, but are not limited to, phosphotriesters, alkyl phosphonates (e.g., methylphosphonates), phosphoramidates, and phosphorothioates ("P=S") and phosphorodithioates ("HS-P=S"). Representative non-phosphorus-containing internucleoside linkage groups include, but are not limited to, methylenemethylimino (-CH 2 -N(CH 3 )-O-CH 2 ), thiodiesters, thiocarbamates (-OC(=O)(NH)-S-); siloxanes (-O-SiH 2 -O-); and N,N'-dimethylhydrazine (-CH 2 -N(CH 3 )-N(CH 3 )-). Methods for preparing phosphorus-containing and non-phosphorus-containing internucleoside linkages are well known to those skilled in the art. Neutral internucleoside linkages include, but are not limited to, phosphotriesters, methylphosphonates, MMI (3'-CH 2 -N(CH 3 )-O-5'), amide-3(3'-CH 2 -C(=O)-N(H)-5'), amide-4(3'-CH 2 -N(H)-C(=O)-5'), methylal (3'-O-CH 2 -O-5'), methoxypropyl and thioformal (3'-S-CH 2 -O-5'). Other neutral internucleoside linkages include nonionic linkages containing siloxanes (dialkylsiloxanes), carboxylates, formamides, sulfides, sulfonates, and amides (see, e.g., Carbohydrate Modifications in Antisense Research; YS Shanghvi and PD Cook, eds., ACS Symposium Series 580; Chapters 3 and 4, 40-65). Other neutral internucleoside linkages include nonionic linkages containing mixed N, O, S, and CH 2 Component part.

[0225] In certain embodiments, the compounds provided herein include at least one modified internucleoside linkage. The modified internucleoside linkage can be placed at any position of the oligonucleotide. For double-stranded compounds, the modified internucleoside linkage can be placed in a sense oligonucleotide, an antisense oligonucleotide, or two oligonucleotides of the double-stranded compound.

[0226] In certain embodiments, the internucleoside linkage modification may be present on each nucleoside of the oligonucleotide. In certain embodiments, the internucleoside linkage modification may be present in an alternating pattern along the oligonucleotide. In certain embodiments, substantially each internucleoside linkage group is a phosphate internucleoside linkage (P=O). In certain embodiments, each internucleoside linkage group of the modified oligonucleotide is a phosphorothioate (P=S). In certain embodiments, each internucleoside linkage group of the modified oligonucleotide is independently selected from phosphorothioate and phosphate internucleoside linkages. In certain embodiments, the pattern of internucleoside linkage modification on each oligonucleotide of the double-stranded compound is the same. In certain embodiments, the pattern of internucleoside linkage modification on each oligonucleotide of the double-stranded compound is different. In certain embodiments, the double-stranded compound comprises 6 to 8 modified internucleoside linkages. In certain embodiments, 6 to 8 modified internucleoside linkages are phosphorothioate internucleoside linkages or phosphonate internucleoside linkages. In certain embodiments, the sense oligonucleotide comprises at least two modified internucleoside linkages at either or both of the 5' and 3' ends. In certain such embodiments, the modified internucleoside linkages are phosphorothioate internucleoside linkages or phosphonate internucleoside linkages. In certain embodiments, the antisense oligonucleotide comprises at least two modified internucleoside linkages at either or both of the 5' and 3' ends. In certain such embodiments, the modified internucleoside linkages are phosphorothioate internucleoside linkages or phosphonate internucleoside linkages.

[0227] In certain embodiments, the double-stranded compound includes an overhang region. In certain embodiments, the double-stranded compound includes a phosphorothioate or phosphonate internucleoside linkage modification in the overhang region. In certain embodiments, the double-stranded compound includes a phosphorothioate or phosphonate internucleoside linkage connecting an overhang nucleotide and a paired nucleotide close to the overhang nucleotide. For example, at least two phosphorothioate internucleoside linkages may be present between the three nucleosides at the end, wherein two of the three nucleosides are overhang nucleosides, and the third is a paired nucleoside close to the overhang nucleoside. These three nucleosides at the end may be at the 3' end of the antisense oligonucleotide, the 3' end of the sense oligonucleotide, the 5' end of the antisense oligonucleotide, or the 5' end of the antisense oligonucleotide.

[0228] In certain embodiments, the modified oligonucleotide comprises one or more internucleoside linkages with a chiral center. Representative chiral internucleoside linkages include, but are not limited to, alkyl phosphonates and phosphorothioates. The modified oligonucleotide comprising an internucleoside linkage with a chiral center can be prepared as a population of modified oligonucleotides comprising stereo-random internucleoside linkages, or as a population of modified oligonucleotides comprising thiophosphate linkages in a specific stereochemical configuration. In certain embodiments, the population of modified oligonucleotides comprises thiophosphate internucleoside linkages, wherein all thiophosphate internucleoside linkages are stereo-random. Such modified oligonucleotides can be produced using a synthetic method that allows each thiophosphate linkage to randomly select a stereochemical configuration. As fully understood by those skilled in the art, each individual thiophosphate of each individual oligonucleotide molecule has a limited stereochemical configuration. In certain embodiments, the population of modified oligonucleotides is enriched in modified oligonucleotides, and the modified oligonucleotides comprise one or more specific thiophosphate internucleoside linkages in an independently selected specific stereochemical configuration. In certain embodiments, the specific configuration of a specific phosphorothioate linkage is present in at least 65% of the molecules in the population. In certain embodiments, the specific configuration of a specific phosphorothioate linkage is present in at least 70% of the molecules in the population. In certain embodiments, the specific configuration of a specific phosphorothioate linkage is present in at least 80% of the molecules in the population. In certain embodiments, the specific configuration of a specific phosphorothioate linkage is present in at least 90% of the molecules in the population. In certain embodiments, the specific configuration of a specific phosphorothioate linkage is present in at least 99% of the molecules in the population. The population of such enriched modified oligonucleotides can be produced using synthetic methods known in the art, such as Oka et al., JACS125, 8307 (2003), Wan et al. Nuc.Acid.Res.42, 13456 (2014) and WO 2017 / 015555. In certain embodiments, the modified oligonucleotide population is rich in modified oligonucleotides with at least one specified phosphorothioate in (Sp) configuration. In certain embodiments, the population of modified oligonucleotides is enriched in modified oligonucleotides having at least one phosphorothioate in the (Rp) configuration.

[0229] Conjugated Group

[0230] In certain embodiments, the compounds described herein comprise or consist of one or more oligonucleotides and optionally one or more conjugated groups. The conjugated group may be connected to either end or both ends of the oligonucleotide and / or in any internal position. In certain embodiments, the conjugated group is connected to the 3' end of the oligonucleotide. In certain embodiments, the conjugated group is connected to the 5' end of the oligonucleotide. In certain embodiments, the oligonucleotide is covalently linked to one or more conjugated groups.

[0231] In certain embodiments, the conjugated group is a terminal group connected to either or both ends of an oligonucleotide. In certain such embodiments, the terminal group is connected to the 3' end of an oligonucleotide. In certain such embodiments, the terminal group is connected to the 5' end of an oligonucleotide. In certain embodiments, the terminal group includes but is not limited to a capping group, a phosphate moiety, a protecting group, a modified or unmodified nucleoside, and two or more nucleosides independently modified or unmodified, such as an overhang.

[0232] In certain embodiments, the conjugated group improves one or more properties of the attached oligonucleotide, including but not limited to pharmacodynamics, pharmacokinetics, stability, activity, half-life, binding, absorption, tissue distribution, cellular distribution, cellular uptake, charge and clearance. In certain embodiments, the conjugated group enhances the affinity of the compound for a selected target (e.g., a molecule, a cell or cell type, a compartment (e.g., a cell or organ compartment), a tissue, an organ or a body region) compared to, for example, a compound lacking such a conjugated group. In certain embodiments, the conjugated group imparts new properties to the attached oligonucleotide, such as a fluorophore or reporter group capable of detecting the oligonucleotide.

[0233] In certain embodiments, conjugate groups include, but are not limited to, intercalators, reporters, polyamines, polyamides, peptides, carbohydrates, vitamin moieties, polyethylene glycols, thioethers, polyethers, cholesterol, thiocholesterol, bile acid moieties, folic acid, lipids, phospholipids, biotin, phenazine, phenanthridine, anthraquinone, adamantane, acridine, fluorescein, rhodamine, coumarin, fluorophores, and dyes.

