Compositions that modulate complement factor b and methods of use thereof

Abstract

Some aspects of the present disclosure provide compounds, compositions, and methods for modulating the expression or activity of Complement Factor B (CFB). In certain aspects, the compounds, compositions, and methods of the present disclosure are useful for reducing expression of CFB mRNA in a cell or animal. In certain aspects, the compounds, compositions, and methods of the present disclosure are useful for reducing expression of CFB protein in a cell or animal.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 63 / 283,177 filed on November 24, 2021, U.S. Provisional Application No. 63 / 287,952 filed on December 9, 2021, U.S. Provisional Application No. 63 / 302,976 filed on January 25, 2022, and U.S. Provisional Application No. 63 / 339,873 filed on May 9, 2022. The disclosure of each prior application is considered part of the disclosure of the present application and is incorporated by reference into the disclosure of the present application in its entirety.

[0003] References to Electronic Sequence Listings

[0004] The contents of the electronic Sequence Listing (A127870010WO00-SEQ-JIB.xml; size: 111,161 bytes; and creation date: November 22, 2022) are incorporated herein by reference in their entirety. Background Art

[0005] Complement factor B (CFB) is an important component of the alternative pathway of complement activation. CFB is a serine protease secreted from the liver. CFB circulates in the blood as a single-chain polypeptide. After activation of the alternative pathway, it is cut by complement factor D to produce non-catalytic chain Ba and catalytic subunit Bb. Active subunit Bb is a serine protease that associates with C3b to form the alternative pathway C3 convertase. The generation of C3 convertase leads to the formation of C5 convertase, which cuts C5 and triggers an event that leads to the formation of a lytic membrane attack complex (MAC). The membrane attack complex forms a transmembrane channel and destroys the phospholipid bilayer of the target cell, leading to cell lysis.

[0006] Inappropriate complement activation promotes many different diseases, including, for example, atypical hemolytic uremic syndrome (aHUS), paroxysmalnocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE) such as lupus nephritis, diabetic nephropathy, membranous nephropathy, polycystic kidney disease, age-related macular degeneration, thrombotic microangiopathy, myasthenia gravis, ischemia and reperfusion injury, and rheumatoid arthritis (RA). Therefore, there is a need to find effective treatments for complement-related diseases. Summary of the invention

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

[0008] In certain embodiments, the animal suffers from a complement pathway-related disease, disorder or condition, or a symptom thereof, or is at risk of a complement pathway-related disease, disorder or condition, or a symptom thereof. In certain embodiments, the disease, disorder or condition is atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE) such as lupus nephritis, diabetic nephropathy, membranous nephropathy, polycystic kidney disease, age-related macular degeneration, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, or rheumatoid arthritis (RA). Certain compounds, compositions, and methods provided herein relate to mitigating tissue damage associated with complement pathway disorders, such as eye damage or renal damage. Certain compounds, compositions and methods provided herein relate to reducing atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE) such as lupus nephritis, diabetic nephropathy, membranous nephropathy, polycystic kidney disease, age-related macular degeneration, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury or rheumatoid arthritis (RA) in animals. In certain embodiments, compounds and compositions provided herein are potent and tolerable, and inhibit CFB expression, which can be used to treat, prevent, improve tissue damage (e.g., eye damage or kidney damage) associated with complement pathway dysregulation or slow its progression. In certain embodiments, the compounds and compositions provided herein are potent and tolerable, and inhibit CFB expression, which can be used to treat, prevent, ameliorate or slow the progression of atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE) such as lupus nephritis, diabetic nephropathy, membranous nephropathy, polycystic kidney disease, age-related macular degeneration, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury or rheumatoid arthritis (RA).

[0009] In certain embodiments, the compounds and compositions comprise one or more features effective for improving efficacy. In certain embodiments, the compounds and compositions comprise one or more features effective for improving tolerance. In certain embodiments, the compounds and compositions comprise one or more features effective for targeting the compounds or compositions to cells or tissues. In certain embodiments, the compounds and compositions are more potent or have greater therapeutic value than the disclosed compounds. DETAILED DESCRIPTION

[0010] It should be understood that both the foregoing summary and the following detailed description are exemplary and explanatory only and do not constitute limitations on 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, are hereby expressly incorporated by reference to the portion of the documents discussed herein and in their entirety as of the filing date of this application.

[0012] It should be understood that the sequence shown in each SEQ ID NO contained herein is independent of any modification of the sugar moiety, internucleoside linkage or nucleobase, even when shown in the context as a modified compound. Therefore, the compound defined by the SEQ ID NO may independently contain one or more modifications to the sugar moiety, internucleoside linkage or nucleobase. The oligomeric compounds cited by the Compound Number or Ref ID NO represent a combination of nucleobase sequences, chemical modifications and motifs.

[0013] Here, unless otherwise expressly stated, the use of the singular includes the plural. For example, a noun used herein without a quantifier modifier refers to one or more than one (i.e., at least one) grammatical object. For example, "element" means one element or more than one element, such as a plurality of elements. Unless otherwise stated, the use of "or" used herein means "and / or". In addition, the use of the term "includes / comprising" and other forms (e.g., variations thereof) is not restrictive and can be used interchangeably with the phrase "including but not limited to".

[0014] definition

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

[0016] "Complement factor B", used interchangeably with the term "CFB", refers to any nucleic acid or protein of CFB. Exemplary nucleotide and amino acid sequences of CFB can be found, for example, in GenBank Accession No. NM_001710.6 (incorporated herein as SEQ ID NO: 1), GenBank Accession No. NC_000006.12 nucleotides 31946095 to 31952084 (incorporated herein as SEQ ID NO: 2), GenBank Accession No. NM_001710.6 (incorporated herein as SEQ ID NO: 3), and GenBank Accession No. NT_113891.3 nucleotides 3423522 to 3429511 (incorporated herein as SEQ ID NO: 4). Additional examples of CFB sequences are readily available through publicly available databases (e.g., GenBank, UniProt, and OMIM). Additional information about CFB can be found, for example, at https: / / www.ncbi.nlm.nih.gov / gene / ? term=CFB. As used herein, CFB also refers to variations of the CFB gene, including variants provided in the SNP database. Many sequence variations in the CFB gene have been identified and can be found, for example, in NCBI dbSNP and UniProt (see, for example, https: / / www.ncbi.nlm.nih.gov / snp / ?term=CFB). "CFB mRNA" means mRNA encoding the CFB protein. CFB can be represented by uppercase or lowercase letters.

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

[0018] "2'-O-methoxyethyl" or "2'-MOE" means 2'-O(CH 2 ) 2 -OCH 3 Modification. Sugars modified with 2'-O-methoxyethyl are modified with 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 the target nucleic acid or region that is complementary to the 3'-most nucleoside of the antisense oligonucleotide.

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

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

[0022] "Administering" and its variations refer to the route by which a compound or composition provided herein is introduced into an individual to achieve its intended function. For example, routes of administration that may 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 condition 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 comprises a region complementary to a target nucleic acid (eg, CFB RNA or a region thereof).

[0026] "Complementarity" about oligonucleotides means that when two core base sequences are aligned in opposite directions, such oligonucleotides or the core base sequence of one or more regions thereof are complementary to another oligonucleotide or nucleic acid or the core base sequence of one or more regions thereof. Unless otherwise indicated, the complementary core bases 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 the administration of two or more compounds in any manner wherein the pharmacological effects of both compounds are manifested in the patient. Co-administration does not require that the two compounds be administered in a single pharmaceutical composition, in the same dosage form, by the same route of administration, or at the same time. The effects of the two compounds do not require that they manifest at the same time. The effects need only overlap for a period of time and do not need to be co-extended. Co-administration includes parallel or sequential administration of one or more compounds.

[0029] "Conjugate group" means a group of atoms attached to an oligonucleotide. The conjugate group is optionally attached to the oligonucleotide via a conjugate linker. For example, the conjugate group may alter the distribution, targeting, or half-life of the compound into which it is incorporated. The 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" about an oligonucleotide means that the nucleobase sequence of such an oligonucleotide or one or more regions thereof matches that 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 comprise one or more different nucleobases. In contrast, "identical" or "100% identity" about an oligonucleotide means that such an oligonucleotide has the same nucleobase as the other oligonucleotide or nucleic acid at each relative position along 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 a target relative to expression or activity in an untreated or control sample, and does not necessarily mean 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, alkylphosphonates and phosphorothioates. The modified oligonucleotides comprising internucleoside linkages with chiral centers can be prepared as modified oligonucleotide groups comprising stereo-random internucleoside linkages, or as modified oligonucleotide groups comprising phosphorothioate linkages of specific stereochemical configurations, as further described below. Unless otherwise indicated, the chiral internucleoside linkages of the modified oligonucleotides described herein can be stereo-random or specific stereochemical configurations.

[0036] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be treated with radioactive isotopes (e.g., tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C)) is radiolabeled. 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 an unnatural ratio of isotopes at one or more atoms that constitute the therapeutic agent. In certain embodiments, an "isotopic variant" of a therapeutic agent contains an unnatural ratio 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 comprises 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 modified oligonucleotide disclosed herein), any hydrogen may be 2 H, or any carbon, for example, may be 13 C, or any nitrogen, for example 15 N, or any oxygen, for example, may be 18 O. In certain embodiments, an "isotopic variant" of a therapeutic agent comprises unnatural proportions of deuterium (D).

[0039] "Mismatch" or "non-complementarity" means that when the first oligonucleotide / nucleic acid and the second oligonucleotide / nucleic acid are aligned in an antiparallel direction, the nucleobase of the first oligonucleotide or nucleic acid is non-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 to the nucleobase to which it hybridizes. As another example, when the first oligonucleotide and the second oligonucleotide are aligned in an antiparallel direction, 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 is modified. In certain embodiments, the compounds described herein comprise at least one modified oligonucleotide.

[0041] "Modulate" means to change or regulate a characteristic in a cell, tissue, organ, or organism. For example, modulating CFB RNA may mean increasing or decreasing the level of CFB RNA and / or CFB protein in a cell, tissue, organ, or organism. A "modulator" effects a change in a cell, tissue, organ, or organism. For example, a CFB compound may be a modulator that decreases the amount of CFB RNA and / or CFB 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 a base of another nucleic acid. "Naturally occurring nucleobases" as used herein 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 lacking a nucleobase.

[0047] "Oligomeric compound" means a compound comprising one or more oligonucleotides and optionally one or more additional features (e.g., conjugated groups or terminal groups). Some examples of oligomeric compounds include single-stranded and double-stranded compounds, such as oligonucleotides, antisense oligonucleotides, interfering RNA compounds (RNAi compounds), microRNA targeting oligonucleotides, site-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 through the RNA-induced silencing complex (RISC) pathway, resulting in sequence-specific degradation and / or sequestration of target nucleic acids via a process known as RNA interference (RNAi). The term "RNAi compound" means other terms equivalent to those used to describe nucleic acid compounds capable of mediating 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, etc. Additionally, the term "RNAi" is intended to refer equivalently to other terms used to describe sequence-specific RNA interference.

[0048] "Oligonucleotide" means a polymer of independently linked nucleosides, each of which may be modified or unmodified.

[0049] 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 "double-stranded oligomeric compound". The oligonucleotides of each oligomeric compound of an oligomeric duplex may include non-complementary protruding nucleosides. In some embodiments, the terms "double-stranded oligomeric compound" and "modified oligonucleotide" are used interchangeably. In other embodiments, the terms "oligoduplex" and "compound" are used interchangeably.

[0050] "Parenteral administration" means administration by 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 a compound to an individual and absorption by the individual, and may be included in the compositions of the present disclosure without causing significant adverse toxicological effects on the patient. Some non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal 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 may be used in the present disclosure.

[0052] "Pharmaceutically acceptable salt" means or refers to a physiologically and pharmacologically acceptable salt of a compound (e.g., an oligomeric compound or oligonucleotide), i.e., a salt that retains the desired biological activity of the parent compound and does not produce undesirable toxicological effects thereon. As used herein, a pharmaceutically acceptable salt is any salt of a compound provided herein that retains its biological properties and is non-toxic or otherwise desirable for pharmaceutical use. Pharmaceutically acceptable salts of the therapeutic agents disclosed herein include salts prepared with relatively non-toxic acids or bases, depending on the specific substituents present in the compounds or modified oligonucleotides described herein.

[0053] 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.

[0054] 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.

[0055] Thus, the compounds of the present disclosure may exist as salts, for example, with pharmaceutically acceptable acids. Such salts may be derived from a variety of organic and inorganic counterions known in the art. Such salts include, but are not limited to: (1) acid addition salts formed with 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, hexanoic 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 , picric 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, hydroxy or (2) salts formed when an acidic proton present in the parent compound undergoes (a) or (b) 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, potassium, calcium, magnesium, aluminum, lithium, zinc and barium hydroxide, or ammonia; or (b) coordination with 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'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, N-methylglucaminepiperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, and the like (see, e.g., Bergeet et al., 1996). al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19).

[0056] Pharmaceutically acceptable salts also include, by way of example only and not limitation, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like, and, when the compound contains a basic functional group, non-toxic organic or inorganic acid salts such as hydrohalides, for example, 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, laurates, methanesulfonic acids. In some embodiments, 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.

[0057] The compound of neutral form 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 be different from multiple salt forms in certain physical properties (such as solubility in polar solvents). In some embodiments, the compound of the present disclosure comprises both basic and acidic functional groups that allow the compound to be converted into base addition salts or acid addition salts. The compound of neutral form can 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 is different from multiple salt forms in certain physical properties (such as solubility in polar solvents), but, unless otherwise specified, the salt disclosed herein is equivalent to the parent form of the compound for the purpose of the present disclosure.

[0058] "Pharmaceutical agent" means a chemical compound that provides a therapeutic benefit when administered to a subject.

[0059] "Phosphorothioate linkage" means a modified phosphate linkage in which one of the non-bridging oxygen atoms is replaced by a sulfur atom.

[0060] "Portion" means a determined number of consecutive (i.e., connected) core bases of a nucleic acid. In certain embodiments, a portion is a determined number of consecutive core bases of a target nucleic acid. In certain embodiments, a portion is a determined number of consecutive core bases of an oligonucleotide.

[0061] "Prevention" means delaying or arresting for a period of time the onset, occurrence or progression of a disease, disorder or condition.

[0062] "RNA interference compound" or "RNAi compound" means a compound that modulates a target nucleic acid and / or a protein encoded by a target nucleic acid at least in part through the RNA-induced silencing complex (RISC) pathway or Ago2 (rather than through RNase H). RNAi compounds include, but are not limited to, double-stranded siRNA, single-stranded siRNA, and microRNA, including microRNA mimics.

[0063] "Sense oligonucleotide" or "sense strand" means the strand of a double-stranded compound that comprises a region that is substantially complementary to a region of the antisense strand of the compound.

[0064] "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 the effects on non-target nucleic acids or proteins.

[0065] "Subunit" with respect to an oligonucleotide means a nucleotide, nucleoside, nucleobase or sugar or a modified nucleotide, nucleoside, nucleobase or sugar as provided herein.

[0066] "Target nucleic acid," "target RNA," and "nucleic acid target" all refer to a nucleic acid that can be targeted by the compounds described herein.

[0067] "Target region" means a portion of a target nucleic acid to which one or more compounds are targeted.

[0068] "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) compared to, e.g., a compound without such a moiety.

[0069] "Terminus group" means a chemical group or group of atoms covalently attached to the terminus of an oligonucleotide.

[0070] "Therapeutically effective amount" or "effective amount" means the amount of a compound, medicament or composition that provides a therapeutic benefit to an individual. "Therapeutically effective amount" or "effective amount" is an amount sufficient for a compound to achieve the stated purpose (e.g., to achieve the effect for which it is administered, to treat, prevent or ameliorate a disease or to alleviate one or more symptoms of a disease or condition) relative to the absence of the compound. An example of a "therapeutically effective amount" or "effective amount" is an amount sufficient to help treat, prevent, ameliorate a disease or alleviate one or more symptoms of a disease. "Relief" of one or more symptoms (and grammatical equivalents of the phrase) means a reduction in the severity or frequency of one or more symptoms, or the elimination of one or more symptoms. A "prophylactically effective amount" of a drug is an amount of the drug that, when administered to a subject, will have the intended preventive effect, such as preventing or delaying the onset (or recurrence) of an injury, disease, pathological condition or condition, or reducing the likelihood of the onset (or recurrence) of an injury, disease, pathological condition or condition 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 ameliorating a disease or condition or its symptoms as described above. For example, for a given parameter, 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%. The therapeutic effect can also be expressed as a "fold" increase or decrease. For example, a therapeutically effective amount can have an effect of at least 1.2 times, 1.5 times, 2 times, 5 times, or more relative to a control.

[0071] The term "treat" and variations thereof refer to any sign of successful treatment or improvement of an injury, disease, pathological condition, or disorder, including any objective or subjective parameter, such as relief; remission; attenuation of symptoms or making an injury, pathological condition, or disorder more tolerable for the patient; slowing the rate of degeneration or decline; making the endpoint of degeneration less debilitating; improving the patient's physical or mental health. Treatment or improvement of symptoms can be based on objective or subjective parameters, including the results of a physical examination. The term "treat" and variations thereof may include prevention of an injury, pathological condition, disorder, or disease. In some embodiments, treatment is prevention. In some embodiments, treatment does not include prevention.