[0234] In certain embodiments, the conjugate group includes an active drug substance, such as aspirin, warfarin, phenylbutazone, ibuprofen, suprofen, fen-bufen, ketoprofen, (S)-(+)-pranoprofen, carprofen, dansylsarcosine, 2,3,5-triiodobenzoic acid, fingolimod, flufenamic acid, folate, benzothiadiazide, chlorothiazide, diazepine, indo-methicin, a barbiturate, a cephalosporin, a sulfonamide, an antidiabetic agent, an antibacterial agent, or an antibiotic.

[0235] In certain embodiments, the conjugated group is a targeting moiety. In certain embodiments, the targeting moiety includes, but is not limited to, a lectin, a glycoprotein, a lipid, a protein, a peptide, a peptide mimetic, a receptor ligand, an antibody, a thyrotropin, a melanocyte stimulating hormone, a surfactant protein A, a carbohydrate, a carbohydrate derivative, a modified carbohydrate, a carbohydrate cluster, a polysaccharide, a modified polysaccharide or a polysaccharide derivative, a mucin carbohydrate, a multivalent lactose, a multivalent galactose, an N-acetyl-galactosamine sugar (GalNAc), an N-acetylglucosamine multivalent mannose, a multivalent fucose, a glycosylated polyamino acid, a multivalent galactose, a transferrin, a bisphosphonate, a polyglutamate, a polyaspartate, a lipid, a cholesterol, a steroid, a bile acid, a folate, vitamin B12, vitamin A, biotin, or an RGD peptide or RGD peptide mimetic.

[0236] In certain embodiments, the conjugate groups may include, but are not limited to, the conjugate groups described in the following references, such as cholesterol (e.g., Letsinger et al., Proc. Natl. Acid. Sci. USA, 1989, 86:6553-6556); cholic acid (e.g., Manoharan et al., Biorg. Med. Chem. Let., 1994, 4:1053-1060); thioethers, such as hexyl-S-tritylthiol (e.g., Manoharan et al., Ann. NY. Acad. Sci., 1992, 660:306-309; Manoharan et al., Biorg. Med. Chem. Let., 1993, 3:2765-2770); thiocholesterol (e.g., Oberhauser et al., Nucl. Acids Res., 1992, 20: 533-538); aliphatic chains, such as dodecandiol or undecyl residues (e.g., Saison-Behmoaras et al., EMBO J, 1991, 10: 1111-1118; Kabanov et al., FEBS Lett., 1990, 259: 327-330; Svinarchuk et al., Biochimie, 1993, 75: 49-54); phospholipids, such as di-hexadecyl-rac-glycerol or 1,2-di-O-hexadecyl-rac-glycero-3-H-phosphonic acid triethyl-ammonium (e.g., Manoharan et al., Tetrahedron Lett., 1995, 36: 3651-3654; Shea et al., Nucl. Acids Res., 1990, 18:3777-3783); polyamine or polyethylene glycol chain (e.g., Manoharan et al., Nucleosides & Nucleotides, 1995, 14:969-973); adamantaneacetic acid (e.g., Manoharan et al., Tetrahedron Lett., 1995, 36:3651-3654); palmityl (e.g., Mishra et al., Biochim. Biophys. Acta, 1995, 1264:229-237); octadecylamine or hexylamino-carbonyloxycholesterol moiety (e.g., Crooke et al., J. Pharmacol. Exp. Ther., 1996, 277: 923-937); tocopherol (e.g., Nishina et al., Molecular Therapy Nucleic Acids, 2015, 4, e220 and Nishina et al., Molecular Therapy, 2008, 16: 734-740); GalNAc and other carbohydrates (e.g., Maier et al., Bioconjugate Chemistry, 2003, 14, 18-29; Rensen et al., J. Med. Chem. 2004, 47, 5798-5808; WO2009 / 073809 and U.S. Patents 8,106,022; 8,450,467 and 8,828,957; and WO2014 / 179445; WO2014 / 179620 and U.S. Patents 9,127,276; 9,181,549 and 10,844,379), each of which is incorporated herein by reference in its entirety.

[0237] The conjugated group can be connected to the oligonucleotide via a conjugated linker. In certain embodiments, the conjugated linker comprises a chain structure, such as a hydrocarbon chain, or an oligomer of a repeating unit or a combination of such repeating units. In certain embodiments, the conjugated linker comprises one or more groups selected from the following: alkyl, amino, oxo, amide, disulfide, polyethylene glycol, ether, thioether and hydroxylamino. In certain embodiments, the conjugated linker comprises at least one phosphorus group. In certain embodiments, the conjugated linker comprises at least one phosphate group. In certain embodiments, the conjugated linker includes at least one neutral linking group. In certain embodiments, the conjugated linker includes but is not limited to pyrrolidine, 8-amino-3,6-dioxaoctanoic acid (ADO), cyclohexane-1-carboxylic acid succinimidyl 4-(N-maleimidomethyl) ester (SMCC) and 6-aminohexanoic acid (AHEX or AHA). Other conjugated linkers include but are not limited to substituted or unsubstituted C 1 -C 10 Alkyl, substituted or unsubstituted C 2 -C 10 Alkenyl, or substituted or unsubstituted C 2 -C 10Alkynyl, wherein the non-limiting list of preferred substituents includes hydroxyl, amino, alkoxy, carboxyl, benzyl, phenyl, nitro, thiol, thioalkoxy, halogen, alkyl, aryl, alkenyl and alkynyl. In certain embodiments, the conjugated joint comprises 1 to 10 joint nucleosides. In certain embodiments, such joint nucleosides may be modified or unmodified nucleosides. It is generally expected that the joint nucleosides are cracked from the compound after it reaches the target tissue. Therefore, the joint nucleosides herein can be connected to each other via a cleavable bond and connected to the remainder of the compound. In this article, joint-nucleosides are not considered as a part of oligonucleotide. Therefore, in the embodiment in which the compound comprises the oligonucleotide composed of the linkage nucleosides of a specified number or range and / or the specified percentage complementarity with the reference nucleic acid and the compound also comprises the conjugated joint containing the conjugated joint comprising the joint nucleosides, those joint nucleosides are not counted in the length of the oligonucleotide and are not used to determine the percentage complementarity of the oligonucleotide with the reference nucleic acid.

[0238] In certain embodiments, conjugate groups and conjugate linkers and other modifications include, but are not limited to, those described in the following references: US 5,994,517; US 6,300,319; US 6,660,720; US 6,906,182; US 7,262,177; US 7,491,805; US 8,106,022; US 7,723,509; US 9,127,276; US2006 / 0148740; US2011 / 0123520; WO2013 / 033230; WO2012 / 037254, Biessen et al., J. Med. Chem. 1995, 38, 1846-1852; Lee et al., Bioorganic & Medicinal Chemistry 2011, 19, 2494-2500; Rensen et al., J. Biol. Chem. 2001, 276, 37577-37584; Rensen et al., J. Med. Chem. 2004, 47, 5798-5808; Sliedregt et al., J. Med. Chem. 1999, 42, 609-618; Valentijn et al., Te trahedron, 1997, 53, 759-770; Lee, Carhohydr Res, 1978, 67, 509-514; Connolly et al., J Biol Chem, 1982, 257, 939-945; Pavia et al., Int J Pep Protein Res, 1983, 22, 539-548; Lee et al., Biochem, 1984, 23, 4255-4261; Lee et al., Glycoconjugate J, 1987, 4, 317-328; Toyokuni et al., Tetrahedron Lett, 1990, 31, 2673-2676; Biessen et al., J Med Chem, 1995, 38, 1538-1546; Valentijn et al., Tetrahedron, 1997, 53, 759-770; Kim et al., Tetrahedron Lett, 1997, 38, 3487-3490; Lee et al., Bioconjug Chem, 1997, 8, 762-765; Kato et al., Glycohiol, 2001, 11, 821-829; Rensen et al., J Biol Chem, 2001, 276, 37577-37584; Lee et al., Methods Enzymol, 2003, 362, 38-43;Westerlind et al., Glycoconj J, 2004, 21, 227-241; Lee et al., Bioorg Med Chem Lett, 2006, 16(19), 5132-5135; Maierhofer et al., Bioorg Med Chem, 2007, 15, 7661-7676; Khorev et al., Bioorg Med Chem, 2008, 16, 5216-5231; Lee et al., Bioorg Med Chem, 2011, 19, 2494-2500; Kornilov a et al., Analyt Biochem, 2012, 425, 43-46; Pujol et al., Angew Che mie Int Ed Engl, 2012, 51, 7445-7448; Biessen et al., J Med Chem, 1995, 38, 1846-1852; Sliedregt et al., J Med Chem, 1999, 42, 609-618; Rensen et al., J Med Chem, 2004, 47, 5798-5808; Rensen et al., Arterioscler Thromh Vase Biol, 2006, 26, 169-175; van Rossenberg et al., Gene Ther, 2004, 11, 457-464; Sato et al., J Am Chem Soc, 2004, 126, 14013-14022; Lee et al., J Org Chem, 2012, 77, 7564-7571; Biessen et al., FASEB J, 2000, 14, 1784-1792; Rajur et al., Bioconjug Chem, 1997, 8, 935-940; Duff et al., Methods Enzymol, 2000, 313, 297-321; Maier et al., Bioconjug Chem, 2003, 14, 18-29; Jayap rakash et al., Org Lett, 2010, 12, 5410-5413; Manoharan, Antisense Nucleic Acid Drug Dev, 2002, 12, 103-128; Merwin et al., Bioconju g Chem, 1994, 5, 612-620; Tomiya et al., Bioorg Med Chem, 2013, 21, 5275-5281; International applications WO1998 / 013381; WO2011 / 038356; WO1997 / 046098; WO2008 / 098788;W02004 / 101619; WO2012 / 037254; WO2011 / 120053; WO2011 / 100131; WO201 1 / 163121; WO2012 / 177947; W02013 / 033230; W02013 / 075035; WO2012 / 0831 85; WO2012 / 083046; W02009 / 082607; WO2009 / 134487; W02010 / 144740; W02 010 / 148013; WO1997 / 020563; W02010 / 088537; W02002 / 043771; W02010 / 12 9709; WO2012 / 068187; WO2009 / 126933; W02004 / 024757; WO2010 / 054406; WO2012 / 089352; WO2012 / 089602; WO2013 / 166121; WO2013 / 165816; U.S. Patents 4,751,219; 7,582,744; 8,552,163; 8,137,695; 6,908,903; 6,383,812; 7,262,177; 6,525,031; 5,994,517; 6,660,720; 6,300,319; 7,723,509; 8,106,0 22; 7,491,805; 7,491,805; 8,541,548; 8,344,125; 8,313,772; 8,349,308; 8,450,467; 8,501,930; 8,158,601; 7,262,177; 6,906,182; 6,620,916; 8,435,491; 8,404,862; 7,851,615; published U.S. patent applications US2011 / 0097264; US2011 / 0097265; US2013 / 0004427; US2003 / 0119724; US2011 / 0207799; US2012 / 00 35115; US2012 / 0230938; US2005 / 0164235; US2006 / 0183886; US2012 / 0136042; US2012 / 0095075; US2013 / 0109817; US2006 / 0148740; US2008 / 0206869; US2012 / 0165393; US2012 / 0101148; US2013 / 0121954; US2011 / 0123520; US2003 / 0077829; US2008 / 0108801; and US2009 / 0203132; each of which is incorporated herein by reference in its entirety. ;

[0239] Certain targeting moieties

[0240] In certain embodiments, the compounds provided herein include a conjugated group. In certain embodiments, the oligonucleotides provided herein include a conjugated group. In certain embodiments, the conjugated group is a targeting moiety. In certain embodiments, the targeting moiety includes one or more GalNAc. In certain embodiments, one or more GalNAc are connected to one or more positions on the furanose ring. In certain embodiments, one or more GalNAc are connected to the 2' or 3' position on the furanose ring. In certain embodiments, the furanose ring is a subunit of an oligonucleotide. In certain embodiments, the furanose ring is the 5' nucleoside sugar of an oligonucleotide. In certain embodiments, the furanose ring is the 5' nucleoside sugar of a sense oligonucleotide. In certain embodiments, the compound or oligonucleotide includes one or more subunits having the following formula or a salt, solvate or hydrate thereof:

[0241]

[0242] in:

[0243] R 1 is H, adenine, guanine, thymine, cytosine, uracil, a carbocyclyl, a heterocyclyl, an aryl, a heteroaryl or a nucleobase isostere;

[0244] R 2 is the oligonucleotide sequence;

[0245] L 1 is alkyl or alkyl-C(═O)—NH-alkyl;

[0246] L 2 is alkyl or alkyl-C(═O)—NH-alkyl;

[0247] L 3 bond, phosphodiester bond, phosphorothioate bond, triazole, tetrazole, amide, reverse amide, carbamate, carbonate, urea, O, S, S(=O), S(=O) 2 , NH, substituted N groups, alkyl, alkenyl, diene, alkynyl, heteroalkyl, phosphate;

[0248] R 3 H, -C=(O)-NH-(CH 2 CH 2 O) j -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc;

[0249] R 4H, -C=(O)-NH-(CH 2 CH 2 O) k -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc;

[0250] R 5 -C=(O)-NH-(CH 2 CH 2 O) m -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc;

[0251] R 6 -C=(O)-NH-(CH 2 CH 2 O) n -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc;

[0252] W and Q are each independently O, NH, CH 2 or CH 2 O;

[0253] S 1 and S 2 Each independently is C(R 7 ) or N, where R 7 Each instance of is independently H, alkyl, heteroalkyl, or halogen;

[0254] j is an integer from 1 to 10, inclusive;

[0255] k is an integer from 1 to 10, inclusive;

[0256] m is an integer from 1 to 10, inclusive; and

[0257] n is an integer from 1 to 10, inclusive.

[0258] In certain embodiments, R 3 , R 4 , R 5 and R 6 In certain embodiments, R 3 , R 5 and R 6 In certain embodiments, R 3 or R 4 For H.

[0259] In certain embodiments, L 1 and L 2 same.

[0260] In certain embodiments, L 1 and L 2 Each is independently an alkyl group; R 3 H, -C=(O)-NH-(CH 2 CH 2 O) j -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 4 H, -C=(O)-NH-(CH 2 CH 2 O) k -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 5 -C=(O)-NH-(CH 2 CH 2 O) m -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; and R 6 -C=(O)-NH-(CH 2 CH 2 O) n -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc.

[0261] In certain embodiments, L 1 and L 2 are each independently alkyl-C(═O)-NH-alkyl; R 3 H, -C=(O)-NH-(CH 2 CH 2 O) j -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 4 H, -C=(O)-NH-(CH 2 CH 2 O) k -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 5 -C=(O)-NH-(CH 2 CH 2 O) m -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; and R 6 -C=(O)-NH-(CH 2 CH2 O) n -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc.

[0262] In certain embodiments, R 4 For H.

[0263] In certain embodiments, L 1 and L 2 Each is independently an alkyl group; R 3 -C=(O)-NH-(CH 2 CH 2 O) j -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 4 H; R 5 -C=(O)-NH-(CH 2 CH 2 O) m -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; and R 6 -C=(O)-NH-(CH 2 CH 2 O) n -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc.

[0264] In certain embodiments, L 1 and L 2 are each independently alkyl-C(═O)-NH-alkyl; R 3 -C=(O)-NH-(CH 2 CH 2 O) j -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 4 H; R 5 -C=(O)-NH-(CH 2 CH 2 O) m -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; and R 6 -C=(O)-NH-(CH 2 CH 2 O) n -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc.

[0265] In certain embodiments, R 3 -C=(O)-NH-(CH 2 CH 2 O) j -GalNAc; R 4 H; R 5 -C=(O)-NH-(CH 2 CH 2 O) m -GalNAc; and R 6 -C=(O)-NH-(CH 2 CH 2 O) n -GalNAc.

[0266] In certain embodiments, R 3 is -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 4 H; R 5 is -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; and R 6 It is -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc.