[0072] As used herein, "treatment" or variations thereof (and as fully understood in the art) also broadly include any method for obtaining a beneficial or desired result (including a clinical result) in terms of a condition of a subject. Beneficial or desired clinical results may include, but are not limited to, alleviating or ameliorating one or more symptoms or conditions, reducing the extent of the disease, stabilizing the disease state (i.e., not causing it to worsen), preventing the spread or spread of the disease, delaying or slowing the progression of the disease, improving or alleviating the disease state, reducing the recurrence of the disease, and alleviating, whether partial or complete, and whether detectable or undetectable. In other words, "treatment" as used herein includes any cure, improvement, or prevention of a disease. Treatment may prevent the occurrence of a disease; inhibit the spread of a disease; alleviate the symptoms of a disease, completely or partially eliminate the underlying cause of the disease, shorten the duration of the disease, or perform a combination of these events.

[0073] As used herein, "treatment" and variations thereof include preventive treatment. Treatment methods include 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 condition, 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 be increased or decreased over the course of a particular treatment or prevention regimen. In some cases, long-term administration may be required. For example, the composition is administered to a subject in an amount and duration sufficient to treat the patient.

[0074] "Treatment" refers to the administration of a compound or pharmaceutical composition to an animal to effect an alteration or improvement of a disease, disorder or condition 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, which can be defined in terms of absolute stereochemistry as (R)- or (S)- or (D)- or (L)- (for amino acids), and individual isomers are all encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include compounds known in the art that are too unstable to be synthesized and / or isolated. 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 intended that the compounds include both E 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 structural arrangement or configuration of the atoms.

[0077] As used herein, the term "tautomer" 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 compounds are within the scope of the present disclosure.

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

[0080] As used herein, "chiral enriched group" means a plurality of molecules of the same molecular formula, wherein the number or percentage of molecules in the group containing a specific stereochemical configuration at a specific chiral center is greater than the number or percentage of molecules containing the same specific stereochemical configuration at the same specific chiral center in the group when the specific chiral center is stereo irregular. The chiral enriched molecule group with multiple chiral centers in each molecule may include one or more stereo irregular 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 hydrogen by deuterium or tritium or the replacement of carbon by an isotopically enriched 13 C or 14 Compounds having the present structures except for substitution of the carbon atoms at C are within the scope of the present disclosure.

[0082] As used herein, "stereo-random chiral center" means a chiral center with a random stereochemical configuration in the context of a group of molecules with the same molecular formula. For example, in a group of molecules comprising a stereo-random chiral center, the number of molecules with a (S) configuration of a stereo-random chiral center can be, but not necessarily, the same as the number of molecules with a (R) configuration of a stereo-random chiral center. It is considered to be random when the stereochemical configuration of a chiral center is not intended to be the result of a synthetic method that controls the stereochemical configuration. In certain embodiments, a stereo-random chiral center is a stereo-random phosphorothioate nucleoside linkage.

[0083] Certain embodiments

[0084] In certain aspects, the disclosure relates to methods, compounds and compositions for inhibiting CFB. In certain embodiments, CFB is specifically inhibited. In certain embodiments, CFB is specifically degraded. In certain embodiments, CFB expression is inhibited. In certain embodiments, CFB translation is inhibited. In certain embodiments, CFB activity is inhibited. In certain embodiments, CFB 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, CFB 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% to 50%, 25% to 50%, 25% to 75%, 50% to 75%, 50% to 99% or 75% to 99% relative to expression, translation or activity in untreated or control samples. In certain embodiments, the expression, translation, or activity of CFB is reduced as measured by any suitable assay, including but not limited to an immunoassay, a hybridization-based assay, or a sequencing-based assay (e.g., RNA-Seq).

[0085] In certain aspects, the disclosure relates to compounds that target CFB nucleic acids. In certain embodiments, the CFB nucleic acid has the following sequence: GENBANK Accession No. NM_001710.6 (incorporated herein as SEQ ID NO: 1), GENBANK Accession No. NC_000006.12 nucleotides 31946095 to 31952084 (incorporated herein as SEQ ID NO: 2), GENBANK Accession No. NM_001710.6 (incorporated herein as SEQ ID NO: 3), and GENBANK Accession No. NT_113891.3 nucleotides 3423522 to 3429511 (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 compounds comprising a modified oligonucleotide (e.g., a modified oligonucleotide of 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, or at least 23 consecutive nucleobases of any one of the nucleobase sequences of SEQ ID NOs: 11 to 44 and 96 to 102. Certain embodiments provide compounds comprising a modified oligonucleotide (e.g., a modified oligonucleotide of 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 to 44 and 96 to 102.

[0088] Certain embodiments provide a compound comprising a modified oligonucleotide having a nucleobase sequence selected from any one of the nucleobase sequences of SEQ ID NOs: 11-44 and 96-102.

[0089] In certain embodiments, the modified oligonucleotide has a nucleobase sequence that is at least 80%, at least 85%, at least 90%, or at least 95% complementary to the nucleobase sequence of 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.

[0090] Certain embodiments provide compounds comprising: a first modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14 to 30, 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, or at least 23 consecutive nucleobases of any one of the nucleobase sequences of SEQ ID NOs: 11 to 110; and a second modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 linked nucleosides) having a region complementary to the first modified oligonucleotide.

[0091] In certain embodiments, the compound comprises: a first modified oligonucleotide (e.g., a modified oligonucleotide of 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, or at least 23 consecutive nucleobases comprising any of the nucleobase sequences provided in Tables 2 and 3; and a second modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide.

[0092] Certain embodiments provide a compound comprising: a first modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 linked nucleosides) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11 to 110; and a second modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 linked nucleosides) having a region complementary to the first modified oligonucleotide.

[0093] Certain embodiments provide a compound comprising: a first modified oligonucleotide having a nucleobase sequence selected from any one of the nucleobase sequences of SEQ ID NOs: 11 to 110; and a second modified oligonucleotide having a length of 19 to 23 linked nucleosides having a region complementary to the first modified oligonucleotide.

[0094] In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 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, or at least 23 consecutive nucleobases of any one of the nucleobase sequences of SEQ ID NO: 96, 97, 100, or 101. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 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, or at least 23 consecutive nucleobases of a nucleobase sequence of SEQ ID NO: 93, 106, 109, or 110. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequence of SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 100, and SEQ ID NO: 101. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequence of SEQ ID NO: 93, SEQ ID NO: 106, SEQ ID NO: 109, and SEQ ID NO: 110. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 96 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 93. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 97 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 106. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 100 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 109. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 101 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 110.

[0095] In certain embodiments, the modified oligonucleotide or the first modified oligonucleotide of any compound herein has a nucleobase sequence that is at least 80%, at least 85%, at least 90%, or at least 95% complementary or identical to the nucleobase sequence of SEQ ID NO: 1 or 3 over its length. In certain embodiments, the modified oligonucleotide or the first modified oligonucleotide has a nucleobase sequence that has at least 1, at least 2, or at least 3 mismatches with a region of the nucleobase sequence of SEQ ID NO: 1 or 3. In certain embodiments, the length of the complementary region between the first strand and 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 first strand and the second modified oligonucleotide or second strand is 21 to 23 linked nucleosides. In certain embodiments, the first modified oligonucleotide is fully complementary to the second modified oligonucleotide.

[0096] In certain embodiments, the first modified oligonucleotide of any of the aforementioned compounds or other compounds herein comprises at least one modification selected from modified internucleoside linkages, modified sugars, and modified nucleobases. In certain embodiments, the second modified oligonucleotide of any of the aforementioned compounds comprises at least one modification selected from 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 phosphorothioate internucleoside linkage or the methylphosphonate internucleoside linkage is at the 3' end of the first modified oligonucleotide or the second modified oligonucleotide or at the 5' end of the first modified oligonucleotide. In certain embodiments, the modified sugar comprises a modification selected from 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 sugars, 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.

[0097] 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 is connected to the 2' or 3' position of the ribosyl ring. In certain embodiments, 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 the following formula or a salt, solvate or hydrate thereof, wherein R is a portion other than the 5' nucleoside in the modified oligonucleotide:

[0098]

[0099]

[0100]

[0101]

[0102]

[0103] In certain embodiments, the conjugate group according to Formula III is represented by the formula:

[0104]

[0105] In certain embodiments, the conjugate group according to Formula V is represented by the formula:

[0106]

[0107] In certain embodiments, the conjugate group according to Formula VIII is represented by the formula:

[0108]

[0109] In certain embodiments, R' is OH. In certain embodiments, R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula I and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula I and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula II and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula II and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula III and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula III and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula IV and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula IV and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula V and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula V and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula VI and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula VI and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula VII and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula VII and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula VIII and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula VIII and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula XII and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula XII and R' is SH.

[0110] In certain embodiments, R' is OH. In certain embodiments, R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula I and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula I and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula II and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula II and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula III and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula III and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula IV and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula IV and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula V and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula V and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula VI and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula VI and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula VII and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula VII and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula VIII and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula VIII and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula XII and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula XII and R' is SH.

[0111] In certain embodiments, R' is O. In certain embodiments, R' is S. In certain embodiments, the 5' nucleoside of a modified oligonucleotide is Formula I and R' is O. In certain embodiments, the 5' nucleoside of a modified oligonucleotide is Formula I and R' is S. In certain embodiments, the 5' nucleoside of a modified oligonucleotide is Formula II and R' is O. In certain embodiments, the 5' nucleoside of a modified oligonucleotide is Formula II and R' is S. In certain embodiments, the 5' nucleoside of a modified oligonucleotide is Formula III and R' is O. In certain embodiments, the 5' nucleoside of a modified oligonucleotide is Formula III and R' is S. In certain embodiments, the 5' nucleoside of a modified oligonucleotide is Formula IV and R' is O. In certain embodiments, the 5' nucleoside of a modified oligonucleotide is Formula IV and R' is S. In certain embodiments, the 5' nucleoside of a modified oligonucleotide is Formula V and R' is O. In certain embodiments, the 5' nucleoside of a modified oligonucleotide is Formula V and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula VI and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula VI and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula VII and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula VII and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula VIII and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula VIII and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula XII and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula XII and R' is S.

[0112] Certain embodiments provide a compound comprising: a first modified oligonucleotide selected from any one of:

[0113] Ref ID NO: IA0478-490, IA0840, IA0842-846, IA0852-862, 1A0872-882, 1A0887-890, IA1010-1012 and IA1015-1018, IS0570-587, IS0969.IS0972-977, IS1023-1027, IS1029, IS1031-1037, IS1042-1046, IS1082, IS1085, IS1086, IS1091-1095, IS1108-1111, IS1236-1239, IS1242, IS1249 and IS1251-1254

[0114] and a second modified oligonucleotide of 14 to 21 linked nucleosides in length that is fully complementary to the first modified oligonucleotide.

[0115] Certain embodiments provide a compound comprising: a first modified oligonucleotide selected from any of the following:

[0116] Ref ID NO: IA0478-490, IA0840, IA0842-846, IA0852-862, IA0872-882, IA0887-890, IA1010-1012 and IA1015-1018

[0117] and a second modified oligonucleotide selected from any one of:

[0118] Ref ID NO: IS0570-587, IS0969, IS0972-977, IS1023-1027, IS1029, IS1031-1037, IS1042-1046, IS10 82, IS1085, IS10N6, IS1091-1095, IS1108-1111, IS1236-1239, IS1242, IS1249 and IS1251-1254.

[0119] Certain embodiments provide a compound comprising a first modified oligonucleotide that is IA0840 and a second modified oligonucleotide that is IS0972.

[0120] Certain embodiments provide compounds comprising a first modified oligonucleotide that is IA0842 and a second modified oligonucleotide that is IS0974.

[0121] Certain embodiments provide compounds comprising a first modified oligonucleotide that is IA0888 and a second modified oligonucleotide that is IS1109.

[0122] Certain embodiments provide compounds comprising a first modified oligonucleotide that is IA0888 and a second modified oligonucleotide that is IS1236.

[0123] Certain embodiments provide compounds comprising a first modified oligonucleotide that is IA1010 and a second modified oligonucleotide that is IS1109.

[0124] Certain embodiments provide compounds comprising a first modified oligonucleotide that is IA1011 and a second modified oligonucleotide that is IS1239.

[0125] Certain embodiments provide compounds comprising a first modified oligonucleotide that is IA1012 and a second modified oligonucleotide that is IS 1242. Certain embodiments provide compounds comprising a first modified oligonucleotide that is IA1016 and a second modified oligonucleotide that is IS1252.

[0126] Certain embodiments provide compounds comprising a first modified oligonucleotide that is IA1017 and a second modified oligonucleotide that is IS1253.

[0127] 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.

[0128] Certain embodiments provide a compound of any of the preceding embodiments as a stereoisomer.

[0129] In one aspect, provided herein are modified oligonucleotides according to the following chemical structure:

[0130] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, Ref ID NO: IA1016 is a modified oligonucleotide according to the aforementioned chemical structure or a pharmaceutically acceptable salt or stereoisomer thereof.

[0131] In one aspect, provided herein are modified oligonucleotides according to the following chemical structure:

[0132] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, Ref ID NO: IS1252 is a modified oligonucleotide according to the aforementioned chemical structure or a pharmaceutically acceptable salt or stereoisomer thereof.

[0133] In one aspect, provided herein are modified oligonucleotides according to the following chemical structure:

[0134] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, Ref ID NO: IA1017 is a modified oligonucleotide according to the aforementioned chemical structure or a pharmaceutically acceptable salt or stereoisomer thereof.

[0135] In one aspect, provided herein are modified oligonucleotides according to the following chemical structure:

[0136] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, Ref ID NO: IS1253 is a modified oligonucleotide according to the aforementioned chemical structure or a pharmaceutically acceptable salt or stereoisomer thereof.

[0137] In one aspect, provided herein are modified oligonucleotides according to the following chemical structure:

[0138] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, Ref ID NO: IA1010 is a modified oligonucleotide according to the aforementioned chemical structure or a pharmaceutically acceptable salt or stereoisomer thereof.

[0139] In one aspect, provided herein are modified oligonucleotides according to the following chemical structure: or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, Ref ID NO: IS1109 is a modified oligonucleotide according to the aforementioned chemical structure or a pharmaceutically acceptable salt or stereoisomer thereof.

[0140] In one aspect, provided herein are modified oligonucleotides according to the following chemical structure:

[0141] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, Ref ID NO: IA1011 is a modified oligonucleotide according to the aforementioned chemical structure or a pharmaceutically acceptable salt or stereoisomer thereof.

[0142] In one aspect, provided herein are modified oligonucleotides according to the following chemical structure: or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, Ref ID NO: IS1239 is a modified oligonucleotide according to the aforementioned chemical structure or a pharmaceutically acceptable salt or stereoisomer thereof.

[0143] In one aspect, provided herein is a sodium salt of a modified oligonucleotide according to the following chemical structure:

[0144] Or a stereoisomer thereof. In certain embodiments, Ref ID NO: IA1016 is a modified oligonucleotide according to the aforementioned chemical structure or a stereoisomer thereof.

[0145] In one aspect, provided herein is a sodium salt of a modified oligonucleotide according to the following chemical structure:

[0146] In certain embodiments, Ref ID NO: IS1252 is a modified oligonucleotide according to the aforementioned chemical structure or a stereoisomer thereof.

[0147] In one aspect, provided herein is a sodium salt of a modified oligonucleotide according to the following chemical structure:

[0148] Or a stereoisomer thereof. In certain embodiments, Ref ID NO: IA1017 is a modified oligonucleotide according to the aforementioned chemical structure or a stereoisomer thereof.

[0149] In one aspect, provided herein is a sodium salt of a modified oligonucleotide according to the following chemical structure:

[0150] In certain embodiments, Ref ID NO: IS1253 is a modified oligonucleotide according to the aforementioned chemical structure or a stereoisomer thereof.

[0151] In one aspect, provided herein is a sodium salt of a modified oligonucleotide according to the following chemical structure:

[0152] Or a stereoisomer thereof. In certain embodiments, Ref ID NO: IA1010 is a modified oligonucleotide according to the aforementioned chemical structure or a stereoisomer thereof.

[0153] In one aspect, provided herein is a sodium salt of a modified oligonucleotide according to the following chemical structure:

[0154] In certain embodiments, Ref ID NO: IS1109 is a modified oligonucleotide according to the aforementioned chemical structure or a stereoisomer thereof.

[0155] In one aspect, provided herein is a sodium salt of a modified oligonucleotide according to the following chemical structure:

[0156] In certain embodiments, Ref ID NO: IA1011 is a modified oligonucleotide according to the aforementioned chemical structure or a stereoisomer thereof.

[0157] In one aspect, provided herein is a sodium salt of a modified oligonucleotide according to the following chemical structure:

[0158] In certain embodiments, Ref ID NO: IS1239 is a modified oligonucleotide according to the aforementioned chemical structure or a stereoisomer thereof.