[0267] In certain embodiments, the compound or oligonucleotide comprises one or more subunits having the following formula or a salt, solvate or hydrate thereof:

[0268]

[0269] in:

[0270] R 9 is H, adenine, guanine, thymine, cytosine or uracil, or adenine, guanine, thymine, cytosine or uracil, each of which comprises a protecting group (PG), a modified nucleobase, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted carbocyclyl, an optionally substituted heterocyclyl or a nucleobase isostere;

[0271] L is a bond, a phosphodiester bond, a phosphorothioate bond, a triazole, a tetrazole, an amide, a reverse amide, a carbamate, a carbonate, a urea, an alkyl group, or a heteroalkyl group;

[0272] R 2 is the oligonucleotide sequence;

[0273] Y 1 O, CH 2 , CH 2O or optionally substituted NH;

[0274] Y 2 O, CH 2 , CH 2 O or optionally substituted NH;

[0275] Y 3 CO, SO 2 、P(O)O、CH 2 -OC(O),CH 2 -NH-C(O), CH 2 -NH-SO 2 or CH 2 ;

[0276] Y 4 CO, SO 2 、P(O)O、CH 2 -OC(O),CH 2 -NH-C(O), CH 2 -NH-SO 2 or CH 2 ;

[0277] n 2 is 0, 1, 2, 3, 4, 5, or 6; and

[0278] Each n 1 、n 3 、n 4 and n 5 is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0279] In certain embodiments, the compound or oligonucleotide comprises one or more subunits having the following formula or a salt, solvate or hydrate thereof:

[0280]

[0281] in:

[0282] Each n is independently 1, 2, 3, 4 or 5;

[0283] Each m is independently 0, 1, 2, 3, 4, 5 or 6;

[0284] Each o is independently 0, 1, 2, 3, 4, 5 or 6;

[0285] L 1 , L 2 and L 3 Each of is independently absent, C(═O) or C(═O)NH;

[0286] Each Y1 are independently O, CH(R a )、S、S(=O)、S(=O) 2 , NH, substituted N groups, NHC(=O), C(=O)NH, P(=O) 2 -O-,P(=O)(=S)-O,P(=S) 2 -O, -OP(=O) 2 -O-, -OP(=O)(=S)-O-, -OP(=S) 2 -O-, -OP(=O) 2 -, -OP(=O)(=S)-,-OP(=S) 2 -;

[0287] Each Y 2 are independently O, CH(R b )、S、S(=O)、S(=O) 2 , NH, substituted N groups, NHC(=O), C(=O)NH, P(=O) 2 -O-,P(=O)(=S)-O,P(=S) 2 -O, -OP(=O) 2 -O-, -OP(=O)(=S)-O-, -OP(=S) 2 -O-, -OP(=O) 2 -, -OP(=O)(=S)-,-OP(=S) 2 -;

[0288] Het 1 、Het 2 and Het 3 Each of is independently optionally substituted heteroaryl or optionally substituted heterocyclyl;

[0289] R 1 are oligonucleotide sequences linked by a bond, a phosphodiester bond, a phosphorothioate bond, a triazole, a tetrazole, an amide, a reverse amide, a carbamate, a carbonate, a urea, an alkyl or a heteroalkyl;

[0290] Each R 5 , R 6 and R 7 Independently

[0291] R 9 is an optionally substituted heterocyclic group;

[0292] Each R a are independently H, alkyl, halo, OR c or SRc ;

[0293] Each R b are independently H, alkyl, halo, OR c or SR c ;and

[0294] Each R c are independently H or alkyl.

[0295] In certain embodiments, the subunit is selected from Formula I to Formula VIII or a salt, solvate or hydrate thereof, wherein R is a modified oligonucleotide other than a 5' nucleoside. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula I and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula I and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula II and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula II and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula III and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula III and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula IV and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula IV and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula V and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula V and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula VI and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula VI and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula VII and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula VII and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula VIII and R' is O.

[0296] In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula VIII and R' is S.

[0297] Target nucleic acid and target region

[0298] In certain embodiments, the compounds described herein comprise or consist of the following: oligonucleotides comprising a region complementary to a target nucleic acid. In certain embodiments, the target nucleic acid is an endogenous RNA molecule. In certain embodiments, the target nucleic acid encodes a protein. In certain embodiments, the target nucleic acid is non-coding. In certain such embodiments, the target nucleic acid is selected from mRNA and pre-mRNA, including introns, exons, and untranslated regions. In certain embodiments, the target RNA is mRNA. In certain embodiments, the target nucleic acid is pre-mRNA. In certain such embodiments, the target region is completely within an exon. In certain such embodiments, the target region is completely within an intron. In certain embodiments, the target region spans an intron / exon junction. In certain embodiments, at least 50% of the target region is located within an intron.

[0299] In certain embodiments, the compounds disclosed herein hybridize with AGT nucleic acids. The most common hybridization mechanism involves hydrogen bonding between complementary nucleobases of nucleic acid molecules. Hybridization can occur under different conditions. Hybridization conditions are sequence dependent and are determined by the properties and composition of the nucleic acid molecules to be hybridized. Methods for determining whether a sequence specifically hybridizes with a target nucleic acid are well known in the art. In certain embodiments, the compounds provided herein specifically hybridize with AGT nucleic acids.

[0300] Nucleotide sequences encoding AGT include, but are not limited to, the following: GENBANK Accession No. NM_000029.4 (incorporated herein as SEQ ID NO: 1), the complementary sequence of nucleotides 230702523 to 230745583 of NC_000001.11 (incorporated herein as SEQ ID NO: 2), NM_001382817.3 (incorporated herein as SEQ ID NO: 3), and nucleotides 5469 to 17068 of NG_008836.2 (incorporated herein as SEQ ID NO: 4).

[0301] Complementarity

[0302] Oligonucleotide provided herein can have the percentage complementarity with the restriction of specific nucleic acid, target region, oligonucleotide or its part.Non-complementary nuclear bases can be allowed, and condition is that oligonucleotide can still hybridize with nucleic acid, oligonucleotide or its part specificity.In certain embodiments, oligonucleotide provided herein or its designated part and target nucleic acid, target region, oligonucleotide or its designated part at least or at most 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% complementarity.In certain embodiments, oligonucleotide provided herein or its designated part and target nucleic acid, target region, oligonucleotide or its designated part 70% to 75%, 75% to 80%, 80% to 85%, 85% to 90%, 90% to 95%, 95% to 100% or any numerical value complementarity between these scopes. Conventional methods can be used to determine the percentage complementarity of oligonucleotides and target nucleic acid, target region, oligonucleotides or their designated parts. For example, wherein 18 of the 20 core bases of the oligonucleotide are complementary to the target region and the oligonucleotide of the specific hybridization will represent 90% complementarity. In this example, the remaining non-complementary core bases can be clustered or interspersed with complementary core bases, and there is no need to be adjacent to each other or adjacent to complementary core bases. Therefore, the oligonucleotide with a length of 18 core bases has four non-complementary core bases in two regions that are fully complementary to the target nucleic acid, and the oligonucleotide will have 77.8% overall complementarity with the target nucleic acid. The percentage complementarity of the region of the oligonucleotide and the target nucleic acid, target region, oligonucleotide or its designated part can be routinely determined using BLAST programs (basic local comparison search tools) as known in the art. In certain embodiments, oligonucleotides described herein or their designated parts are fully complementary (i.e. 100% complementary) to target nucleic acid, target region, oligonucleotide or its designated part. For example, oligonucleotides can be fully complementary to target nucleic acid, target region, oligonucleotide or its designated part. As used herein, "fully complementary" means that each nucleobase of an oligonucleotide is complementary to the corresponding nucleobase of a target nucleic acid, a target region, an oligonucleotide, or a designated portion thereof. For example, a 20 nucleobase oligonucleotide is fully complementary to a target sequence of 400 nucleobases in length, as long as the corresponding 20 nucleobase portions of the target nucleic acid are fully complementary to the compound. "Fully complementary" may also be used to refer to a designated portion of a first and / or second nucleic acid. For example, a 20 nucleobase portion of a 30 nucleobase oligonucleotide may be "fully complementary" to a 20 nucleobase region of a target sequence of 400 nucleobases in length. If the target sequence has a corresponding 20 nucleobase portion, wherein each nucleobase is partially complementary to the 20 nucleobase portion of the compound, then the 20 nucleobase portions of the 30 nucleobase compound are fully complementary to the target sequence.At the same time, the entire 30 nucleobase compound may or may not be fully complementary to the target sequence, depending on whether the remaining 10 nucleobases of the compound are also complementary to the target sequence.

[0303] In certain embodiments, oligonucleotides described herein comprise one or more mismatched core bases relative to target nucleic acid, target region, oligonucleotide or its designated portion. In certain embodiments, relative to target nucleic acid or its designated portion, a length of or at most 12,13,14,15,16,17,18,19,20,21,22 or 23 core bases described herein oligonucleotides comprise no more than 4, no more than 3, no more than 2 or no more than 1 non-complementary core base. In certain embodiments, relative to target nucleic acid, target region, oligonucleotide or its designated portion, a length of or at most 14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29 or 30 core bases described herein oligonucleotides comprise no more than 6, no more than 5, no more than 4, no more than 3, no more than 2 or no more than 1 non-complementary core base. In certain embodiments, the mismatch is at position 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 from the 5' end of the oligonucleotide. In certain embodiments, the mismatch is at position 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, 13 or 14 from the 3' end of the oligonucleotide. In certain embodiments, the mismatch forms a wobble base pair with the corresponding nucleobase on the target nucleic acid. For example, in certain embodiments, the mismatch forms a wobble base pair selected from hypoxanthine (nucleobase of inosine) and uracil (I:U base pair); guanine and uracil (G:U base pair); hypoxanthine and adenine (I:A base pair); and hypoxanthine and cytosine (I:C base pair). Therefore, in certain embodiments, the mismatched nucleobase on the oligonucleotide comprises hypoxanthine, guanine or uracil.