[0159] In one aspect, provided herein are compounds according to the following chemical structure:

[0160] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, compound No. RD2830 is a compound according to the aforementioned chemical structure or a pharmaceutically acceptable salt or stereoisomer thereof.

[0161] In one aspect, provided herein are compounds according to the following chemical structure:

[0162] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, compound No. RD2831 is a compound according to the aforementioned chemical structure or a pharmaceutically acceptable salt or stereoisomer thereof.

[0163] In one aspect, provided herein are compounds according to the following chemical structure:

[0164] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, compound No. RD2795 is a compound according to the aforementioned chemical structure or a pharmaceutically acceptable salt or stereoisomer thereof.

[0165] In one aspect, provided herein are compounds according to the following chemical structure:

[0166] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, compound No. RD2798 is a compound according to the aforementioned chemical structure or a pharmaceutically acceptable salt or stereoisomer thereof.

[0167] In one aspect, provided herein is a sodium salt of a compound according to the following chemical structure: In certain embodiments, compound No. RD2830 is a compound according to the aforementioned chemical structure or a pharmaceutically acceptable salt or stereoisomer thereof.

[0168] In one aspect, provided herein is a sodium salt of a compound according to the following chemical structure: In certain embodiments, compound No. RD2831 is a compound according to the aforementioned chemical structure or a pharmaceutically acceptable salt or stereoisomer thereof.

[0169] In one aspect, provided herein is a sodium salt of a compound according to the following chemical structure: In certain embodiments, compound No. RD2795 is a compound according to the aforementioned chemical structure or a pharmaceutically acceptable salt or stereoisomer thereof.

[0170] In one aspect, provided herein is a sodium salt of a compound according to the following chemical structure: In certain embodiments, compound No. RD2798 is a compound according to the aforementioned chemical structure or a pharmaceutically acceptable salt or stereoisomer thereof.

[0171] In certain embodiments, provided herein are populations of modified oligonucleotides, wherein all phosphorothioate internucleoside linkages of the modified oligonucleotides are stereo-irregular. In certain embodiments, provided herein are populations of compounds, wherein all phosphorothioate internucleoside linkages of the modified oligonucleotides are stereo-irregular.

[0172] Certain embodiments provide compositions comprising a compound of any of the preceding embodiments and a pharmaceutically acceptable carrier.

[0173] Certain embodiments provide a composition comprising a compound of any preceding embodiment for use in therapy.

[0174] Certain embodiments provide methods of treating, preventing or ameliorating a disease, disorder or condition associated with CFB in an individual, comprising administering to the individual a compound that targets CFB, thereby treating, preventing or ameliorating the disease.

[0175] In certain embodiments, a compound or composition of any of the foregoing embodiments is administered to an individual. In certain embodiments, the disease, disorder or condition is atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE) such as lupus nephritis, diabetic nephropathy, membranous nephropathy, polycystic kidney disease, age-related macular degeneration, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury or rheumatoid arthritis (RA). In certain embodiments, administration of the compound inhibits or reduces or improves atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE) such as lupus nephritis, diabetic nephropathy, membranous nephropathy, polycystic kidney disease, age-related macular degeneration, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, rheumatoid arthritis (RA), or symptoms thereof.

[0176] In certain embodiments, the compound of any of the preceding embodiments or a composition comprising the compound is administered to an individual in a therapeutically effective amount. In certain embodiments, the composition comprising the compound of any of the preceding embodiments is administered to an individual at a dosage level sufficient to deliver about 1 to 100 mg / kg of individual body weight. In certain embodiments, the compound of any of the preceding embodiments or a composition comprising the compound is administered to an individual at a fixed dose of about 25 mg to about 1,000 mg. In certain embodiments, the compound or composition is administered to an individual once or more in a day up to the dosage level or fixed dose.

[0177] In certain embodiments, the composition comprising a compound of any preceding embodiment is applied to an individual every day, every week, every month, every quarter or every year. In certain embodiments, the compound of any preceding embodiment or a composition comprising a compound is applied to an individual about once a quarter (that is, once every three months) to about once a year. In certain embodiments, the compound of any preceding embodiment or a composition comprising a compound is applied to an individual about once a quarter, about once every six months or about once a year.

[0178] Certain embodiments provide a method of inhibiting CFB expression in a cell, comprising contacting the cell with a compound targeting CFB, thereby inhibiting the expression of CFB 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 atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE) such as lupus nephritis, diabetic nephropathy, membranous nephropathy, polycystic kidney disease, age-related macular degeneration, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, or rheumatoid arthritis (RA).

[0179] Certain embodiments provide a method of reducing or inhibiting atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE) such as lupus nephritis, diabetic nephropathy, membranous nephropathy, polycystic kidney disease, age-related macular degeneration, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, rheumatoid arthritis (RA), or any symptom thereof in an individual, comprising administering to a subject a combination of: A compound targeting CFB is administered to a subject, thereby reducing or inhibiting atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE) such as lupus nephritis, diabetic nephropathy, membranous nephropathy, polycystic kidney disease, age-related macular degeneration, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, rheumatoid arthritis (RA), or any symptoms thereof in the subject. In certain embodiments, the individual suffers from or is at risk of suffering from atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE) such as lupus nephritis, diabetic nephropathy, membranous nephropathy, polycystic kidney disease, age-related macular degeneration, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, rheumatoid arthritis (RA), or any symptom thereof. In certain embodiments, the compound is a compound targeting CFB. In certain embodiments, the compound is any of the aforementioned compounds. In certain embodiments, the compound or composition is administered parenterally.

[0180] Certain embodiments provide a compound targeting CFB for treating, preventing or improving a disease, disorder or condition associated with CFB. In certain embodiments, the disease, disorder or condition is atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE) such as lupus nephritis, diabetic nephropathy, membranous nephropathy, polycystic kidney disease, age-related macular degeneration, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury or rheumatoid arthritis (RA). In certain embodiments, the compound is a compound targeting CFB. In certain embodiments, the compound is any of the aforementioned compounds.

[0181] Certain embodiments provide the use of a compound targeting CFB in the preparation of a drug for treating, preventing or improving a disease, disorder or condition associated with CFB. In certain embodiments, the disease, disorder or condition is atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE) such as lupus nephritis, diabetic nephropathy, membranous nephropathy, polycystic kidney disease, age-related macular degeneration, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury or rheumatoid arthritis (RA). In certain embodiments, the compound is a compound targeting CFB. In certain embodiments, the compound is any of the aforementioned compounds.

[0182] Certain indications

[0183] In certain aspects, the disclosure relates to methods of inhibiting CFB expression by administering a compound targeting CFB, which can be used to treat, prevent or improve a disease, disorder or condition associated with CFB in an individual. In certain embodiments, the compound can be a CFB-specific inhibitor. In certain embodiments, the compound can be an antisense oligonucleotide, an oligomeric compound or an oligonucleotide targeting CFB.

[0184] In certain aspects, the disclosure relates to treating, preventing or ameliorating diseases, disorders or conditions associated with CFB. In certain embodiments, diseases, disorders or conditions associated with CFB that can be treated, prevented and / or improved using the methods provided herein include atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE) such as lupus nephritis, diabetic nephropathy, membranous nephropathy, polycystic kidney disease, age-related macular degeneration, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury or rheumatoid arthritis (RA). Certain compounds provided herein relate to compounds and compositions for alleviating in animals atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE) such as lupus nephritis, diabetic nephropathy, membranous nephropathy, polycystic kidney disease, age-related macular degeneration, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, rheumatoid arthritis (RA), or any symptom thereof.

[0185] In certain embodiments, a method for treating, preventing or ameliorating a disease, disorder or condition associated with CFB in an individual comprises administering to the individual a compound comprising a CFB-specific inhibitor, thereby treating, preventing or ameliorating the disease, disorder or condition. In certain embodiments, the individual is identified as suffering from a disease, disorder or condition associated with CFB or at risk of suffering from a disease, disorder or condition associated with CFB. In certain embodiments, the disease, disorder or condition is liver disease, kidney disease or eye disease. In certain embodiments, the compound comprises an antisense oligonucleotide targeting CFB. In certain embodiments, the compound comprises an oligonucleotide targeting CFB. In certain embodiments, the compound comprises a modified oligonucleotide of length (e.g., 14 to 30, 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, or at least 23 consecutive nucleobases of a nucleobase sequence of any one of SEQ ID NOs: 11 to 44 and 96 to 102. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of length 14 to 30, e.g., 14 to 23 linked nucleosides) having a nucleobase sequence comprising a nucleobase sequence of any one of SEQ ID NOs: 11 to 44 and 96 to 102. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from a nucleobase sequence of any one of SEQ ID NOs: 11 to 44 and 96 to 102. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 linked nucleosides) having a nucleobase sequence comprising any one of the nucleobase sequences of SEQ ID NOs: 24, 25, 42, 96, 97, 98, and 100. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from any one of the nucleobase sequences of SEQ ID NOs: 24, 25, 42, 96, 97, 98, and 100. 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 a single-stranded compound can be 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 linked nucleosides. In certain embodiments, a double-stranded compound can comprise two oligonucleotides of the same or different lengths, as described elsewhere herein.In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 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, or at least 23 consecutive nucleobases of a nucleobase sequence of SEQ ID NO: 96, 97, 100, or 101. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 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, or at least 23 consecutive nucleobases of a nucleobase sequence of SEQ ID NO: 93, 106, 109, or 110. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequence of SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 100, and SEQ ID NO: 101. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequence of SEQ ID NO: 93, SEQ ID NO: 106, SEQ ID NO: 109, and SEQ ID NO: 110. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 96 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 93. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 97 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 106. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 100 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 109. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 101 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 110. In any of the foregoing embodiments, the compound can be an antisense oligonucleotide or an oligomeric compound.In certain embodiments, the compound comprises: a first modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14 to 30, 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, or at least 23 consecutive nucleobases of any one of the nucleobase sequences of SEQ ID NOs: 11 to 110; and a second modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 linked nucleosides) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises: a first modified oligonucleotide (e.g., a modified oligonucleotide of 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 to 110; and a second modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, e.g., 14 to 23 linked nucleosides in length) 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 nucleobase sequence of any one of SEQ ID NOs: 11 to 110; and a second modified oligonucleotide of 19 to 23 linked nucleosides in length having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound is administered parenterally to a subject. In certain embodiments, administration of the compound improves, preserves or prevents atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), such as lupus nephritis, diabetic nephropathy, membranous nephropathy, polycystic kidney disease, age-related macular degeneration, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, rheumatoid arthritis (RA), or any symptom thereof in an animal.

[0186] In certain embodiments, a method of treating, preventing, or ameliorating atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE) such as lupus nephritis, diabetic nephropathy, membranous nephropathy, polycystic kidney disease, age-related macular degeneration, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, rheumatoid arthritis (RA), or any symptom thereof in an animal comprises administering to the individual Compounds comprising a specific inhibitor of CFB are administered to treat, prevent or improve atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE) such as lupus nephritis, diabetic nephropathy, membranous nephropathy, polycystic kidney disease, age-related macular degeneration, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, rheumatoid arthritis (RA), or any symptom thereof. In certain embodiments, the compound comprises an antisense oligonucleotide targeting CFB. In certain embodiments, the compound comprises an oligonucleotide targeting CFB. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 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, or at least 23 consecutive nucleobases of any one of the nucleobase sequences of SEQ ID NOs: 11 to 44 and 96 to 102. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising a nucleobase sequence of any one of SEQ ID NOs: 11 to 44 and 96 to 102. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequence of any one of SEQ ID NOs: 11 to 44 and 96 to 102. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising any one of the nucleobase sequences of SEQ ID NOs: 24, 25, 42, 96, 97, 98, and 100. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequence of any one of SEQ ID NOs: 24, 25, 42, 96, 97, 98, and 100. In any of the foregoing embodiments, the compound can be single-stranded or double-stranded.In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 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, or at least 23 consecutive nucleobases of a nucleobase sequence of SEQ ID NO: 96, 97, 100, or 101. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 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, or at least 23 consecutive nucleobases of a nucleobase sequence of SEQ ID NO: 93, 106, 109, or 110. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequence of SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 100, and SEQ ID NO: 101. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequence of SEQ ID NO: 93, SEQ ID NO: 106, SEQ ID NO: 109, and SEQ ID NO: 110. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 96 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 93. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 97 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 106. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 100 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 109. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 101 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 110. In any of the foregoing embodiments, the compound can be an antisense oligonucleotide or an oligomeric compound.In certain embodiments, the compound comprises: a first modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14 to 30, 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, or at least 23 consecutive nucleobases of any one of the nucleobase sequences of SEQ ID NOs: 11 to 110; and a second modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 linked nucleosides) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises: a first modified oligonucleotide (e.g., a modified oligonucleotide of 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 to 110; and a second modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, e.g., 14 to 23 linked nucleosides in length) 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 nucleobase sequence of any one of SEQ ID NOs: 11 to 110; and a second modified oligonucleotide of 19 to 23 linked nucleosides in length having a region complementary to the first modified oligonucleotide. In certain embodiments, administration of the compound improves, maintains or prevents atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE) such as lupus nephritis, diabetic nephropathy, membranous nephropathy, polycystic kidney disease, age-related macular degeneration, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, rheumatoid arthritis (RA), or any symptom thereof in an animal. In certain embodiments, an individual is identified as having, or at risk of having, a disease, disorder or condition associated with CFB.

[0187] In certain embodiments, a method of inhibiting CFB expression in an individual suffering from a disease, disorder or condition associated with CFB or at risk of suffering from a disease, disorder or condition associated with CFB comprises administering to the individual a compound comprising a CFB-specific inhibitor, thereby inhibiting the expression of CFB in the individual. In certain embodiments, administration of the compound inhibits the expression of CFB in the liver. In certain embodiments, the disease, disorder or condition is a complement pathway-related disease, disorder or condition or is atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE) such as lupus nephritis, diabetic nephropathy, membranous nephropathy, polycystic kidney disease, age-related macular degeneration, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, or rheumatoid arthritis (RA). In certain embodiments, the individual suffers from or is at risk of suffering from atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE) such as lupus nephritis, diabetic nephropathy, membranous nephropathy, polycystic kidney disease, age-related macular degeneration, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, or rheumatoid arthritis (RA). In certain embodiments, the compound comprises an antisense oligonucleotide targeting CFB. In certain embodiments, the compound comprises an oligonucleotide targeting CFB. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 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, or at least 23 consecutive nucleobases of a nucleobase sequence of any one of SEQ ID NOs: 11 to 44 and 96 to 102. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising a nucleobase sequence of any one of SEQ ID NOs: 11 to 44 and 96 to 102. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from a nucleobase sequence of any one of SEQ ID NOs: 11 to 44 and 96 to 102. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising any one of the nucleobase sequences of SEQ ID NOs: 24, 25, 42, 96, 97, 98, and 100.In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequence of any one of SEQ ID NOs: 24, 25, 42, 96, 97, 98, and 100. In any of the foregoing embodiments, the compound can be single-stranded or double-stranded. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 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, or at least 23 consecutive nucleobases of a nucleobase sequence of SEQ ID NOs: 96, 97, 100, or 101. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 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, or at least 23 consecutive nucleobases of a nucleobase sequence of SEQ ID NO: 93, 106, 109, or 110. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequence of SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 100, and SEQ ID NO: 101. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequence of SEQ ID NO: 93, SEQ ID NO: 106, SEQ ID NO: 109, and SEQ ID NO: 110. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 96 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 93. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 97 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 106. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 100 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 109. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 101 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 110. In any of the foregoing embodiments, the compound can be an antisense oligonucleotide or an oligomeric compound.In certain embodiments, the compound comprises: a first modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14 to 30, 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, or at least 23 consecutive nucleobases of any one of the nucleobase sequences of SEQ ID NOs: 11 to 110; and a second modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 linked nucleosides) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises: a first modified oligonucleotide (e.g., a modified oligonucleotide of 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 to 110; and a second modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, e.g., 14 to 23 linked nucleosides in length) 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 nucleobase sequence of any one of SEQ ID NOs: 11 to 110; and a second modified oligonucleotide of 19 to 23 linked nucleosides in length having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound is administered parenterally to a subject. In certain embodiments, the compound is administered to improve, maintain or prevent atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE) such as lupus nephritis, diabetic nephropathy, membranous nephropathy, polycystic kidney disease, age-related macular degeneration, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, rheumatoid arthritis (RA), or any symptom thereof. In certain embodiments, the method of inhibiting CFB expression in a cell comprises contacting the cell with a compound comprising a CFB-specific inhibitor, thereby inhibiting the expression of CFB 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 having or at risk of having atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE) such as lupus nephritis, diabetic nephropathy, membranous nephropathy, polycystic kidney disease, age-related macular degeneration, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, or rheumatoid arthritis (RA). In certain embodiments, the compound comprises an antisense oligonucleotide targeted to CFB.In certain embodiments, the compound comprises an oligonucleotide targeting CFB. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 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, or at least 23 consecutive nucleobases of any one of the nucleobase sequences of SEQ ID NOs: 11 to 44 and 96 to 102. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 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 to 44 and 96 to 102. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequence of any one of SEQ ID NOs: 11 to 44 and 96 to 102. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising any one of the nucleobase sequences of SEQ ID NOs: 24, 25, 42, 96, 97, 98, and 100. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequence of any one of SEQ ID NOs: 24, 25, 42, 96, 97, 98, and 100. In any of the foregoing embodiments, the compound may be single-stranded or double-stranded. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 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, or at least 23 consecutive nucleobases of a base sequence of SEQ ID NO: 96, 97, 100, or 101. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 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, or at least 23 consecutive nucleobases of a base sequence of SEQ ID NO: 93, 106, 109, or 110. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequence of SEQ ID NO: 96, SEQ ID NO: 100, and SEQ ID NO: 101.In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from the group consisting of SEQ ID NO: 93, SEQ ID NO: 106, SEQ ID NO: 109, and SEQ ID NO: 110. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 96 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 93. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 97 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 106. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 100 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 109. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 101 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 110. 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., a modified oligonucleotide having a length of 14 to 30, 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, or at least 23 consecutive nucleobases of any one of the nucleobase sequences of SEQ ID NOs: 11 to 110; and a second modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 linked nucleosides) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises: a first modified oligonucleotide (e.g., a modified oligonucleotide of 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 to 110; and a second modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, e.g., 14 to 23 linked nucleosides in length) 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 nucleobase sequence of any one of SEQ ID NOs: 11 to 110; and a second modified oligonucleotide of 19 to 23 linked nucleosides in length having a region complementary to the first modified oligonucleotide.

[0188] In certain embodiments, the invention reduces or inhibits a complement pathway-related disease, disorder or condition or atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), such as lupus nephritis, diabetic nephropathy, membranous nephropathy, polycystic kidney disease, age-related macular degeneration, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, or rheumatoid arthritis in an individual suffering from or at risk of suffering from a CFB-related disease. The method of treating arthritis (RA) comprises administering a compound comprising a specific inhibitor of CFB to an individual, thereby reducing or inhibiting a complement pathway-related disease, disorder or condition or atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE) such as lupus nephritis, diabetic nephropathy, membranous nephropathy, polycystic kidney disease, age-related macular degeneration, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury or rheumatoid arthritis (RA) in the individual. In certain embodiments, the individual suffers from or is at risk of suffering from atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE) such as lupus nephritis, diabetic nephropathy, membranous nephropathy, polycystic kidney disease, age-related macular degeneration, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, or rheumatoid arthritis (RA). In certain embodiments, the compound comprises an antisense oligonucleotide targeting CFB. In certain embodiments, the compound comprises an oligonucleotide targeting CFB. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 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, or at least 23 consecutive nucleobases of a nucleobase sequence of any one of SEQ ID NOs: 11 to 44 and 96 to 102. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising a nucleobase sequence of any one of SEQ ID NOs: 11 to 44 and 96 to 102. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from a nucleobase sequence of any one of SEQ ID NOs: 11 to 44 and 96 to 102.In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 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: 24, 25, 42, 96, 97, 98, and 100. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequence of any one of SEQ ID NOs: 24, 25, 42, 96, 97, 98, and 100. In any of the foregoing embodiments, the compound can be single-stranded or double-stranded. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 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, or at least 23 consecutive nucleobases of a nucleobase sequence of SEQ ID NO: 96, 97, 100, or 101. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 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, or at least 23 consecutive nucleobases of a nucleobase sequence of SEQ ID NO: 93, 106, 109, or 110. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequence of SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 100, and SEQ ID NO: 101. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequence of SEQ ID NO: 93, SEQ ID NO: 106, SEQ ID NO: 109, and SEQ ID NO: 110. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 96 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 93. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 97 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 106. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 100 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 109.In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 101 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 110. In any of the foregoing embodiments, the compound can be an antisense oligonucleotide or an oligomeric compound. In certain embodiments, the compound comprises: a first modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 linked nucleosides) 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, or at least 23 consecutive nucleobases of any of the nucleobase sequences of SEQ ID NO: 11 to 110; and a second modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 linked nucleosides) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises: a first modified oligonucleotide (e.g., a modified oligonucleotide of 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 to 110; and a second modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, e.g., 14 to 23 linked nucleosides in length) 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 nucleobase sequence of any one of SEQ ID NOs: 11 to 110; and a second modified oligonucleotide of 19 to 23 linked nucleosides in length 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 or being at risk of having a disease, disorder, or condition associated with CFB.

[0189] Certain embodiments relate to compounds comprising CFB specific inhibitors for the treatment of diseases, disorders or conditions associated with CFB. In certain embodiments, the disease, disorder or condition is atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE) such as lupus nephritis, diabetic nephropathy, membranous nephropathy, polycystic kidney disease, age-related macular degeneration, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury or rheumatoid arthritis (RA). In certain embodiments, the compound comprises an antisense oligonucleotide targeting CFB. In certain embodiments, the compound comprises an oligonucleotide targeting CFB. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 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, or at least 23 consecutive nucleobases of a nucleobase sequence of any one of SEQ ID NOs: 11 to 44 and 96 to 102. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising a nucleobase sequence of any one of SEQ ID NOs: 11 to 44 and 96 to 102. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from a nucleobase sequence of any one of SEQ ID NOs: 11 to 44 and 96 to 102. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 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: 24, 25, 42, 96, 97, 98, and 100. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequence of any one of SEQ ID NOs: 24, 25, 42, 96, 97, 98, and 100. In any of the foregoing embodiments, the compound can be single-stranded or double-stranded. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 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, or at least 23 consecutive nucleobases of a nucleobase sequence of SEQ ID NO: 96, 97, 100, or 101.In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 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, or at least 23 consecutive nucleobases of a nucleobase sequence of SEQ ID NO: 93, 106, 109, or 110. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequence of SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 100, and SEQ ID NO: 101. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequence of SEQ ID NO: 93, SEQ ID NO: 106, SEQ ID NO: 109, and SEQ ID NO: 110. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 96 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 93. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 97 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 106. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 100 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 109. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 101 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 110. In any of the foregoing embodiments, the compound can be an antisense oligonucleotide or an oligomeric compound. In certain embodiments, the compound comprises: a first modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14 to 30, 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, or at least 23 consecutive nucleobases of any one of the nucleobase sequences of SEQ ID NOs: 11 to 110; and a second modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 linked nucleosides) having a region complementary to the first modified oligonucleotide.In certain embodiments, the compound comprises: a first modified oligonucleotide (e.g., a modified oligonucleotide of 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 to 110; and a second modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, e.g., 14 to 23 linked nucleosides in length) 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 nucleobase sequence of any one of SEQ ID NOs: 11 to 110; and a second modified oligonucleotide of 19 to 23 linked nucleosides in length having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound is administered parenterally to a subject.

[0190] Certain embodiments relate to compounds comprising a CFB specific inhibitor for alleviating or inhibiting complement pathway-related diseases, disorders or conditions or atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE) such as lupus nephritis, diabetic nephropathy, membranous nephropathy, polycystic kidney disease, age-related macular degeneration, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury or rheumatoid arthritis (RA), or any symptoms thereof. In certain embodiments, the compound comprises an antisense oligonucleotide targeting CFB. In certain embodiments, the compound comprises an oligonucleotide targeting CFB. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 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, or at least 23 consecutive nucleobases of a nucleobase sequence of any one of SEQ ID NOs: 11 to 44 and 96 to 102. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising a nucleobase sequence of any one of SEQ ID NOs: 11 to 44 and 96 to 102. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from a nucleobase sequence of any one of SEQ ID NOs: 11 to 44 and 96 to 102. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 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: 24, 25, 42, 96, 97, 98, and 100. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequence of any one of SEQ ID NOs: 24, 25, 42, 96, 97, 98, and 100. In any of the foregoing embodiments, the compound can be single-stranded or double-stranded. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 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, or at least 23 consecutive nucleobases of a nucleobase sequence of SEQ ID NO: 96, 97, 100, or 101.In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 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, or at least 23 consecutive nucleobases of a nucleobase sequence of SEQ ID NO: 93, 106, 109, or 110. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequence of SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 100, and SEQ ID NO: 101. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequence of SEQ ID NO: 93, SEQ ID NO: 106, SEQ ID NO: 109, and SEQ ID NO: 110. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 96 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 93. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 97 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 106. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 100 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 109. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 101 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 110. In any of the foregoing embodiments, the compound can be an antisense oligonucleotide or an oligomeric compound. In certain embodiments, the compound comprises: a first modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14 to 30, 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, or at least 23 consecutive nucleobases of any one of the nucleobase sequences of SEQ ID NOs: 11 to 110; and a second modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 linked nucleosides) having a region complementary to the first modified oligonucleotide.In certain embodiments, the compound comprises: a first modified oligonucleotide (e.g., a modified oligonucleotide of 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 to 110; and a second modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, e.g., 14 to 23 linked nucleosides in length) 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 nucleobase sequence of any one of SEQ ID NOs: 11 to 110; and a second modified oligonucleotide of 19 to 23 linked nucleosides in length having a region complementary to the first modified oligonucleotide.

[0191] Certain embodiments relate to the use of compounds comprising CFB specific inhibitors for the manufacture or preparation of drugs for treating diseases, disorders or conditions associated with CFB. Certain embodiments relate to the use of compounds comprising CFB specific inhibitors for the preparation of drugs for treating diseases, disorders or conditions associated with CFB. In certain embodiments, the disease, disorder or condition is a complement pathway-related disease, disorder or condition. In certain embodiments, the disease, disorder or condition is atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE) such as lupus nephritis, diabetic nephropathy, membranous nephropathy, polycystic kidney disease, age-related macular degeneration, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury or rheumatoid arthritis (RA). In certain embodiments, the compound comprises an antisense oligonucleotide targeting CFB. In certain embodiments, the compound comprises an oligonucleotide targeting CFB. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 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, or at least 23 consecutive nucleobases of a nucleobase sequence of any one of SEQ ID NOs: 11 to 44 and 96 to 102. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising a nucleobase sequence of any one of SEQ ID NOs: 11 to 44 and 96 to 102. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from a nucleobase sequence of any one of SEQ ID NOs: 11 to 44 and 96 to 102. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 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: 24, 25, 42, 96, 97, 98, and 100. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequence of any one of SEQ ID NOs: 24, 25, 42, 96, 97, 98, and 100. In any of the foregoing embodiments, the compound can be single-stranded or double-stranded.In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 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, or at least 23 consecutive nucleobases of a nucleobase sequence of SEQ ID NO: 96, 97, 100, or 101. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 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, or at least 23 consecutive nucleobases of a nucleobase sequence of SEQ ID NO: 93, 106, 109, or 110. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequence of SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 100, and SEQ ID NO: 101. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequence of SEQ ID NO: 93, SEQ ID NO: 106, SEQ ID NO: 109, and SEQ ID NO: 110. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 96 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 93. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 97 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 106. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 100 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 109. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 101 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 110. In any of the foregoing embodiments, the compound can be an antisense oligonucleotide or an oligomeric compound.In certain embodiments, the compound comprises: a first modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14 to 30, 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, or at least 23 consecutive nucleobases of any one of the nucleobase sequences of SEQ ID NOs: 11 to 110; and a second modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 linked nucleosides) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises: a first modified oligonucleotide (e.g., a modified oligonucleotide of 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 to 110; and a second modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, e.g., 14 to 23 linked nucleosides in length) 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 nucleobase sequence of any one of SEQ ID NOs: 11 to 110; and a second modified oligonucleotide of 19 to 23 linked nucleosides in length having a region complementary to the first modified oligonucleotide.

[0192] Certain embodiments relate to the use of a compound comprising a CFB-specific inhibitor for the manufacture or preparation of a medicament for reducing or inhibiting a complement pathway-related disease, disorder or condition, or a symptom thereof, in an individual suffering from a complement pathway-related disease or at risk of suffering from a complement pathway-related disease. In certain embodiments, the complement pathway-related disease is atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE) such as lupus nephritis, diabetic nephropathy, membranous nephropathy, polycystic kidney disease, age-related macular degeneration, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, or rheumatoid arthritis (RA). Certain embodiments relate to the use of a compound comprising a CFB-specific inhibitor for the preparation of a medicament for treating a disease, disorder, or condition associated with CFB. In certain embodiments, the disease, disorder or condition is atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE) such as lupus nephritis, diabetic nephropathy, membranous nephropathy, polycystic kidney disease, age-related macular degeneration, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury or rheumatoid arthritis (RA). In certain embodiments, the compound comprises an antisense oligonucleotide targeting CFB. In certain embodiments, the compound comprises an oligonucleotide targeting CFB. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 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, or at least 23 consecutive nucleobases of a nucleobase sequence of any one of SEQ ID NOs: 11 to 44 and 96 to 102. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising a nucleobase sequence of any one of SEQ ID NOs: 11 to 44 and 96 to 102. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from a nucleobase sequence of any one of SEQ ID NOs: 11 to 44 and 96 to 102. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 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: 24, 25, 42, 96, 97, 98, and 100.In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequence of any one of SEQ ID NOs: 24, 25, 42, 96, 97, 98, and 100. In any of the foregoing embodiments, the compound can be single-stranded or double-stranded. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 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, or at least 23 consecutive nucleobases of a nucleobase sequence of SEQ ID NOs: 96, 97, 100, or 101. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 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, or at least 23 consecutive nucleobases of a nucleobase sequence of SEQ ID NO: 93, 106, 109, or 110. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequence of SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 100, and SEQ ID NO: 101. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequence of SEQ ID NO: 93, SEQ ID NO: 106, SEQ ID NO: 109, and SEQ ID NO: 110. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 96 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 93. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 97 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 106. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 100 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 109. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 101 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 110. In any of the foregoing embodiments, the compound can be an antisense oligonucleotide or an oligomeric compound.In certain embodiments, the compound comprises: a first modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14 to 30, 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, or at least 23 consecutive nucleobases of any one of the nucleobase sequences of SEQ ID NOs: 11 to 110; and a second modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 linked nucleosides) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises: a first modified oligonucleotide (e.g., a modified oligonucleotide of 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 to 110; and a second modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, e.g., 14 to 23 linked nucleosides in length) 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 any one of the nucleobase sequences of SEQ ID NOs: 11 to 110; and a second modified oligonucleotide of 19 to 23 linked nucleosides in length having a region complementary to the first modified oligonucleotide.

[0193] In any of the foregoing methods or uses, the compound may be an oligomeric compound. In any of the foregoing methods or uses, the compound may be single-stranded or double-stranded. In any of the foregoing methods or uses, the compound may target CFB. In certain embodiments, the compound comprises a modified oligonucleotide 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 has a nucleobase sequence that is at least 80%, at least 85%, at least 90%, at least 95%, or 100% complementary to the nucleobase sequence described in SEQ ID NO: 1 or 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 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 connected nucleosides. In certain embodiments, the modified oligonucleotide has such a nucleobase sequence: it has at least 1, at least 2 or at least 3 mismatches with the region of the nucleobase of SEQ ID NO: 1 or 3.

[0194] In any of the aforementioned methods or uses, the compound comprises a first modified oligonucleotide 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 connected 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 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 modified oligonucleotide or the second modified oligonucleotide or at the 5' end of the first modified oligonucleotide or the second modified oligonucleotide. In certain embodiments, the first modified oligonucleotide or the second modified oligonucleotide comprises one or more modified sugars. In certain embodiments, each nucleoside of the first modified oligonucleotide or the second modified oligonucleotide comprises a modified sugar. In certain embodiments, the modified sugar comprises a modification selected from halogen, alkoxy and bicyclic sugar. In certain embodiments, the modified sugar comprises a modification selected from: 2'-MOE, 2'-F and 2'-OMe or a combination thereof. In certain embodiments, the first modified oligonucleotide or the second modified oligonucleotide comprises no more than ten 2'-F sugar modifications. In certain embodiments, the first modified oligonucleotide or the second modified oligonucleotide comprises no more than five 2'-F sugar modifications.

[0195] 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, one or more GalNAc is connected to the 2' or 3' position of the ribosyl ring. In certain embodiments, 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 Formulas I to VIII and XII 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 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 Formula VIII and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula XII, 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 XII and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula XII and R' is S.

[0196] In any of the aforementioned methods or uses, the compound comprises: a first modified oligonucleotide selected from any one of the following:

[0197] IA0478-490, IA0840, IA0842-846, IA0852-862, IA0872-882, IA0887-890, IA1010-1012, and IA1015-1018

[0198] and a second modified oligonucleotide of 14 to 21 linked nucleosides in length that is fully complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide selected from:

[0199] IA0478-490, IA0840, IA0842-846, IA0852-862, IA0872-882, IA0887-890, IA1010-1012, and IA1015-1018

[0200] and a second modified oligonucleotide selected from:

[0201] IS0570-587, IS0969, IS0972-977, IS1023-1027, IS1029, IS1031-1037, IS1042-1046, IS1082, IS1085, IS1086, IS1091-1095, IS1108-1111, JS1236-1239, IS1242, IS1249 and IS1251-1254.