[0304] In certain embodiments, the oligonucleotides described herein may be complementary to a portion of a nucleic acid. As used herein, "portion" refers to a defined number of continuous nucleobases within a region of a nucleic acid. "Portion" may also refer to a defined number of continuous nucleobases of an oligonucleotide. In certain embodiments, an oligonucleotide is partially complementary to at least 8 nucleobases of a nucleic acid. In certain embodiments, an oligonucleotide is partially complementary to at least 9 nucleobases of a nucleic acid. In certain embodiments, an oligonucleotide is partially complementary to at least 10 nucleobases of a nucleic acid. In certain embodiments, an oligonucleotide is partially complementary to at least 11 nucleobases of a nucleic acid. In certain embodiments, an oligonucleotide is partially complementary to at least 12 nucleobases of a nucleic acid. In certain embodiments, an oligonucleotide is partially complementary to at least 13 nucleobases of a nucleic acid. In certain embodiments, an oligonucleotide is partially complementary to at least 14 nucleobases of a nucleic acid. In certain embodiments, an oligonucleotide is partially complementary to at least 15 nucleobases of a nucleic acid. In certain embodiments, an oligonucleotide is partially complementary to at least 16 nucleobases of a nucleic acid. Also contemplate the following oligonucleotide, it is partially complementary to at least 9,10,17,18,19,20,21,22,23 or more core bases of nucleic acid, or partially complementary to the core bases of the range limited by any two of these values.In certain embodiments, the oligonucleotide is an antisense oligonucleotide.In certain embodiments, a part of an antisense oligonucleotide is compared with the isometric portion of a target nucleic acid.In certain embodiments, a part of 8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24 or 25 core bases is compared with the isometric portion of a target nucleic acid.In certain embodiments, the oligonucleotide is a sense oligonucleotide.In certain embodiments, a part of a sense oligonucleotide is compared with the isometric portion of an antisense oligonucleotide. In certain embodiments, a portion of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobases of a sense oligonucleotide is compared to an equal length portion of an antisense oligonucleotide.

[0305] Identity

[0306] Oligonucleotides provided herein may also have a defined percentage of identity with a specific nucleic acid, target region, oligonucleotide or a designated portion thereof. As used herein, if an oligonucleotide has the same nuclear base pairing ability, it is identical to a sequence disclosed herein. For example, a DNA containing thymidine rather than uracil in a disclosed RNA sequence will be considered identical to an RNA sequence, because both uracil and thymidine pair with adenine. Shortened and extended forms of the compounds described herein and compounds with different bases relative to the compounds provided herein are also contemplated. Different bases may be adjacent to each other or dispersed throughout the compound. The percentage identity of an oligonucleotide is calculated based on the number of bases with the same base pairing relative to the sequence being compared therewith. In certain embodiments, an oligonucleotide described herein or a portion thereof has or has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with one or more of a nucleic acid, an oligonucleotide or a portion thereof disclosed herein. In certain embodiments, the oligonucleotides described herein have about 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a particular nucleic acid or oligonucleotide or portion thereof, or any percentage identity between such values.

[0307] In certain embodiments, oligonucleotides may have one or more mismatched core bases. In certain such embodiments, mismatches are at positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 from the 5' end of the oligonucleotide. In certain such embodiments, mismatches are at positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, 13 or 14 from the 3' end of the oligonucleotide. In certain embodiments, a portion of an oligonucleotide is compared with an equal length portion of a target nucleic acid. In certain embodiments, a portion of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 core bases is compared with an equal length portion of a target nucleic acid. In certain embodiments, an oligonucleotide is a sense oligonucleotide. In certain embodiments, a portion of a sense oligonucleotide is compared with an equal length portion of a target nucleic acid. In certain embodiments, a portion of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobases is compared to an equal length portion of a target nucleic acid.

[0308] Pharmaceutical compositions and preparations

[0309] The compounds described herein may be mixed with pharmaceutically acceptable active or inert substances for the preparation of pharmaceutical compositions or formulations. The compositions and methods for preparing pharmaceutical compositions depend on multiple criteria, including but not limited to the route of administration, the extent of the disease, or the dose to be administered. Certain embodiments provide pharmaceutical compositions comprising one or more compounds or their salts. In certain embodiments, the compound is an antisense oligonucleotide. In certain embodiments, the compound is an oligomeric compound. In certain embodiments, the compound comprises or consists of one or more modified oligonucleotides. In certain such embodiments, the pharmaceutical composition comprises one or more compounds and a suitable pharmaceutically acceptable diluent or carrier. In certain embodiments, the pharmaceutical composition comprises one or more compounds and a sterile saline solution. In certain embodiments, such pharmaceutical compositions consist of a compound and a sterile saline solution. In certain embodiments, the sterile saline is a pharmaceutical grade saline. In certain embodiments, the pharmaceutical composition comprises one or more compounds and sterile water. In certain embodiments, the pharmaceutical composition consists of a compound and sterile water. In certain embodiments, the sterile water is a pharmaceutical grade water. In certain embodiments, the pharmaceutical composition comprises one or more compounds and phosphate buffered saline (PBS). In certain embodiments, the pharmaceutical composition consists of a compound and sterile PBS. In certain embodiments, the sterile PBS is pharmaceutical grade PBS.

[0310] The compounds described herein that target AGT can be used in pharmaceutical compositions by combining the compounds with suitable pharmaceutically acceptable diluents or carriers. In certain embodiments, the pharmaceutically acceptable diluent is water, such as sterile water suitable for injection. Therefore, in one embodiment, a pharmaceutical composition comprising a compound targeting AGT and a pharmaceutically acceptable diluent is employed in the methods described herein. In certain embodiments, the pharmaceutically acceptable diluent is water. In certain embodiments, the compound comprises or consists of one or more modified oligonucleotides provided herein.

[0311] The pharmaceutical composition comprising the compound provided herein encompasses any pharmaceutically acceptable salt, ester or salt of such ester, or any other oligonucleotide that can (directly or indirectly) provide a biologically active metabolite or its residue when applied to an animal (including humans). In certain embodiments, the compound is an antisense oligonucleotide. In certain embodiments, the compound is an oligomeric compound. In certain embodiments, the compound comprises or consists of one or more modified oligonucleotides. Therefore, for example, the disclosure also relates to pharmaceutically acceptable salts, prodrugs, pharmaceutically acceptable salts of such prodrugs and other bioequivalents of the compound. Suitable pharmaceutically acceptable salts include, but are not limited to, sodium salts and potassium salts. Prodrugs may include additional nucleosides incorporated into one or both ends of the compound, which are cleaved in vivo by endogenous nucleases to form active compounds. In certain embodiments, the compound or composition also comprises a pharmaceutically acceptable carrier or diluent.

[0312] Example

[0313] The following examples describe methods for identifying lead compounds targeting AGT. Certain compounds are known for having high potency and tolerability.

[0314] The following examples are only used to illustrate the compounds described herein and are not intended to limit the compounds described herein. The following examples and related sequence tables attached to this application can identify the sequence as "RNA" or "DNA"; however, as disclosed herein, those sequences can be modified by any combination of chemical modifications. It will be readily understood by those skilled in the art that in some cases, the nomenclature of "RNA" or "DNA" in the sequence is arbitrary. For example, an oligonucleotide comprising a nucleoside containing a 2'-OH sugar moiety and a thymine base can be described as a DNA with a modified sugar (2'-OH for the natural 2'-H of DNA) or an RNA with a modified base (methylated uracil for the natural uracil of RNA). Therefore, the nucleic acid sequences provided herein, including but not limited to those in the sequence table, are intended to cover nucleic acids containing any combination of natural or modified RNA and / or DNA, including but not limited to such nucleic acids with modified nucleobases.

[0315] Each reference cited in this application is incorporated herein by reference in its entirety.

[0316] Table 1

[0317] Chemical nomenclature

[0318]

[0319]

[0320] Table 2 Compound sequences and target positions on SEQ ID NO: 1

[0321]

[0322]

[0323] Table 3 Chemical properties of compounds

[0324]

[0325]

[0326] Example 1: Effects of modified oligonucleotides targeting human AGT in hAGT transgenic mice

[0327] Compounds RD2836 and RD2838 were evaluated in hAGT transgenic mice. Two groups of 5 hAGT mice were injected with a single 3 mg / kg subcutaneous dose of oligonucleotide or PBS on the first day of the study. Serum was collected on the first day (before administration), the 8th, 15th, 22nd, 29th, 35th, 43rd and 57th days. According to the manufacturer's protocol (IBL America #27412), ELISA specific for human angiotensinogen was used to quantify circulating AGT levels. AGT inhibition data are expressed as a percentage of baseline values ​​(first day before administration) and are presented as group means for each compound.

[0328] Table 4 Average AGT inhibition

[0329]

[0330] Example 2: Dose response of modified oligonucleotides targeting human AGT in hAGT transgenic mice

[0331] Compounds RD2833, RD2836, RD2837 and RD2838 were evaluated in hAGT transgenic mice. Sixteen groups of 5 hAGT mice were injected with a single subcutaneous dose of oligonucleotide or PBS on the first day of the study. Oligonucleotides were administered at three doses: 0.5 mg / kg, 1.5 mg / kg and 4.5 mg / kg. Serum was collected on the 1st day (before administration), the 8th, 15th and 22nd day. Future collection will be carried out on the 29th, 36th and 43rd day. According to the manufacturer's protocol (IBL America #27412), ELISA specific for human angiotensinogen was used to quantify circulating AGT levels. AGT inhibition data are expressed as a percentage of baseline values ​​(first day before administration) and are presented as group means for each compound.

[0332] Table 5 Average AGT inhibition

[0333]

[0334] Example 3: Effects of modified oligonucleotides targeting human AGT in cynomolgus monkeys

[0335] Compounds RD2915, RD2916, RD2917, RD2833, RD2836, RD2837 and RD2838 were evaluated in cynomolgus monkeys. Before the study, the monkeys were kept in isolation, during which the general health of the animals was observed daily. On the first day of the study, seven groups of 2 cynomolgus monkeys (or 3 for RD2838) were injected with a single 5mg / kg subcutaneous dose of oligonucleotide. All animals were bled for serum analysis on days -6 and 1 (before administration), 4, 8, 15, 22 and 29. Future collection will be carried out on days 36, 43, 50, 57 and 64. The described scheme was approved by the Institutional Animal Care and Use Committee (IACUC). According to the manufacturer's scheme (IBL America #27412), circulating AGT levels were quantified using an ELISA that was specific to human angiotensinogen (and cross-reactive with cynomolgus monkeys). AGT inhibition data are expressed as a percentage of baseline values ​​(average of pre-dose Day -6 and Day 1) and are presented as group means for each compound. Clinical chemistry was performed on Day -6 and will be performed on Day 64.

[0336] Table 6 Average AGT inhibition

[0337]

[0338] Example 4: Effects of modified oligonucleotides targeting human AGT in cynomolgus monkeys

[0339] Compounds RD3048, RD3049, RD3050, RD3051, RD3057 and RD3058 were evaluated in cynomolgus monkeys. Before the study, monkeys were kept in isolation, and the general health of the animals was observed daily during this period. Six groups of 2 cynomolgus monkeys were injected with a single 5mg / kg subcutaneous dose of oligonucleotide on the 1st day of the study. All animals were bled for serum analysis on the 6th day and the 1st day (before administration), the 4th, 8th, 15th, 22nd, 29th, 36th, 43rd, 50th, 57th and 64th days. The described scheme was approved by the Institutional Animal Care and Use Committee (IACUC). According to the manufacturer's scheme (IBL America #27412), the circulating AGT level was quantified using an ELISA that was specific to human angiotensinogen (and cross-reactive with cynomolgus monkeys). AGT inhibition data will be evaluated. Clinical chemistry will be carried out on the 6th day and the 64th day.

[0340] Example 5: Effects of modified oligonucleotides targeting human AGT in cynomolgus monkeys

[0341] Compounds RD3051 and RD3057 were evaluated in cynomolgus monkeys. Before the study, monkeys were kept in isolation, and the general health of the animals was observed daily during this period. On the first day of the study, two groups of 2 cynomolgus monkeys were injected with a single 5mg / kg subcutaneous dose of oligonucleotide. On the 6th day and the 1st day (before administration), the 8th, 15th, 22nd, 29th, 36th, 43rd, 50th, 57th and 64th days, all animals were blood drawn for serum analysis. The described scheme was approved by the Institutional Animal Care and Use Committee (IACUC). According to the manufacturer's scheme (IBL America #27412), the circulating AGT level was quantified using an ELISA that was specific to human angiotensinogen (and cross-reactive with cynomolgus monkeys). AGT inhibition data were expressed as a percentage of baseline values ​​(mean values ​​of the 6th day and the 1st day before administration) and presented as the group mean values ​​of each compound. Clinical chemistry was carried out on the 6th day and the 64th day. There was no test article-related effect on body weight and all serum chemistry values ​​were within the reference range.

[0342] Table 7 Average AGT inhibition

[0343]

[0344] Table 8 Body weight (kg)

[0345] Compound Day 1 Day 64 RD3051 cynomolgus monkey #1 4.5 4.9 RD3051 Cynomolgus Monkey #2 4.9 5.4 RD3057 Crab-eating monkey #1 4.3 4.7 RD3057 Crab-eating monkey #2 4.4 4.3

[0346] Table 9 Liver function markers

[0347]

[0348] Table 10 Renal function markers

[0349]

[0350] Example 6: Effects of modified oligonucleotides targeting human AGT in cynomolgus monkeys

[0351] Compound RD3050 and RD3058 were evaluated in cynomolgus monkeys. Before the study, monkeys were kept in isolation, and the general health of animals was observed daily during this period. On the first day of the study, two groups of each 2 cynomolgus monkeys were injected with a single 5mg / kg subcutaneous dose of oligonucleotide. At -6 days and at the 1st day (before administration), the 8th, 15th, 22nd, 29th, 36th, 43th, 50th, 57th, 64th, 71st, 78th, 85th, 92nd, 99th, 106th, 113th and 120th days, all animals were blood drawn for serum analysis. The described scheme was approved by the Institutional Animal Care and Use Committee (IACUC). According to the manufacturer's scheme (IBL America #27412), the ELISA with specificity (and cross-reactivity with cynomolgus monkeys) for human angiotensinogen was used to quantify the circulating AGT level. AGT inhibition data were expressed as the percentage of baseline values ​​(mean values ​​of -6 days and the 1st day before administration) and presented as the group mean values ​​of each compound. Clinical chemistries were performed on Days -6 and 120 for RD3050 and RD3058. There were no test article related effects on body weight and all serum chemistry values ​​were within reference ranges.

[0352] Table 11 Average AGT inhibition

[0353]

[0354] Table 12 Body weight (kg)

[0355] Compound Day 1 Day 120 RD3050 cynomolgus monkey #1 4.2 4.9 RD3050 Crab-eating monkey #2 2.5 2.8 RD3058 Cynomolgus Monkey #1 4.8 5.5 RD3058 Crab-eating monkey #2 4.4 4.8

[0356] Table 13

[0357] Liver function markers

[0358]

[0359] Table 14 Renal function markers

[0360]

[0361] Example 7: Effects of modified oligonucleotides targeting human AGT in cynomolgus monkeys

[0362] Compound RD3058 was evaluated in cynomolgus monkeys. Before the study, the monkeys were kept in isolation, during which the general health of the animals was observed daily. On the first day of the study, two groups of cynomolgus monkeys were each injected with a single subcutaneous dose of oligonucleotide. In one group, 2 monkeys were administered with 0.5mg / kg. In the second group, 3 monkeys were injected with 3mg / kg. All animals were bled for serum analysis on days -6 and 1 (before administration), 8, 15, 22, 29, 36, 43, 50, 57 and 64. On days 71, 78, 85 and 92, additional collection was performed on the 3mg / kg group. The described scheme was approved by the Institutional Animal Care and Use Committee (IACUC). According to the manufacturer's scheme (IBL America #27412), circulating AGT levels were quantified using an ELISA that was specific to human angiotensinogen (and cross-reactive with cynomolgus monkeys). AGT inhibition data are expressed as a percentage of baseline values ​​(average of pre-dose Day -6 and Day 1) and are presented as group means for each compound. Clinical chemistry was performed on Day -6 and Day 64 (0.5 mg / kg) or Day 92 (3 mg / kg) for RD3058.