[0202] Certain embodiments provide a compound comprising a first modified oligonucleotide of IA0840 and a second modified oligonucleotide of IS0972. Certain embodiments provide a compound comprising a first modified oligonucleotide of IA0842 and a second modified oligonucleotide of IS0974. Certain embodiments provide a compound comprising a first modified oligonucleotide of IA0888 and a second modified oligonucleotide of IS1109. Certain embodiments provide a compound comprising a first modified oligonucleotide of IA0888 and a second modified oligonucleotide of IS1236. Certain embodiments provide a compound comprising a first modified oligonucleotide of IA1010 and a second modified oligonucleotide of IS1109. Certain embodiments provide a compound comprising a first modified oligonucleotide of IA1011 and a second modified oligonucleotide of IS1239. Certain embodiments provide a compound comprising a first modified oligonucleotide of IA1012 and a second modified oligonucleotide of IS1242. Certain embodiments provide compounds comprising a first modified oligonucleotide that is IA1016 and a second modified oligonucleotide that is IS 1252. Certain embodiments provide compounds comprising a first modified oligonucleotide that is IA1017 and a second modified oligonucleotide that is IS1253.

[0203] 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 as described in any one of the preceding embodiments and a pharmaceutically acceptable carrier.

[0204] 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 in a therapeutically effective amount. In certain embodiments, the compound of any of the foregoing embodiments or a composition comprising the compound is administered to an individual at a dosage level sufficient to deliver about 1 to 100 mg / kg of individual body weight. In certain embodiments, the compound of any of the foregoing embodiments or a composition comprising the compound is administered to an individual at a fixed dose of about 25 mg to about 1,000 mg. In certain embodiments, the composition is administered to an individual once or more in a day up to the dosage level or fixed dose.

[0205] In any of the aforementioned methods or uses, the compound of any of the aforementioned embodiments or the composition comprising the compound is applied to the individual every day, every week, every month, every quarter or every year. In certain embodiments, the compound of any of the aforementioned embodiments or the composition comprising the compound is applied to the individual about once a quarter (that is, once every three months) to about once a year. In certain embodiments, the compound of any of the aforementioned embodiments or the composition comprising the compound is applied to the individual about once a quarter, about once every six months or about once a year.

[0206] Certain compounds

[0207] In certain aspects, the disclosure relates to compounds 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 or a portion thereof.

[0208] In certain aspects, the disclosure relates to compounds 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 or a portion thereof.

[0209] In certain aspects, the disclosure relates to compounds comprising or consisting of antisense oligonucleotides.In certain embodiments, the antisense oligonucleotide has a nucleobase sequence that is complementary to a nucleobase sequence of a target nucleic acid or a portion thereof.

[0210] In some aspects, the disclosure relates to compounds as single-stranded compounds. In some embodiments, the single-stranded compound comprises an oligomeric compound or consists of an oligomeric compound. In some embodiments, such an oligomeric compound comprises an oligonucleotide and an optional conjugated group or consists of an oligonucleotide and an optional conjugated group. In some embodiments, the oligonucleotide is a modified oligonucleotide. In some embodiments, the oligonucleotide is an antisense oligonucleotide. In some embodiments, the oligonucleotide or modified oligonucleotide of the single-stranded compound comprises a self-complementary nucleobase sequence. In some aspects, the disclosure relates to compounds as double-stranded compounds. In some embodiments, the double-stranded compound comprises an oligomeric compound or consists of an oligomeric compound. In some embodiments, the double-stranded compound comprises a first oligonucleotide and a second oligonucleotide. In some embodiments, the first oligonucleotide has a region complementary to the target nucleic acid, and the second oligonucleotide has a region complementary to the first modified oligonucleotide. In some embodiments, the double-stranded compound comprises a modified oligonucleotide. In some embodiments, the modified oligonucleotide has a region complementary to the target nucleic acid. In some embodiments, the double-stranded compound comprises a first modified oligonucleotide and a second modified oligonucleotide. In certain embodiments, the first modified oligonucleotide has a region complementary to the target nucleic acid, and the second modified oligonucleotide has a region complementary to 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.

[0211] In certain embodiments, the compound described herein comprises a conjugated group. In certain embodiments, the first oligonucleotide or the first modified oligonucleotide of the double-stranded compound comprises a conjugated group. In certain embodiments, the second oligonucleotide or the second modified oligonucleotide of the double-stranded compound comprises 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 comprise a conjugated group.

[0212] In certain embodiments, the length of the compound is 14 to 30 connected nucleosides. In certain embodiments, the length of the first oligonucleotide or the first modified oligonucleotide of the double-stranded compound is 14 to 30 connected nucleosides. In certain embodiments, the length of the second oligonucleotide or the second modified oligonucleotide is 14 to 30 connected nucleosides. In certain embodiments, the oligonucleotide or the modified oligonucleotide of the double-stranded compound is flat-ended at one end or both ends of the compound. In certain embodiments, the oligonucleotide or the modified oligonucleotide of the double-stranded compound comprises non-complementary protruding nucleosides at one end or both ends of the compound.

[0213] In certain embodiments, the compound has a nucleobase sequence comprising at least 14 consecutive nucleobases of any one of SEQ ID NOs: 11 to 44 and 96 to 102. 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 to 44 and 96 to 102.

[0214] Some examples of single-stranded and double-stranded compounds include, but are not limited to, oligonucleotides, antisense oligonucleotides, siRNAs, microRNA targeting oligonucleotides, site-occupying 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).

[0215] 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.

[0216] In certain embodiments, the compounds described herein include oligonucleotides of subunits connected in length from 12 to 30. In certain embodiments, the compounds described herein include oligonucleotides of subunits connected in length from 12 to 23. In certain embodiments, the compounds described herein include oligonucleotides of subunits connected in length from 14 to 30. In certain embodiments, the compounds described herein include oligonucleotides of subunits connected in length from 14 to 23. In certain embodiments, the compounds described herein include oligonucleotides of subunits connected in length from 15 to 30. In certain embodiments, the compounds described herein include oligonucleotides of subunits connected in length from 15 to 23. In certain embodiments, the compounds described herein include oligonucleotides of subunits connected in length from 16 to 30. In certain embodiments, the compounds described herein include oligonucleotides of subunits connected in length from 16 to 23. In certain embodiments, the compounds described herein include oligonucleotides of subunits connected in length from 17 to 30. In certain embodiments, the compounds described herein include oligonucleotides of subunits connected in length from 17 to 23. In certain embodiments, the compound described herein comprises an oligonucleotide of a subunit of 18 to 30 connections in length. In certain embodiments, the compound described herein comprises an oligonucleotide of a subunit of 18 to 23 connections in length. In certain embodiments, the compound described herein comprises an oligonucleotide of a subunit of 19 to 30 connections in length. In certain embodiments, the compound described herein comprises an oligonucleotide of a subunit of 19 to 23 connections in length. In other words, such oligonucleotides are respectively 12 to 30 subunits connected, 12 to 23 subunits connected, 14 to 30 subunits connected, 14 to 23 subunits connected, 15 to 30 subunits connected, 15 to 23 subunits connected, 16 to 30 subunits connected, 16 to 23 subunits connected, 17 to 30 subunits connected, 17 to 23 subunits connected, 18 to 30 subunits connected, 18 to 23 subunits connected, 19 to 30 subunits connected or 19 to 23 subunits connected. In certain embodiments, the compounds described herein comprise oligonucleotides of 14 connected subunits in length. In certain embodiments, the compounds described herein comprise oligonucleotides of 16 connected subunits in length. In certain embodiments, the compounds described herein comprise oligonucleotides of 17 connected subunits in length. In certain embodiments, the compounds described herein comprise oligonucleotides of 18 connected subunits in length. In certain embodiments, the compounds described herein comprise oligonucleotides of 19 connected subunits in length. In certain embodiments, the compounds described herein comprise oligonucleotides of 20 connected subunits in length.In certain embodiments, the compounds described herein comprise oligonucleotides of subunits connected in length of 21. In certain embodiments, the compounds described herein comprise oligonucleotides of subunits connected in length of 22. In certain embodiments, the compounds described herein comprise oligonucleotides of subunits connected in length of 23. In other embodiments, the compounds described herein comprise oligonucleotides of subunits connected in 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. In certain such embodiments, the compounds described herein comprise an oligonucleotide of 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.

[0217] In certain embodiments, the compound may also include additional moieties, such as conjugated groups or delivery moieties. In certain embodiments, such compounds are oligomeric compounds, and the additional moieties are connected to oligonucleotides. In certain embodiments, the conjugated groups are connected to the nucleosides of oligonucleotides.

[0218] In certain embodiments, the compound may be shortened or truncated. For example, one or more subunits may be missing from the 5' end (5' truncation) or alternatively from the 3' end (3' truncation) of the oligonucleotide.

[0219] In certain embodiments, the compound may be extended. For example, one or more subunits may be attached to the 3' end or the 5' end of the oligonucleotide. In certain embodiments, at least one subunit (e.g.,

[0220] 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

[0221] or more subunits) is connected to the 5' end of the oligonucleotide. In certain embodiments, at least one subunit (e.g.,

[0222] 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,

[0223] In some embodiments, at least one subunit (e.g.,

[0224] 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,

[0225] or more subunits) are connected to the 5' ends of two oligonucleotides of the double-stranded compound. In certain embodiments, at least one subunit (e.g.,

[0226] 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,

[0227] In some embodiments, the subunit is connected to the 3' end of the two oligonucleotides of the double-stranded compound (for example, 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 some 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 different. In some 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 is the same. In some 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 is different. The situation in which the subunit is connected to the two oligonucleotides of the double-stranded compound at the same end can occur at one end or both ends of the double-stranded compound. In some embodiments, the subunit connected to the 3' and / or 5' end is modified.

[0228] 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.

[0229] In certain embodiments, the compounds described herein may comprise any of the oligonucleotide sequences targeting CFB described herein. In certain embodiments, the compounds may be double-stranded.

[0230] In certain embodiments, the compound comprises an oligonucleotide having a nucleobase sequence 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 the nucleobase sequences of SEQ ID NOs: 11 to 44 or 96 to 102. 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 SEQ ID NOs: 96, 97, 100, or 101. 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 SEQ ID NO: 93, 106, 109, or 110. 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: 96 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: 93. 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:97 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:106. 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: 100 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: 109.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: 101 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: 110. In certain embodiments, the oligonucleotides are modified oligonucleotides.

[0231] In certain embodiments, the compound comprises ribonucleotides, wherein for any sequence provided herein, the oligonucleotide has uracil (U) instead of thymine (T). In certain embodiments, the compound comprises deoxyribonucleotides, wherein for any sequence provided herein, the oligonucleotide has thymine (T) instead of uracil (U).

[0232] Some mechanisms

[0233] In certain embodiments, the compound described herein comprises a modified oligonucleotide or is composed of a modified oligonucleotide. In certain embodiments, the compound described herein comprises an antisense oligonucleotide or is composed of an antisense oligonucleotide. In certain embodiments, the compound comprises an oligomeric compound or is composed of an oligomeric compound. In certain embodiments, the compound described herein can hybridize with a target nucleic acid. In certain embodiments, the compound described herein selectively affects one or more target nucleic acids. Such a compound comprises such a core base sequence: it hybridizes with one or more target nucleic acids, thereby producing 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 such a manner that causes significant undesirable activity.

[0234] In certain embodiments, the hybridization of the compound described herein with the target nucleic acid results in the recruitment of one or more proteins that cause the cleavage of the target nucleic acid. For example, some of the compounds described herein or a portion of the compound are loaded into an RNA-induced silencing complex (RISC), ultimately resulting in the cleavage of the target nucleic acid. For example, some of the compounds described herein cause the target nucleic acid to be cleaved by Argonaute. The compound loaded into RISC is an RNAi compound. The RNAi compound can be double-stranded (siRNA) or single-stranded (ssRNA).

[0235] In certain embodiments, the hybridization of compound and target nucleic acid described herein will not result in the recruitment of proteins that cut the target nucleic acid. In certain such embodiments, the hybridization of compound and target nucleic acid results in the change of target nucleic acid splicing. In certain embodiments, the hybridization of compound and target nucleic acid results in the inhibition of binding interaction between target nucleic acid and protein or other nucleic acids. In certain such embodiments, the hybridization of compound and target nucleic acid results in the change of RNA processing. In certain such embodiments, the hybridization of compound and target nucleic acid results in the change of target nucleic acid translation.

[0236] The activity produced by hybridization of the compound to the target nucleic acid can be observed directly or indirectly. In certain embodiments, the observation or detection of activity involves observing or detecting a change in the amount of a target nucleic acid or a protein encoded by such a target nucleic acid, a change in the ratio of a splice variant of a nucleic acid or protein, and / or a phenotypic change in a cell or animal.

[0237] Some modifications

[0238] In certain aspects, the disclosure relates to compounds comprising or consisting of oligonucleotides. Oligonucleotides are composed of linked nucleosides. In certain embodiments, the oligonucleotide can be unmodified RNA or DNA, or can be modified. In certain embodiments, the oligonucleotide is a modified oligonucleotide. In certain embodiments, relative to unmodified RNA or DNA, the modified oligonucleotide comprises at least one modified sugar, modified nucleobase or modified internucleoside linkage. In certain embodiments, the oligonucleotide has a modified nucleoside. The modified nucleoside may comprise a modified sugar, a modified nucleobase or both a modified sugar and a modified nucleobase. The modified oligonucleotide may also include terminal modifications, such as 5'-terminal modifications and 3'-terminal modifications.

[0239] Sugar modifications and motifs

[0240] 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 substitutes described herein.

[0241] 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.

[0242] In certain embodiments, 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 at the 2' position of the non-bicyclic modified sugar include, but are not limited to, halogen, allyl, amino, azido, SH, CN, OCN, CF 3 、OCF 3 、F、Cl、Br、SCH 3 、SOCH 3 、SO 2 CH 3 、ONO 2 , ΝΟ 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 alkyl, alkenyl and alkynyl may be substituted or unsubstituted C 1 To C 10 Alkyl or C 2 To C 10 In some embodiments, the substituents at the 2' position include, but are not limited to, alkaryl, aralkyl, O-alkaryl, and O-aralkyl. In some 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 substituents at the 2' position include, but are 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 OCH 2 C(=O)-N(H)CH 3 (“NMA”).

[0243] In certain embodiments, the substituents at the 4' position suitable for non-bicyclic modified sugars include but are not limited to alkoxy (e.g., methoxy), alkyl, and those described in Manoharan et al., WO 2015 / 106128. In certain embodiments, the substituents at the 5' position suitable for 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 at 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' end nucleoside or the 5' position of the 5' end 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.

[0244] In certain embodiments, modified sugar is a bicyclic sugar. Bicyclic sugar is a modified sugar comprising two rings, wherein the second ring is formed by connecting the bridge of two atoms in the first ring, thereby forming a bicyclic structure. In certain embodiments, bicyclic sugar comprises two atoms of the 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, bicyclic sugar comprises the bridge between 4' and 2' furanose ring atoms. In certain embodiments, bicyclic sugar comprises the bridge between 5' 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'-CH 2 -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' (e.g., Chattopadhyaya el al., J. Org. Chem., 2009, 74, 118-134 and 4'-CH 2 -C(=CH 2 )-2' and its analogs (e.g., U.S. Patent No. 8,278,426). The entire contents of each of the foregoing are hereby incorporated 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:

[0245] U.S. Patent 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; 7,399,845; 7,427,672; 7,569,686; 7,741,457; 8,022,193; 8,030,467; 8,278,425; 8,278,426; 8,278,283; US 2008 / 0039618; and US 2009 / 0012281, US 2013 / 0190383; and WO 2013 / 036868,

[0246] Its entire contents are hereby incorporated herein by reference.Any of the aforementioned bicyclic nucleosides with one or more stereochemical sugar configurations can be prepared, including, for example, α-L-ribofuranose and β-D-ribofuranose (see, for example, WO99 / 14226).Unless otherwise indicated, the bicyclic nucleosides specified herein are β-D configurations.

[0247] In certain embodiments, the modified sugar is a sugar substitute. In certain embodiments, the sugar substitute has an oxygen atom, for example, replaced by a sulfur, carbon or nitrogen atom. In certain such embodiments, the sugar substitute may also include bridging and / or non-bridging substituents as described herein. In certain embodiments, the sugar substitute includes a ring having other than 5 atoms. In certain such embodiments, the sugar substitute includes a cyclobutyl moiety replacing a pentofuranosyl sugar. In certain embodiments, the sugar substitute includes a six-membered ring replacing a pentofuranosyl sugar. In certain embodiments, the sugar substitute includes a tetrahydropyran ("THP") replacing a pentofuranosyl sugar. In certain embodiments, the sugar substitute includes a morpholino replacing a pentofuranosyl sugar. Representative U.S. patents that teach the preparation of such modified sugar structures include, but are not limited to

[0248] 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; 5 ,591,722; 5,597,909; 5,610,300; 5,627,053; 5,639,873; 5,646,265; 5,658,873; 5,670,633; 5,700,920; 7,875,733; 7,939,677, 8,088,904; 8,440,803 and 9,005,906,

[0249] The entire contents of each of the foregoing are hereby incorporated herein by reference.