[0363] Table 15 Average AGT inhibition

[0364]

[0365] Example 8: Effects of modified oligonucleotides targeting human AGT in cynomolgus monkeys

[0366] Compound RD3058 was evaluated in cynomolgus monkeys. Before the study, monkeys were kept in isolation, and the general health of animals was observed daily during this period. Three untreated animals were selected for study and randomly assigned to 2 groups; control group and dosage group. RD3058 was administered to the dosage group by subcutaneous injection of twice the dosage with a dosage volume of 0.5mL / kg at a dosage level of 30mg / kg / agent at 3 week intervals (the 1st day and the 22nd day). Observation includes vitality, clinical observation (cage side observation and detailed clinical observation), body weight, food consumption, clinical pathology (clinical chemistry, hematology and coagulation), organ weight and macroscopic and microscopic pathology. Based on the overall results, the RD3058 of two repeated doses was well tolerated with 30mg / kg / agent in cynomolgus monkeys.

[0367] SEQ ID NO:1

[0368]

[0369]

Claims

1. A compound comprising a modified oligonucleotide of 14 to 23 linked nucleosides in length, the modified oligonucleotide 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 consecutive nucleobases of any one of the nucleobase sequences SEQ ID NOs: 11-20.

2. A compound comprising a modified oligonucleotide having a length of 14 to 23 linked nucleosides, the modified oligonucleotide having a nucleobase sequence comprising any one of the nucleobase sequences SEQ ID NOs: 11-20.

3. A compound comprising a modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs: 11-20.

4. The compound of any one of claims 1-3, wherein the modified oligonucleotide is at least 80%, at least 85%, at least 90% or at least 95% complementary to SEQ ID NO: 1 or SEQ ID NO:

3.

5. The compound of any one of claims 1-4, wherein the modified oligonucleotide comprises at least one modification selected from a modified internucleoside linkage, a modified sugar, and a modified nucleobase.

6. The compound of any one of claims 1-5, wherein the compound is double-stranded.

7. A compound comprising a first modified oligonucleotide and a second modified oligonucleotide, wherein the first modified oligonucleotide has a length of 14 to 23 linked nucleosides and has a core base sequence of 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 consecutive core bases comprising any one of the core base sequence SEQ ID NO: 11-20 or 31-42, and the second modified oligonucleotide has a length of 14 to 23 linked nucleosides and has a complementary region to the first modified oligonucleotide.

8. A compound comprising a first modified oligonucleotide and a second modified oligonucleotide, wherein the first modified oligonucleotide has a length of 14 to 23 linked nucleosides and has a nucleobase sequence comprising any one of a nucleobase sequence SEQ ID NO: 11-20 or 31-42, and the second modified oligonucleotide has a length of 14 to 23 linked nucleosides and has a complementary region to the first modified oligonucleotide.

9. A compound comprising a first modified oligonucleotide and a second modified oligonucleotide, wherein the first modified oligonucleotide has a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs: 11-20 and 31-42, and the second modified oligonucleotide has a length of 19 to 23 linked nucleosides and has a complementary region to the first modified oligonucleotide.

10. The compound of any one of claims 7-9, wherein the first modified oligonucleotide has at least 80%, at least 85%, at least 90% or at least 95% complementarity or identity to SEQ ID NO: 1 or SEQ ID NO: 3 over its length.

11. A compound as described in any one of claims 7-10, wherein the first modified oligonucleotide has at least 1, at least 2, at least 3 mismatches with a region of SEQ ID NO: 1 or SEQ ID NO: 3 that is identical in length to the first modified oligonucleotide.

12. The compound of any one of claims 7-11, wherein the length of the complementary region between the first modified oligonucleotide and the second modified oligonucleotide is 14 to 23 linked nucleosides.

13. A compound as described in any one of claims 7-11, wherein the length of the complementary region between the first modified oligonucleotide and the second modified oligonucleotide is 19 to 23 linked nucleosides.

14. A compound as described in any one of claims 7-11, wherein the length of the complementary region between the first modified oligonucleotide and the second modified oligonucleotide is 21 to 23 linked nucleosides.

15. The compound of any one of claims 7-11, wherein the first modified oligonucleotide is fully complementary to the second modified oligonucleotide.

16. The compound of any one of claims 7-15, wherein the first modified oligonucleotide comprises at least one modification selected from a modified internucleoside linkage, a modified sugar, and a modified nucleobase.

17. The compound of any one of claims 7-16, wherein the second modified oligonucleotide comprises at least one modification selected from the group consisting of a modified internucleoside linkage, a modified sugar, and a modified nucleobase.

18. The compound of any one of claims 5, 16 and 17, wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage or a methylphosphonate internucleoside linkage.

19. The compound of claim 18, wherein the phosphorothioate internucleoside linkage or the methylphosphonate internucleoside linkage is at the 3' end of the first or second modified oligonucleotide or at the 5' end of the first modified oligonucleotide.

20. The compound of any one of claims 5, 16 and 17, wherein the modified sugar comprises a modification selected from the group consisting of halogen, alkoxy and bicyclic sugar.

21. The compound of claim 20, wherein the modified sugar comprises a 2'-F modification.

22. The compound of claim 20, wherein the modified sugar comprises a 2'-OMe modification.

23. A compound as described in any one of claims 7-15, wherein each nucleoside of the first modified oligonucleotide comprises a modified sugar.

24. A compound as described in any one of claims 7-15, wherein each nucleoside of the second modified oligonucleotide comprises a modified sugar.

25. The compound of claim 23 or 24, wherein the modified sugar comprises a modification selected from the group consisting of halogen, alkoxy, and bicyclic sugar, or a combination thereof.

26. The compound of claim 25, wherein the modified sugar comprises a modification selected from the group consisting of LNA, cEt, 2'-MOE, 2'-F, 2'-OMe and 2'-deoxy or a combination thereof.

27. The compound of claim 23, wherein the first modified oligonucleotide comprises no more than ten 2'-F sugar modifications.

28. The compound of claim 24, wherein the second modified oligonucleotide comprises no more than five 2'-F sugar modifications.

29. A compound as claimed in any one of the preceding claims comprising a conjugated group.

30. The compound of claim 29, wherein the conjugated group is attached to the 5' end of the modified oligonucleotide.

31. The compound of claim 29 or 30, wherein the conjugated group comprises a targeting moiety.

32. The compound of claim 31, wherein the targeting moiety comprises one or more GalNAc.

33. The compound of claim 32, wherein the modified oligonucleotide is the second modified oligonucleotide.

34. The compound of claim 32 or 33, wherein the one or more GalNAc's are attached to the 2' or 3' position of the ribosyl ring of the 5' nucleoside of the modified oligonucleotide.

35. The compound of claim 34, wherein the 5' nucleoside has the formula: in: R 9 is H, adenine, guanine, thymine, cytosine or uracil, or adenine, guanine, thymine, cytosine or uracil, each of which comprises a protecting group (PG), a modified nucleobase, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted carbocyclyl, an optionally substituted heterocyclyl or a nucleobase isostere; L is a bond, a phosphodiester bond, a phosphorothioate bond, a triazole, a tetrazole, an amide, a reverse amide, a carbamate, a carbonate, a urea, an alkyl group, or a heteroalkyl group; R 2 is the oligonucleotide sequence; Y1 is O, CH2, CH2O or optionally substituted NH; Y2 is O, CH2, CH2O or optionally substituted NH; Y3 is CO, SO2, P(O)O, CH2-OC(O), CH2-NH-C(O), CH2-NH-SO2 or CH2; Y4 is CO, SO2, P(O)O, CH2-OC(O), CH2-NH-C(O), CH2-NH-SO2 or CH2; n2 is 0, 1, 2, 3, 4, 5 or 6; and Each of n1, n3, n4 and n5 is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

36. The compound of claim 34, wherein the 5' nucleoside is selected from any one of Formula I to Formula VIII, and wherein R' is S, and R is the portion of the modified oligonucleotide other than the 5' nucleoside.

37. The compound of claim 34, wherein the 5' nucleoside is selected from any one of Formula I to Formula VIII, and wherein R' is O, and R is the portion of the modified oligonucleotide other than the 5' nucleoside.

38. A compound comprising a first modified oligonucleotide and a second modified oligonucleotide, wherein the first modified oligonucleotide is selected from the group consisting of any one of Ref ID NO: IA0500, IA1019, IA1022-1024, IA1027, IA1093-1095 and IA1103, and the second modified oligonucleotide has a length of 14 to 21 linked nucleosides and is fully complementary to the first modified oligonucleotide.