[0250] In some embodiments, the sugar surrogate comprises a non-cyclic portion. In certain embodiments, the sugar surrogate is an unlocked nucleic acid ("UNA (unlocked nucleic acid)"). UNA is an unlocked non-cyclic nucleic acid in which any bond of the sugar has been removed to form an unlocked "sugar" residue. In one example, UNA also encompasses monomers in which the bond between C1' and C4' has been removed (i.e., a covalent carbon-oxygen-carbon bond between C1' and C4' carbons). In another example, the C2'-C3' bond of the sugar (i.e., a covalent carbon-carbon bond between C2' and C3' carbons) has been removed. Representative U.S. publications teaching the preparation of UNA include, but are not limited to, U.S. Patent No. 8,314,227; and U.S. Patent Publication Nos. 2013 / 0096289, 2013 / 0011922, and 2011 / 0313020, the entire contents of each of which are hereby incorporated herein by reference. In certain embodiments, sugar surrogates include peptide nucleic acids ("PNA (peptidenucleic acid)"), 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., US2013 / 130378, the entire contents of which are hereby incorporated by reference herein. Many other bicyclic and tricyclic sugars and sugar surrogate ring systems that can be used for modified nucleosides are known in the art.

[0251] In certain 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 in a defined pattern or "sugar motif" along the oligonucleotide or a region thereof. In some cases, such sugar motifs include, but are not limited to, any sugar modification pattern described herein.

[0252] In certain embodiments, oligonucleotides include gapmer sugar motifs. Gapmer oligonucleotides include or consist of the following: regions with two external "wing" regions and central or internal "gap" regions. The gapmer and wing regions form a continuous sequence of nucleosides, wherein the majority of nucleosides sugars of each wing are different from the majority of nucleosides sugars of the interval. In certain embodiments, the wing regions include most of modified sugars, and the gap includes most of unmodified sugars. In certain embodiments, the nucleosides of the interval are deoxynucleosides. Compounds with gapmer sugar motifs are described in, for example, U.S. Patent No. 8,790,919, the entire contents of which are incorporated herein by reference.

[0253] 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 include more than one triplet sugar motif. In certain embodiments, the identical sugar modification of the triplet sugar motif is a 2'-F modification. For example, compounds with triplet sugar motifs are disclosed in U.S. Patent No. 10,668,170, the entire contents of which are incorporated herein by reference.

[0254] 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 the cleavage site. In certain embodiments, the oligonucleotides of the double-stranded compound may include more than one quadruplex sugar motif. In certain embodiments, the identical 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 at about the 10th, 11th and 12th positions from the 5' end. In certain embodiments, counting from the first nucleoside at the 5' terminus of the sense oligonucleotide, or counting from the first paired nucleotide in the duplex region at the 5' terminus of the sense oligonucleotide, the quadruplex sugar motif is at position 8, 9, 10, 11; position 9, 10, 11, 12; position 10, 11, 12, 13; position 11, 12, 13, 14; or position 12, 13, 14, 15 of the sense oligonucleotide. In certain embodiments, counting from the first nucleoside at the 5' terminus of the antisense oligonucleotide, or counting from the first paired nucleotide in the duplex region at the 5' terminus of the antisense oligonucleotide, the quadruplex sugar motif is at position 8, 9, 10, 11; position 9, 10, 11, 12; position 10, 11, 12, 13; position 11, 12, 13, 14; or position 12, 13, 14, 15 of the antisense oligonucleotide. The cleavage site may vary depending on the length of the duplex region of the double-stranded compound and may alter the position of the quadruplex accordingly.

[0255] In certain embodiments, the oligonucleotide comprises an alternating sugar motif. In certain embodiments, one or both oligonucleotides of the double-stranded compound comprise an alternating sugar motif. An oligonucleotide having an alternating sugar motif comprises at least two different sugar modifications, wherein one or more consecutive nucleosides comprising a first sugar modification alternate with one or more consecutive nucleosides comprising a second sugar modification and one or more consecutive nucleosides comprising a third sugar modification, and so on. For example, if A, B, and C each represent a modification type of a nucleoside, the alternating motif can be

[0256] "ABABABABABAB...," "AABBAABBAABB...," "AABAABAABAAB, "AAABAAABAAAB...," "AAABBBAAABBB...," or "ABCABCABCABC..." etc.

[0257] In certain embodiments, the alternating sugar motif is repeated 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 along the oligonucleotide. In certain embodiments, the alternating sugar motif is composed of two different sugar modifications. In certain embodiments, the alternating sugar motif comprises 2'-OMe and 2'-F sugar modifications.

[0258] In certain embodiments, each nucleoside of oligonucleotide is modified independently by one or more sugar modifications provided herein. In certain embodiments, each oligonucleotide of double-stranded compound has one or more sugar motifs provided herein independently. In certain embodiments, the oligonucleotide comprising sugar motif is modified completely, because each nucleoside except the nucleoside comprising sugar motif comprises sugar modification.

[0259] Nucleobase modifications and motifs

[0260] In certain embodiments, the compounds described herein comprise modified oligonucleotides. In certain embodiments, modified oligonucleotides comprise one or more nucleosides containing modified nucleobases. In certain embodiments, modified oligonucleotides comprise one or more nucleosides that do not contain nucleobases, referred to as abasic nucleosides.

[0261] In certain embodiments, the modified nucleobase is selected from the group consisting of: 5-substituted pyrimidines, 6-azapyrimidines, alkyl or alkynyl substituted pyrimidines, alkyl substituted purines, and N-2, N-6, and O-6 substituted purines. 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-azouracil, 6-azocytosine, 6-azothymine, 5-ribosyluracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-sulfanyl, 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-deazaadenine, 7-deazaguanine, 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 expanded bases and fluorinated bases. Further modified nucleobases include tricyclic pyrimidines such as 1,3-diazepine Oxazine-2-one, 1,3-diazaphenothiazine-2-one and 9-(2-aminoethoxy)-1,3-diazaphene Modified nucleobases may also include those in which the purine or pyrimidine base is replaced by other heterocycles (eg, 7-deaza-adenine, 7-deazaguanosine, 2-aminopyridine, and 2-pyridone).

[0262] Other nucleobases include those disclosed below:

[0263] U.S. Patent 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 to 859; Kroschwitz, JL, Ed., John Wiley & Sons, 1990, 858-859; Englisch et al. al., Angewandte Chemie, Intemational Edition, 1991, 30, 613: Sanghvi, YS, Chapter 15, dsRNA Research and Applications, pages 289 to 302; Antisense Research and Applications, Crooke, ST and Lebleu, B., Eds., CRC Press, 1993, 273-288; Aotisense Drug Technology, Crooke ST, Ed., CRC Press, 2008, 163-166and 442-443 (Chapters 6 and 15),

[0264] Each of which is hereby incorporated herein by reference.

[0265] Disclosures teaching the preparation of some of the above-mentioned modified nucleobases, as well as other modified nucleobases, include, but are not limited to, U.S. Applications 2003 / 0158403 and 2003 / 0175906;

[0266] U.S. Patents 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; 5,7 50,692; 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,

[0267] The entire contents of each of which are hereby incorporated herein by reference.

[0268] In certain embodiments, the compounds described herein comprise oligonucleotides. In certain embodiments, oligonucleotides comprise modified and / or unmodified nucleobases arranged in a defined pattern or motif along an oligonucleotide or its region. In certain embodiments, each nucleobase is modified. In certain embodiments, none of the nucleobases is modified. 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.

[0269] 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.

[0270] Internucleoside linkage modifications and motifs

[0271] The 3' to 5' phosphodiester linkage is a naturally occurring internucleoside linkage in 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-containing modified internucleoside linkages include, but are not limited to, phosphotriesters, alkylphosphonates (e.g., methylphosphonates), hypophosphites, and thiophosphates ("P=S") and dithiophosphates ("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, carboxamides, sulfides, sulfonates, and amides (see, e.g., Carbohydrate Modifications in Antisense Research; YS Shanghvi and P.D. 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 Non-ionic bonding of components.

[0272] 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.

[0273] In certain embodiments, the internucleoside linkage modification may occur on each nucleoside of the oligonucleotide. In certain embodiments, the internucleoside linkage modification may occur 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 alkylphosphonate internucleoside linkages. In certain embodiments, the sense oligonucleotide comprises at least two modified internucleoside linkages at one or both of the 5' and 3' ends. In certain such embodiments, the modified internucleoside linkages are phosphorothioate internucleoside linkages or alkylphosphonate internucleoside linkages. In certain embodiments, the antisense oligonucleotide comprises at least two modified internucleoside linkages at one or both of the 5' and 3' ends. In certain such embodiments, the modified internucleoside linkages are phosphorothioate internucleoside linkages or alkylphosphonate internucleoside linkages.

[0274] In certain embodiments, the double-stranded compound includes an overhang region. In certain embodiments, the double-stranded compound includes a phosphorothioate or alkylphosphonate internucleoside linkage modification in the overhang region. In certain embodiments, the double-stranded compound includes a phosphorothioate or alkylphosphonate internucleoside linkage, and the linkage connects the overhang nucleotide and the paired nucleotide adjacent to the overhang nucleotide. For example, at least two phosphorothioate internucleoside linkages may be present between the three nucleosides at the end, two of which are overhang nucleosides, and the third is a paired nucleoside adjacent 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.

[0275] 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, alkylphosphonates and phosphorothioates. The modified oligonucleotide comprising an internucleoside linkage with a chiral center can be prepared as a modified oligonucleotide group comprising a stereo-irregular internucleoside linkage, or as a modified oligonucleotide group comprising a phosphorothioate linkage of a specific stereochemical configuration. In certain embodiments, the modified oligonucleotide group comprises a phosphorothioate internucleoside linkage, wherein all phosphorothioate internucleoside linkages are stereo-irregular. Such modified oligonucleotides can be produced using a synthetic method, which results in the random selection of the stereochemical configuration of each phosphorothioate linkage. As known to those skilled in the art, each single phosphorothioate in each single oligonucleotide molecule has a limited stereochemical configuration. In certain embodiments, the modified oligonucleotide group enrichment comprises one or more specific, independently selected specific phosphorothioate internucleoside linkages of the stereochemical configuration. In certain embodiments, the specific configuration of a specific phosphorothioate linkage is present in at least 65% of the molecules in the group. In certain embodiments, the specific configuration of a specific phosphorothioate linkage is present in at least 70% of the molecules in the group. In certain embodiments, the specific configuration of a specific phosphorothioate linkage is present in at least 80% of the molecules in the group. In certain embodiments, the specific configuration of a specific phosphorothioate linkage is present in at least 90% of the molecules in the group. In certain embodiments, the specific configuration of a specific phosphorothioate linkage is present in at least 99% of the molecules in the group. Such enriched modified oligonucleotide groups can be produced using synthetic methods known in the art, for example, Oka et al., JACS125, 8307 (2003), Wan et al. Nuc. Acid. Res. 42, 13456 (2014) and the method described in WO 2017 / 015555. In certain embodiments, the modified oligonucleotide group is enriched with a modified oligonucleotide of at least one of the phosphorothioates shown in (Sp) configuration. In certain embodiments, the population of modified oligonucleotides is enriched for modified oligonucleotides having at least one phosphorothioate in the (Rp) configuration.

[0276] Conjugated Group

[0277] In certain embodiments, the compound described herein comprises or consists of one or more oligonucleotides and optionally one or more conjugated groups. The conjugated group can be connected to one or both ends of the oligonucleotide and / or at 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.

[0278] In certain embodiments, the conjugated group is an end group connected to one or both ends of an oligonucleotide. In certain such embodiments, the end group is connected to the 3' end of an oligonucleotide. In certain such embodiments, the end group is connected to the 5' end of an oligonucleotide. In certain embodiments, the end 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 independently modified or unmodified nucleosides, such as an overhang.

[0279] In certain embodiments, the conjugated group modifies one or more properties of the connected oligonucleotide, including but not limited to pharmacodynamics, pharmacokinetics, stability, activity, half-life, binding, absorption, tissue distribution, cell distribution, cellular uptake, charge and removal. In certain embodiments, the conjugated group enhances the affinity of the compound to the selected target, such as a molecule, cell or cell type, compartment (e.g., cell or organ compartment), tissue, organ or body region, compared to a compound without such a conjugated group. In certain embodiments, the conjugated group imparts new properties to the connected oligonucleotide, for example, enabling detection of a fluorophore or reporter group of an oligonucleotide.

[0280] 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.

[0281] In certain embodiments, the conjugate group includes an active drug substance, for example, aspirin, warfarin, phenylbutazone, ibuprofen, suprofen, fen-bufen, ketoprofen, (S)-(+)-pranoprofen, carprofen, dansylsarcosine, 2,3,5-triiodobenzoic acid, fingolimod, flufenamic acid, folinic acid, benzothiadiazide, chlorothiazide, diazepam, (diazepine), indo-methicin, barbiturates, cephalosporins, sulfonamides, antidiabetic agents, antibacterial agents, or antibiotics.

[0282] 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, N-acetyl-galactosamine (GalNAc), N-acetylglucosamine multivalent mannose, multivalent fucose, a glycosylated polyamino acid, a multivalent galactose, transferrin, a bisphosphonate, polyglutamic acid, polyaspartic acid, a lipid, cholesterol, a steroid, a bile acid, folic acid, vitamin B12, vitamin A, biotin, or an RGD peptide or RGD peptide mimetic.

[0283] In certain embodiments, the conjugate groups may include, but are not limited to, the conjugate groups described in the following references: for example, 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, for example, 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, for example, dodecanediol or undecyl residues (e.g., Saison-Behmoaras et al., EMBOJ, 1991, 10: 1111-1118; Kabanov et al., FEBS Lett., 1990, 259: 327-330; Svinarchuk et al., Biochimie, 1993, 75: 49-54); phospholipids, for example, di-hexadecyl-rac-glycerol or triethylammonium 1,2-di-O-hexadecyl-rac-glycerol-3-H-phosphonate (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; WO 2009 / 073809 and U.S. Patents 8,106,022; 8,450,467 and 8,828,957; and WO 2014 / 179445; WO 2014 / 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. .

[0284] The conjugated group can be connected to the oligonucleotide through a conjugated linker. In certain embodiments, the conjugated linker comprises a chain structure (e.g., 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 alkyl, amino, oxo, amide, disulfide, polyethylene glycol, ether, thioether, and hydroxylamino groups. 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 comprises 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), succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (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 joints-nucleosides. In certain embodiments, such joints-nucleosides can be modified or unmodified nucleosides. It is generally expected that the joint-nucleosides will be cut from the compound after the compound reaches the target tissue. Therefore, the joint-nucleosides herein can be connected to each other and connected to the remainder of the compound by a cleavable bond. In this article, joint-nucleosides are not considered to be a part of oligonucleotides. Therefore, in the embodiment in which the compound comprises a conjugated nucleosides containing a specific number or range and / or has a specific complementarity percentage with a reference nucleic acid, and the compound also comprises a conjugated joint containing a joint-nucleoside conjugated joint, these joints-nucleosides are not counted in the length of the oligonucleotide and are not used to determine the complementarity percentage of the oligonucleotide for the reference nucleic acid.

[0285] In certain embodiments, conjugated groups and conjugated linkers and other modifications include, but are not limited to, those described in the following references:

[0286] 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; US 2006 / 0148740; US 2011 / 0123520;

[0287] 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 etal.,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.,Tetrahedron,1997,53,759-770;Lee,Carhohydr Res,1978,67,509-514;Connolly etal.,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.,JMed Chem,1995,38,1538-1546;Valentijn et al.,Tetrahedron,1997,53,759-770;Kimet 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.,BioorgMed Chem,2008,16,5216-523I;Lee et al.,Bioorg Med Chem,2011,19,2494-2500;Komilova et al.,Analyt Biochem,2012,425,43-46;Pujol et al.,Angew Chemie IntEd Engl,2012,51,7445-7448;Biessen et al.,J Med Chem,1995,38,1846-1852;Sliedregt et al.,J Med Chem,1999,429-668;Rensen et al. al.,J Med Chem,2004,47,5798-5808;Rensen et al.、Arterioscler Thromh Vase Biol,2006,26,169-175;vanRossenberg et al.,Gene Ther,2004,11,457-464;Sato et al.,JAm Chem Soc,2004,126,14013-14022;Lee et al.,J Org Chem,2012,757-751;Biessen et al. al.,FASEBJ,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;Jayaprakash et al.,Org Lett,2010,12,5410-5413;Manoharan,Antisense NucleicAcid Drug Dev,2002,12,103-128;Merwin et al.,Bioconjog Chem,1994,206-2016; et al.,Bioorg Med Chem,2013,21,5275-5281;.

[0288] WO1998 / 013381;WO2011 / 038356;WO1997 / 046098;

[0289] W02008 / 098788; W02004 / 101619; WO2012 / 037254; WO2011 / 120055; WO201 1 / 100131; WO2011 / 163121; WO2012 / 177947; W02013 / 033230; W02013 / 0750 35; WO2012 / 083185; WO2012 / 083046; W02009 / 082607; WO2009 / 134487; W02 010 / 144740; W02010 / 148013; WO1997 / 020563; W02010 / 088537; W02002 / 04 3771; WO2010 / 129709; WO2012 / 068187; WO2009 / 126933; WO2004 / 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; 8,106,022; 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 / 0 207799; US2012 / 0035115; 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;

[0290] Each of which is incorporated herein by reference in its entirety.

[0291] Certain targeting moieties

[0292] In certain embodiments, the compounds provided herein include a conjugated group. In certain embodiments, the oligonucleotides or modified 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 is connected to one or more positions on the furanose ring. In certain embodiments, one or more GalNAc is connected to the 2' or 3' position on the furanose ring. In certain embodiments, the furanose ring is a subunit of an oligonucleotide or a modified oligonucleotide. In certain embodiments, the furanose ring is the 5' nucleoside sugar of an oligonucleotide or a modified oligonucleotide. In certain embodiments, the furanose ring is the 5' nucleoside sugar of a sense oligonucleotide or a modified oligonucleotide. In certain embodiments, the compound, oligonucleotide or modified oligonucleotide includes one or more subunits or salts, solvates or hydrates thereof having the following formula:

[0293]

[0294] in:

[0295] R 1 is H, adenine, guanine, thymine, cytosine, uracil, a carbocyclyl, a heterocyclyl, an aryl, a heteroaryl, or a nucleobase isostere;

[0296] R 2 is an oligonucleotide sequence, a modified oligonucleotide or a compound;

[0297] L 1 is alkyl or alkyl-C(═O)—NH-alkyl;

[0298] L 2 is alkyl or alkyl-C(═O)—NH-alkyl;

[0299] L 3 is bond, phosphodiester bond, phosphorothioate bond, triazole, tetrazole, amide, reverse amide, carbamate, carbonate, urea, O, S, S(=O), S(=O) 2 , NH, a substituted N group, an alkyl, an alkenyl, a diene group, an alkynyl, a heteroalkyl, or a phosphate;

[0300] R 3 is H, -C=(O)-NH-(CH 2 CH 2 O)j -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc;

[0301] R 4 is H, -C=(O)-NH-(CH 2 CH 2 O) k -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc;

[0302] R 5 is -C=(O)-NH-(CH 2 CH 2 O) m -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc;

[0303] R 6 is -C=(O)-NH-(CH 2 CH 2 O) n -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc;

[0304] W and Q are each independently O, NH, CH 2 or CH 2 O;

[0305] 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;

[0306] j is an integer from 1 to 10, inclusive;

[0307] k is an integer from 1 to 10, inclusive;

[0308] m is an integer from 1 to 10, inclusive; and

[0309] n is an integer from 1 to 10, inclusive.

[0310] 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, R3 or R 4 It's H.

[0311] In certain embodiments, L 1 and L 2 are the same.

[0312] In certain embodiments, L 1 and L 2 are each independently an alkyl group; R 3 is H, -C=(O)-NH-(CH 2 CH 2 O) j -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 4 is H, -C=(O)-NH-(CH 2 CH 2 O) k -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 5 is -C=(O)-NH-(CH 2 CH 2 O) m -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; and R 6 is -C=(O)-NH-(CH 2 CH 2 O) n -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc.

[0313] In certain embodiments, L 1 and L 2 are each independently alkyl-C(═O)-NH-alkyl; R 3 is H, -C=(O)-NH-(CH 2 CH 2 O) j -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 4 is H, -C=(O)-NH-(CH 2 CH 2 O) k -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 5 is -C=(O)-NH-(CH 2 CH 2O) m -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; and R 6 is -C=(O)-NH-(CH 2 CH 2 O) n -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc.

[0314] In certain embodiments, R 4 It's H.

[0315] In certain embodiments, L 1 and L 2 are each independently an alkyl group; R 3 is -C=(O)-NH-(CH 2 CH 2 O) j -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 4 It is H; R 5 is -C=(O)-NH-(CH 2 CH 2 O) m -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; and R 6 is -C=(O)-NH-(CH 2 CH 2 O) n -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc.

[0316] In certain embodiments, L 1 and L 2 are each independently alkyl-C(═O)-NH-alkyl; R 3 is -C=(O)-NH-(CH 2 CH 2 O) j -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 4 It is H; R 5 is -C=(O)-NH-(CH 2 CH 2 O) m -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; and R 6is -C=(O)-NH-(CH 2 CH 2 O) n -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc.

[0317] In certain embodiments, R 3 is -C=(O)-NH-(CH 2 CH 2 O) j -GalNAc; R 4 It is H; R 5 is -C=(O)-NH-(CH 2 CH 2 O) m -GalNAc; and R 6 is -C=(O)-NH-(CH 2 CH 2 O) n -GalNAc.

[0318] In certain embodiments, R 3 is -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 4 It is 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.

[0319] In certain embodiments, the compound, modified oligonucleotide or oligonucleotide comprises one or more subunits having the formula: or a salt, solvate or hydrate thereof:

[0320]

[0321] in:

[0322] R 9 is H, adenine, guanine, thymine, cytosine or uracil, or is 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;

[0323] L is a bond, a phosphodiester bond, a phosphorothioate bond, a triazole, a tetrazole, an amide, a transamide, a carbamate, a carbonate, a urea, an alkyl group, or a heteroalkyl group;

[0324] R 2 is an oligonucleotide sequence, a modified oligonucleotide or a compound;

[0325] Y 1 O, CH 2 , CH 2 O or optionally substituted NH;

[0326] Y 2 O, CH 2 , CH 2 O or optionally substituted NH;

[0327] Y 3 It’s CO, SO 2 、P(O)O、CH 2 -OC(O),CH 2 -NH-C(O), CH 2 -NH-SO 2 or CH 2 ;

[0328] Y 4 It’s CO, SO 2 、P(O)O、CH 2 -OC(O),CH 2 -NH-C(O), CH 2 -NH-SO 2 or CH 2 ;

[0329] n 2 is 0, 1, 2, 3, 4, 5, or 6; and

[0330] n 1 、n 3 、n 4 and n 5 Each independently is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0331] In certain embodiments, the compound, modified oligonucleotide or oligonucleotide comprises one or more subunits having the formula: or a salt, solvate or hydrate thereof:

[0332]

[0333] in:

[0334] Each n is independently 1, 2, 3, 4 or 5;

[0335] Each m is independently 0, 1, 2, 3, 4, 5 or 6;

[0336] Each o is independently 0, 1, 2, 3, 4, 5 or 6;

[0337] L 1 , L 2 and L 3 each independently is absent, C(═O) or C(═O)NH;

[0338] Each Y 1 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 -;

[0339] 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 -;

[0340] Het 1 、Het 2 and Het 3 are each independently an optionally substituted heteroaryl or an optionally substituted heterocyclyl;

[0341] R 1 is an oligonucleotide sequence, modified oligonucleotide or compound joined 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;

[0342] R 5 , R 6 and R 7 Each independently is

[0343] R 9 is an optionally substituted heterocyclyl;

[0344] Each R a are independently H, alkyl, halogen, OR c or SR c ;

[0345] Each R b are independently H, alkyl, halogen, OR c or SR c ;and

[0346] Each R c is independently H or alkyl.

[0347] In certain embodiments, R' is OH. In certain embodiments, R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula I and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula I and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula II and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula II and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula III and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula III and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula IV and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula IV and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula V and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula V and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula VI and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula VI and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula VII and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula VII and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula VIII and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula VIII and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula XII and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula XII and R' is SH.

[0348] In certain embodiments, the subunit is selected from Formulas I to VIII and XII or salts, solvates or hydrates 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 Formula V and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula VI and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula VI and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula VII and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula VII and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula VIII and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula VIII and R' is S. In certain embodiments, the subunit is Formula XII 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 XII and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is Formula XII and R' is S.

[0349] Target nucleic acid and target region

[0350] In certain embodiments, the compound described herein comprises an oligonucleotide or is composed of an oligonucleotide, and the oligonucleotide comprises 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 intronic regions, exonic regions, 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 exons. In certain such embodiments, the target region is completely within introns. In certain embodiments, the target region spans intron / exon connections. In certain embodiments, at least 50% of the target region is within introns.

[0351] In certain embodiments, the compounds disclosed herein hybridize with CFB 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 CFB nucleic acids.

[0352] Nucleotide sequences encoding CFB include, but are not limited to, the following: GENBANK Accession No. NM_001710.6 (incorporated herein as SEQ ID NO: 1), nucleotides 31946095 to 31952084 of GENBANK Accession No. NC_000006.12 (incorporated herein as SEQ ID NO: 2), GENBANK Accession No. NM_001710.6 (incorporated herein as SEQ ID NO: 3), and nucleotides 3423522 to 3429511 of GENBANK Accession No. NT_113891.3 (incorporated herein as SEQ ID NO: 4).

[0353] Complementarity

[0354] Oligonucleotide provided herein can have the complementary percentage ratio of qualification with specific nucleic acid, target region, oligonucleotide or its part.Non-complementary core base can be allowed, and prerequisite is that oligonucleotide keeps can with nucleic acid, oligonucleotide or its part specific hybridization.In certain embodiments, oligonucleotide provided herein or its specific part and target nucleic acid, target region, oligonucleotide or its specific part at least or up to 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 specific part and target nucleic acid, target region, oligonucleotide or its specific part have 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. The complementarity percentage of oligonucleotide and target nucleic acid, target region, oligonucleotide or its specific part can be determined using conventional methods.For example, wherein 18 of the 20 core bases of oligonucleotide are complementary to the target region and therefore the oligonucleotide of specific hybridization will represent 90% complementarity.In this example, the remaining non-complementary core base can be clustered or interspersed with complementary core base, and does not need to be adjacent to each other or adjacent to complementary core base.Therefore, the oligonucleotide of length 18 core bases has four non-complementary core bases, and its flank is two regions that are fully complementary to the target nucleic acid, and the total complementarity with the target nucleic acid is 77.8%.BLAST programs known in the art (basic local alignment search tool (basic local alignment search tool)) can be used to routinely determine the complementarity percentage of the region of oligonucleotide and target nucleic acid, target region, oligonucleotide or its specific part.In certain embodiments, oligonucleotide described herein or its specific part are fully complementary to target nucleic acid, target region, oligonucleotide or its specific part (i.e. 100% complementary).For example, oligonucleotide can be fully complementary to target nucleic acid, target region, oligonucleotide or its specific part. As used herein, "complete complementarity" means that each core base of an oligonucleotide is complementary to the corresponding core base of a target nucleic acid, a target region, an oligonucleotide or a specific portion thereof. For example, a 20 core base oligonucleotide is completely complementary to a target sequence of 400 core bases, as long as there are corresponding 20 core base portions in the target nucleic acid that are completely complementary to the compound. "Complete complementarity" can also be used to refer to a specific portion of the first and / or second nucleic acid. For example, 20 core base portions in a 30 core base oligonucleotide can be "completely complementary" to 20 core base regions in a target sequence of 400 core bases. If the target sequence has a corresponding 20 core base portions in which each core base is partially complementary to the 20 core base portions in the compound, the 20 core base portions in the 30 core base compound are completely 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.

[0355] In certain embodiments, relative to target nucleic acid, target region, oligonucleotide or its specific part, oligonucleotide described herein comprises one or more mispaired core base.In certain embodiments, relative to target nucleic acid or its specific part, the length described herein is or as many as 12,13,14,15,16,17,18,19,20,21,22 or 23 core base oligonucleotide comprises 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 specific part, the length described herein is or as many as 14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29 or 30 core base oligonucleotide comprises 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 the following: 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.

[0356] In certain embodiments, the oligonucleotides described herein may be complementary to a portion of a nucleic acid. "A portion" as used herein refers to a continuous nucleobase of a limited number in a nucleic acid region. "A portion" may also refer to a continuous nucleobase of a limited number of oligonucleotides. In certain embodiments, at least 8 nucleobase portions in an oligonucleotide are complementary to nucleic acids. In certain embodiments, at least 9 nucleobase portions in an oligonucleotide are complementary to nucleic acids. In certain embodiments, at least 10 nucleobase portions in an oligonucleotide are complementary to nucleic acids. In certain embodiments, at least 11 nucleobase portions in an oligonucleotide are complementary to nucleic acids. In certain embodiments, at least 12 nucleobase portions in an oligonucleotide are complementary to nucleic acids. In certain embodiments, at least 13 nucleobase portions in an oligonucleotide are complementary to nucleic acids. In certain embodiments, at least 14 nucleobase portions in an oligonucleotide are complementary to nucleic acids. In certain embodiments, at least 15 nucleobase portions in an oligonucleotide are complementary to nucleic acids. In certain embodiments, at least 16 nucleobase portions in an oligonucleotide are complementary to nucleic acids. It is also contemplated that at least 9, 10, 17, 18, 19, 20, 21, 22, 23 or more core base portions in nucleic acid, or the range limited by any two of these values ​​are complementary oligonucleotides. In certain embodiments, oligonucleotides are antisense oligonucleotides. In certain embodiments, the part of antisense oligonucleotides is compared with the isometric portion of target nucleic acid. In certain embodiments, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 core base portions are compared with the isometric portion of target nucleic acid. In certain embodiments, oligonucleotides are sense oligonucleotides. In certain embodiments, the part of sense oligonucleotides is compared with the isometric portion of antisense oligonucleotides. In certain embodiments, an 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobase portion of a sense oligonucleotide is compared to an equal length portion of an antisense oligonucleotide.

[0357] Identity

[0358] Oligonucleotides provided herein can also have a limited percentage identity with specific nucleic acids, target regions, oligonucleotides or their specific parts. As used herein, if the oligonucleotide has the same core base pairing ability, it is identical to the sequence disclosed herein. For example, a DNA containing a thymidine replacing the uracil in the disclosed RNA sequence will be considered identical to the RNA sequence, because both uracil and thymidine are paired with adenine. It is also contemplated that the shortened and extended forms of the compounds described herein and the compounds with different bases relative to the compounds provided herein. Different bases can be adjacent to each other or dispersed throughout the compound. The identity percentage of an oligonucleotide is calculated according to the number of bases with the same base pairing relative to the sequence compared thereto. In certain embodiments, oligonucleotides described herein or its part and nucleic acid disclosed herein, oligonucleotides or its part one or more have or have at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% homogeneity.In certain embodiments, oligonucleotides described herein and specific nucleic acid or oligonucleotides or its part have about 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% homogeneity, or any percentage between such values.

[0359] In certain embodiments, oligonucleotide can have the core base of one or more mispairings.In certain such embodiments, mispairing is at the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th or 14th position from the 5' end of oligonucleotide.In certain such embodiments, mispairing is at the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th or 14th position from the 3' end of oligonucleotide.In certain embodiments, the part of oligonucleotide is compared with the isometric part of target nucleic acid.In certain embodiments, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 core base parts are compared with the isometric part of target nucleic acid.In certain embodiments, oligonucleotide is a sense oligonucleotide.In certain embodiments, the part of sense oligonucleotide is compared with the isometric part of target nucleic acid. In certain embodiments, an 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobase portion is compared to an equal length portion of a target nucleic acid.

[0360] Pharmaceutical compositions and preparations

[0361] The compounds described herein can be mixed with pharmaceutically active substances or inert substances for the preparation of pharmaceutical compositions or formulations. The compositions and methods for preparing pharmaceutical compositions depend on many 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 one or more modified oligonucleotides 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 a pharmaceutical composition consists of a compound and a sterile saline solution. In certain embodiments, sterile saline is 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, sterile water is 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 a pharmaceutical grade PBS.

[0362] By combining the compounds targeting CFB described herein with a suitable pharmaceutically acceptable diluent or carrier, the compounds can be used in pharmaceutical compositions. In certain embodiments, the pharmaceutically acceptable diluent is water, such as sterile water suitable for injection. Therefore, in one embodiment, the methods described herein employ a pharmaceutical composition comprising a compound targeting CFB and a pharmaceutically acceptable diluent. In certain embodiments, the pharmaceutically acceptable diluent is water. In certain embodiments, the compound comprises one or more modified oligonucleotides provided herein or consists of one or more modified oligonucleotides provided herein.

[0363] The pharmaceutical composition comprising the compound provided herein encompasses any pharmaceutically acceptable salt, ester or salt of such ester or any other oligonucleotide, which can provide (directly or indirectly) its biologically active metabolite or residue after being 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 one or more modified oligonucleotides or is composed of one or more modified oligonucleotides. Therefore, for example, the disclosure also relates to a pharmaceutically acceptable salt, a prodrug, a pharmaceutically acceptable salt of such a prodrug, and other bioequivalents of the compound. Suitable pharmaceutically acceptable salts include, but are not limited to, sodium salts and potassium salts. Prodrugs may be included in other nucleosides incorporated into one end or both ends of the compound, which are cut by endogenous nucleases in vivo to form active compounds. In certain embodiments, the compound or composition also comprises a pharmaceutically acceptable carrier or diluent.

[0364] It should be understood that the examples and embodiments described herein are for illustrative purposes only, and that those skilled in the art will appreciate various modifications or variations based thereon, and that the modifications or variations will be included within the spirit and scope of the present application and within the scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

[0365] Some other implementations

[0366] Certain embodiments include Embodiment 1 to Embodiment 97 below.