39. A compound comprising a first modified oligonucleotide and a second modified oligonucleotide, wherein the first modified oligonucleotide is selected from the group consisting of Ref ID NO: IA0500, IA1019, IA1022-1024, IA1027, IA1093-1095 and IA1103, and the second modified oligonucleotide is selected from the group consisting of Ref ID NO: IS1255, IS1258, IS1259, IS1260, IS1279, IS1280, IS1372-1375, IS1381 and IS1382.

40. A compound comprising a first modified oligonucleotide selected from the group consisting of Ref ID NO: IA1024, IA1094 and IA1103 and a second modified oligonucleotide selected from the group consisting of Ref ID NO: IS1260, IS1374 and IS1382.

41. The compound of any one of claims 1-40, wherein the compound is in the form of a pharmaceutically acceptable salt.

42. The compound of claim 41, wherein the pharmaceutically acceptable salt is a sodium salt.

43. The compound of claim 41, wherein the pharmaceutically acceptable salt is a potassium salt.

44. A modified oligonucleotide according to the following chemical structure: or a pharmaceutically acceptable salt or stereoisomer thereof.

45. The modified oligonucleotide of claim 44, wherein the pharmaceutically acceptable salt is a sodium salt or a potassium salt.

46. ​​The modified oligonucleotide of claim 45, which is a sodium salt according to the following chemical structure: or a stereoisomer thereof.

47. A modified oligonucleotide according to the following chemical structure: or a pharmaceutically acceptable salt or stereoisomer thereof.

48. The modified oligonucleotide of claim 47, wherein the pharmaceutically acceptable salt is a sodium salt or a potassium salt.

49. The modified oligonucleotide of claim 48, which is a sodium salt according to the following chemical structure: or a stereoisomer thereof.

50. A modified oligonucleotide according to the following chemical structure: or a pharmaceutically acceptable salt or stereoisomer thereof.

51. The modified oligonucleotide of claim 50, wherein the pharmaceutically acceptable salt is a sodium salt or a potassium salt.

52. The modified oligonucleotide of claim 51 which is a sodium salt according to the following chemical structure: or a stereoisomer thereof.

53. A modified oligonucleotide according to the following chemical structure: or a pharmaceutically acceptable salt or stereoisomer thereof.

54. The modified oligonucleotide of claim 53, wherein the pharmaceutically acceptable salt is a sodium salt or a potassium salt.

55. The modified oligonucleotide of claim 54, which is a sodium salt according to the following chemical structure: or a stereoisomer thereof.

56. A compound according to the following chemical structure: or a pharmaceutically acceptable salt or stereoisomer thereof.

57. The compound of claim 56, wherein the pharmaceutically acceptable salt is a sodium salt or a potassium salt.

58. The compound of claim 57, which is a sodium salt according to the following chemical structure: or a stereoisomer thereof.

59. A compound according to the following chemical structure: or a pharmaceutically acceptable salt or stereoisomer thereof.

60. The compound of claim 59, wherein the pharmaceutically acceptable salt is a sodium salt or a potassium salt.

61. The compound of claim 60, which is a sodium salt according to the following chemical structure: or a stereoisomer thereof.

62. A composition comprising the compound or modified oligonucleotide of any one of claims 1-61, and a pharmaceutically acceptable carrier.

63. A composition comprising a compound or modified oligonucleotide as claimed in any one of the preceding claims for use in therapy.

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

65. A method of administering to a subject a compound or modified oligonucleotide of any one of claims 1-61 or a composition of claim 62 or 63.

66. The method of claim 64 or 65, wherein the disease, disorder or condition is a RAAS-related disease, disorder or condition or a symptom thereof, hypertension, resistant hypertension, fibrosis, renal disease, chronic kidney disease, cardiovascular disease (e.g., coronary heart disease, heart failure, stroke, myocardial infarction, atrial fibrillation, aneurysm and peripheral arterial disease), organ damage (e.g., heart, liver or kidney), inflammatory bowel disease or cognitive impairment.

67. The method of any one of claims 64-66, wherein administration of the compound inhibits or reduces or improves RAAS-related diseases, disorders or conditions or symptoms thereof, hypertension, resistant hypertension, fibrosis, renal disease, chronic kidney disease, cardiovascular disease (e.g., coronary heart disease, heart failure, stroke, myocardial infarction, atrial fibrillation, aneurysm and peripheral arterial disease), organ damage (e.g., heart, liver or kidney), inflammatory bowel disease or cognitive impairment.

68. A method of inhibiting the expression of AGT in a cell, the method comprising contacting the cell with a compound that targets AGT, thereby inhibiting the expression of AGT in the cell.

69. The method of claim 68, wherein the cell is in the liver of the individual.

70. The method of claim 69, wherein the subject has or is at risk for developing a RAAS-associated disease, disorder or condition or a symptom thereof, hypertension, resistant hypertension, fibrosis, renal disease, chronic kidney disease, cardiovascular disease (e.g., coronary heart disease, heart failure, stroke, myocardial infarction, atrial fibrillation, aneurysm, and peripheral arterial disease), organ damage (e.g., heart, liver, or kidney), inflammatory bowel disease, or cognitive impairment.

71. A method of reducing or inhibiting a subject's RAAS-related disease, disorder or condition or symptoms thereof, hypertension, resistant hypertension, fibrosis, nephropathy, chronic kidney disease, cardiovascular disease (e.g., coronary heart disease, heart failure, stroke, myocardial infarction, atrial fibrillation, aneurysm and peripheral arterial disease), organ damage (e.g., heart, liver or kidney), inflammatory bowel disease or cognitive impairment, the method comprising administering to the subject a compound targeting AGT, thereby reducing or inhibiting the subject's RAAS-related disease, disorder or condition or symptoms thereof, hypertension, resistant hypertension, fibrosis, nephropathy, chronic kidney disease, cardiovascular disease (e.g., coronary heart disease, heart failure, stroke, myocardial infarction, atrial fibrillation, aneurysm and peripheral arterial disease), organ damage (e.g., heart, liver or kidney), inflammatory bowel disease or cognitive impairment.

72. The method of claim 71, wherein the subject has or is at risk for developing a RAAS-associated disease, disorder or condition or a symptom thereof, hypertension, resistant hypertension, fibrosis, renal disease, chronic kidney disease, cardiovascular disease (e.g., coronary heart disease, heart failure, stroke, myocardial infarction, atrial fibrillation, aneurysm, and peripheral arterial disease), organ damage (e.g., heart, liver, or kidney), inflammatory bowel disease, or cognitive impairment.

73. The method of any one of claims 64-72, wherein the compound is a compound that targets AGT.

74. The method of any one of claims 64-73, wherein the compound or modified oligonucleotide is a compound or modified oligonucleotide as described in any one of claims 1-61 or a composition as described in claim 62 or 63.

75. The method of claim 74, wherein the compound or composition is administered parenterally.

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

77. The use of claim 76, wherein the disease, disorder or condition is a RAAS-related disease, disorder or condition or a symptom thereof, hypertension, resistant hypertension, fibrosis, renal disease, chronic kidney disease, cardiovascular disease (e.g., coronary heart disease, heart failure, stroke, myocardial infarction, atrial fibrillation, aneurysm and peripheral arterial disease), organ damage (e.g., heart, liver or kidney), inflammatory bowel disease or cognitive impairment.

78. The use according to claim 76 or 77, wherein the compound is a compound targeting AGT.

79. The use of any one of claims 76-78, wherein the compound or modified oligonucleotide is a compound or modified oligonucleotide as described in any one of claims 1-61 or a composition as described in claim 62 or 63.

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

81. The use of claim 80, wherein the disease is a RAAS-related disease, disorder or condition or a symptom thereof, hypertension, resistant hypertension, fibrosis, renal disease, chronic kidney disease, cardiovascular disease (e.g., coronary heart disease, heart failure, stroke, myocardial infarction, atrial fibrillation, aneurysm and peripheral arterial disease), organ damage (e.g., heart, liver or kidney), inflammatory bowel disease or cognitive impairment.

82. The use according to claim 80 or 81, wherein the compound is a compound targeting AGT.

83. The use of any one of claims 80-82, wherein the compound or modified oligonucleotide is a compound or modified oligonucleotide as described in any one of claims 1-61 or a composition as described in claim 62 or 63.

84. The method or use of any of the preceding claims, wherein the compound or composition is administered to the individual from about once every three months to about once a year.

85. The method or use of any of the preceding claims, wherein the compound or composition is administered to the individual approximately once every three months, approximately once every six months, or approximately once a year.

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