[0367] Embodiment 1. A compound comprising a modified oligonucleotide of 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, or at least 20 consecutive nucleobases of any one of the nucleobase sequences of SEQ ID NOs: 11 to 44 or 96 to 102.

[0368] Embodiment 2. A compound comprising a modified oligonucleotide of 14 to 23 linked nucleosides in length having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11 to 44 or 96 to 102.

[0369] Embodiment 3. A compound comprising a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequence of any one of SEQ ID NOs: 11 to 44 and 96 to 102.

[0370] Embodiment 4. The compound of any one of Embodiments 1 to 3, wherein the nucleobase sequence of the modified oligonucleotide is at least 80%, at least 85%, at least 90% or at least 95% complementary to the nucleobase sequence of SEQ ID NO: 1 or 3.

[0371] Embodiment 5. The compound of any one of Embodiments 1 to 4, wherein the modified oligonucleotide comprises at least one modification selected from the group consisting of a modified internucleoside linkage, a modified sugar, and a modified nucleobase.

[0372] Embodiment 6. The compound of any one of Embodiments 1 to 5, wherein the compound is double-stranded.

[0373] Embodiment 7. A compound comprising: a first modified oligonucleotide having a length of 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, or at least 20 consecutive nucleobases of any one of the nucleobase sequences of SEQ ID NOs: 11 to 110; and a second modified oligonucleotide having a length of 14 to 23 linked nucleosides having a region complementary to the first modified oligonucleotide.

[0374] Embodiment 8. A compound comprising: a first modified oligonucleotide having a length of 14 to 23 linked nucleosides having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11 to 110; and a second modified oligonucleotide having a length of 14 to 23 linked nucleosides having a region complementary to the first modified oligonucleotide.

[0375] Embodiment 9. A compound comprising: a first modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequence of any one of SEQ ID NOs: 11 to 110; and a second modified oligonucleotide having a length of 19 to 23 linked nucleosides having a region complementary to the first modified oligonucleotide.

[0376] Embodiment 10. The compound of any one of Embodiments 7 to 9, wherein the nucleobase sequence of the first modified oligonucleotide is at least 80%, at least 85%, at least 90% or at least 95% complementary or identical to the nucleobase sequence of SEQ ID NO: 1 or 3 over its length.

[0377] Embodiment 11. The compound of any one of Embodiments 7 to 10, wherein the nucleobase sequence of the first modified oligonucleotide has at least 1, at least 2, or at least 3 mismatches with a region of the nucleobase sequence of SEQ ID NO: 1 or 3, and the region is the same length as the first modified oligonucleotide.

[0378] Embodiment 12. The compound of any one of Embodiments 7 to 11, wherein the length of the region of complementarity between the first modified oligonucleotide and the second modified oligonucleotide is 14 to 23 linked nucleosides.

[0379] Embodiment 13. The compound of any one of Embodiments 7 to 11, wherein the length of the region of complementarity between the first modified oligonucleotide and the second modified oligonucleotide is 19 to 23 linked nucleosides.

[0380] Embodiment 14. The compound of any one of Embodiments 7 to 11, wherein the length of the region of complementarity between the first modified oligonucleotide and the second modified oligonucleotide is 21 to 23 linked nucleosides.

[0381] Embodiment 15. The compound of any one of Embodiments 7 to 11, wherein the first modified oligonucleotide is fully complementary to the second modified oligonucleotide.

[0382] Embodiment 16. The compound of any one of Embodiments 7 to 15, wherein the first modified oligonucleotide comprises at least one modification selected from the group consisting of a modified internucleoside linkage, a modified sugar, and a modified nucleobase.

[0383] Embodiment 17. The compound of any one of Embodiments 7 to 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.

[0384] Embodiment 18. The compound of any one of Embodiments 5, 16, and 17, wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage or a methylphosphonate internucleoside linkage.

[0385] Embodiment 19. The compound of Embodiment 18, wherein the phosphorothioate internucleoside linkage or the methylphosphonate internucleoside linkage is at the 3' end of the first modified oligonucleotide or the second modified oligonucleotide or at the 5' end of the first modified oligonucleotide.

[0386] Embodiment 20. The compound of any one of Embodiments 5, 16, and 17, wherein the modified sugar comprises a modification selected from the group consisting of a halogen, an alkoxy group, and a bicyclic sugar.

[0387] Embodiment 21. The compound of Embodiment 20, wherein the modified sugar comprises a 2'-F modification.

[0388] Embodiment 22. The compound of Embodiment 20, wherein the modified sugar comprises a 2'-OMe modification.

[0389] Embodiment 23. The compound of any one of Embodiments 7 to 15, wherein each nucleoside of the first modified oligonucleotide comprises a modified sugar.

[0390] Embodiment 24. The compound of any one of Embodiments 7 to 15, wherein each nucleoside of the second modified oligonucleotide comprises a modified sugar.

[0391] Embodiment 25. The compound of Embodiment 23 or 24, wherein the modified sugar comprises a modification selected from the group consisting of a halogen, an alkoxy group, and a bicyclic sugar, or a combination thereof.

[0392] Embodiment 26. The compound of Embodiment 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.

[0393] Embodiment 27. The compound of Embodiment 23, wherein the first modified oligonucleotide comprises no more than ten 2'-F sugar modifications.

[0394] Embodiment 28. The compound of Embodiment 24, wherein the second modified oligonucleotide comprises no more than five 2'-F sugar modifications.

[0395] Embodiment 29. The compound of any of the preceding embodiments, comprising a conjugated group.

[0396] Embodiment 30. The compound of Embodiment 29, wherein the conjugate group is attached to the 5' end of the modified oligonucleotide.

[0397] Embodiment 31. The compound of Embodiment 29 or 30, wherein the conjugated group comprises a targeting moiety.

[0398] Embodiment 32. The compound of Embodiment 31, wherein the targeting moiety comprises one or more GalNAc.

[0399] Embodiment 33. The compound of Embodiment 32, wherein the modified oligonucleotide is the second modified oligonucleotide.

[0400] Embodiment 34. The compound of Embodiment 32 or 33, wherein the one or more GalNAc groups are attached to the 2' or 3' position of the ribosyl ring of the 5' nucleoside of the modified oligonucleotide.

[0401] Embodiment 35. The compound of Embodiment 34, wherein the 5' nucleoside has the formula:

[0402]

[0403] in:

[0404] R 9 is H, adenine, guanine, thymine, cytosine or uracil, or is adenine, guanine, thymine, cytosine or uracil, each comprising 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;

[0405] L is a bond, a phosphodiester bond, a phosphorothioate bond, a triazole, a tetrazole, an amide, a transamide, a carbamate, a carbonate, a urea, an alkyl group, or a heteroalkyl group;

[0406] R 2 is an oligonucleotide sequence or a modified oligonucleotide;

[0407] Y 1 O, CH 2 , CH 2 O or optionally substituted NH;

[0408] Y 2 O, CH 2 , CH 2 O or optionally substituted NH;

[0409] Y 3 It’s CO, SO 2 、P(O)O、CH 2 -OC(O),CH 2 -NH-C(O), CH 2 -NH-SO 2 or CH 2 ;

[0410] Y 4 It’s CO, SO 2 、P(O)O、CH 2 -OC(O),CH 2 -NH-C(O), CH 2 -NH-SO 2 or CH 2 ;

[0411] n 2 is 0, 1, 2, 3, 4, 5, or 6; and

[0412] n 1 、n 3 、n 4 and n 5 Each independently is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0413] Embodiment 36. The compound of Embodiment 34, wherein the 5' nucleoside is selected from any one of Formulas I to VIII and XII, and wherein R' is S or SH, and R is a portion of the modified oligonucleotide other than the 5' nucleoside.

[0414] Embodiment 37. The compound of Embodiment 34, wherein the 5' nucleoside is selected from any one of Formulas I to VIII and XII, and wherein R' is O or OH, and R is a portion of the modified oligonucleotide other than the 5' nucleoside.

[0415] Embodiment 38. A compound comprising a first modified oligonucleotide having a nucleobase sequence selected from any one of the nucleobase sequences of SEQ ID NOs: 11 to 110; and a second modified oligonucleotide having a length of 14 to 21 linked nucleosides that is fully complementary to the first modified oligonucleotide.

[0416] Embodiment 39. A compound comprising: a first modified oligonucleotide having a nucleobase sequence selected from any one of:

[0417] Ref ID NO: IA0478-490, IA0840, IA0842-846, IA0852-862, IA0872-882, IA0887-890, IA1010-1012, and IA1015-1018

[0418] and a second modified oligonucleotide of 14 to 21 linked nucleosides in length that is fully complementary to the first modified oligonucleotide.

[0419] Embodiment 40. A compound comprising: a first modified oligonucleotide having a nucleobase sequence selected from any one of:

[0420] Ref ID NO: IA0478-490, IA0840, IA0842-846, IA0852-862, IA0872-882, IA0887-890, IA1010-1012, and IA1015-1018, and a second modified oligonucleotide having a nucleobase sequence selected from any one of:

[0421] Nucleobase sequences of Ref ID NO: IS0570-587, IS0969, IS0972-977, IS1023-1027, IS1029, IS1031-1037, IS1042-1046, IS1082, IS1085, IS1086, IS1091-1095, IS1108-1111, IS1236-1239, IS1242, IS1249 and IS1251-1254.

[0422] Embodiment 41. A compound comprising a first modified oligonucleotide having a nucleobase sequence selected from any one of the following: Ref ID NO: IA0840, IA0842, IA0888, IA1010-1012. and IA1016; and a second modified oligonucleotide having a nucleobase sequence selected from any one of the following:

[0423] Nucleobase sequences of Ref ID NO: IS0972, IS0974, IS1109, IS1236, IS1239, IS1242 and IS1252.

[0424] Embodiment 42. The compound of any one of Embodiments 1 to 41, wherein the compound is in the form of a pharmaceutically acceptable salt.

[0425] Embodiment 43. The compound of Embodiment 42, wherein the pharmaceutically acceptable salt is the sodium salt.

[0426] Embodiment 44. The compound of Embodiment 42, wherein the pharmaceutically acceptable salt is a potassium salt.

[0427] Embodiment 45. A modified oligonucleotide according to the following chemical structure:

[0428] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0429] Embodiment 46. A modified oligonucleotide according to the following chemical structure:

[0430] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0431] Embodiment 47. A modified oligonucleotide according to the following chemical structure:

[0432] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0433] Embodiment 48. A modified oligonucleotide according to the following chemical structure:

[0434] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0435] Embodiment 49. A modified oligonucleotide according to the following chemical structure:

[0436] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0437] Embodiment 50. A modified oligonucleotide according to the following chemical structure:

[0438] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0439] Embodiment 51. A modified oligonucleotide according to the following chemical structure:

[0440] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0441] Embodiment 52. A modified oligonucleotide according to the following chemical structure:

[0442] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0443] Embodiment 53. The modified oligonucleotide of any one of Embodiments 45 to 52, wherein the pharmaceutically acceptable salt is a sodium salt or a potassium salt.

[0444] Embodiment 54. The modified oligonucleotide of Embodiment 53, which is a sodium salt according to the following chemical structure:

[0445] or a stereoisomer thereof.

[0446] Embodiment 55. The modified oligonucleotide of Embodiment 53, which is a sodium salt according to the following chemical structure:

[0447] or a stereoisomer thereof.

[0448] Embodiment 56. The modified oligonucleotide of Embodiment 53, which is a sodium salt according to the following chemical structure:

[0449] or a stereoisomer thereof.

[0450] Embodiment 57. The modified oligonucleotide of Embodiment 53, which is a sodium salt according to the following chemical structure:

[0451] or a stereoisomer thereof.

[0452] Embodiment 58. The modified oligonucleotide of Embodiment 53, which is a sodium salt according to the following chemical structure:

[0453] or a stereoisomer thereof.

[0454] Embodiment 59. The modified oligonucleotide of Embodiment 53, which is a sodium salt according to the following chemical structure:

[0455] or a stereoisomer thereof.

[0456] Embodiment 60. The modified oligonucleotide of Embodiment 53, which is a sodium salt according to the following chemical structure:

[0457] or a stereoisomer thereof.

[0458] Embodiment 61. The modified oligonucleotide of Embodiment 53, which is a sodium salt according to the following chemical structure:

[0459] or a stereoisomer thereof.

[0460] Embodiment 62. A compound according to the following chemical structure:

[0461] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0462] Embodiment 63. A compound according to the following chemical structure:

[0463] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0464] Embodiment 64. A compound according to the following chemical structure:

[0465] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0466] Embodiment 65. A compound according to the following chemical structure:

[0467] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0468] Embodiment 66. The compound of any one of Embodiments 62 to 65, wherein the pharmaceutically acceptable salt is a sodium salt or a potassium salt.

[0469] Embodiment 67. The compound of Embodiment 66, which is a sodium salt according to the following chemical structure:

[0470] or a stereoisomer thereof.

[0471] Embodiment 68. The compound of Embodiment 66, which is a sodium salt according to the following chemical structure:

[0472] or a stereoisomer thereof.

[0473] Embodiment 69. The compound of Embodiment 66, which is a sodium salt according to the following chemical structure:

[0474] or a stereoisomer thereof.

[0475] Embodiment 70. The compound of Embodiment 66, which is a sodium salt according to the following chemical structure:

[0476] or a stereoisomer thereof.

[0477] Embodiment 71. A composition comprising the compound or modified oligonucleotide of any one of embodiments 1 to 70 and a pharmaceutically acceptable carrier.

[0478] Embodiment 72. A composition comprising a compound or modified oligonucleotide according to any one of the preceding embodiments for use in therapy.

[0479] Embodiment 73. A method of administering the compound or modified oligonucleotide of any one of embodiments 1 to 70 or the composition of embodiment 71 or 72 to a subject in need thereof.

[0480] Embodiment 74. A method for treating, preventing or ameliorating a disease, disorder or condition associated with complement factor B (CFB), comprising administering a compound or modified oligonucleotide targeting CFB to a subject in need thereof, thereby treating, preventing or ameliorating the disease, disorder or condition.

[0481] Embodiment 75. The method of Embodiment 74, wherein the disease, disorder or condition is a complement pathway disease.

[0482] Embodiment 76. The method of any one of Embodiments 73 to 75, wherein administration of the compound inhibits, alleviates and / or ameliorates the disease, disorder, condition, or symptoms thereof.

[0483] Embodiment 77. A method of inhibiting the expression of CFB in a cell, comprising contacting the cell with a compound or modified oligonucleotide targeting CFB, thereby inhibiting the expression of CFB in the cell.

[0484] Embodiment 78. The method of Embodiment 77, wherein the cell is in the liver of the individual.

[0485] Embodiment 79. The method of Embodiment 78, wherein the subject has or is at risk of having a complement pathway disease, disorder, condition, or a symptom thereof.

[0486] Embodiment 80. A method of reducing or inhibiting a complement pathway disease, disorder, condition, or a symptom thereof, comprising administering to a subject in need thereof a compound or modified oligonucleotide targeting CFB.

[0487] Embodiment 81. The method of Embodiment 80, wherein the subject has or is at risk of having a complement pathway disease, disorder or condition, or a symptom thereof.

[0488] Embodiment 82. The method of any one of Embodiments 74 to 81, wherein the disease, disorder or condition is atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), diabetic nephropathy, membranous nephropathy, polycystic kidney disease, age-related macular degeneration, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, or rheumatoid arthritis (RA).

[0489] Embodiment 83. The method of any one of Embodiments 74 to 82, wherein the disease, disorder or condition is lupus nephritis.

[0490] Embodiment 84. The method of any one of Embodiments 74 to 83, wherein the compound is a compound that targets CFB.

[0491] Embodiment 85. The method of any one of Embodiments 74 to 84, wherein the compound is a compound or a modified oligonucleotide of any one of Embodiments 1 to 70 or a composition of Embodiment 71 or 72.

[0492] Embodiment 86. The method of Embodiment 85, wherein the compound, modified oligonucleotide or composition is administered parenterally.

[0493] Embodiment 87. Use of a compound targeting CFB for treating, preventing or ameliorating a disease, disorder or condition associated with CFB, comprising administering a compound targeting CFB or a modified oligonucleotide to a subject in need thereof.

[0494] Embodiment 88. The use of Embodiment 87, wherein the disease is a complement pathway disease, disorder, condition, or a symptom thereof.

[0495] Embodiment 89. The use of embodiment 87 or 88, wherein the compound is a compound targeting CFB.

[0496] Embodiment 90. The use of any one of embodiments 87 to 89, wherein the compound is a compound or a modified oligonucleotide of any one of embodiments 1 to 70 or a composition of embodiment 71 or 72.

[0497] Embodiment 91. Use of a compound targeting CFB in the preparation of a medicament for treating, preventing or ameliorating a disease, disorder or condition associated with CFB.

[0498] Embodiment 92. The use of any one of Embodiments 87 to 91, wherein the disease is a complement pathway disease, disorder or condition, or a symptom thereof, atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), diabetic nephropathy, membranous nephropathy, polycystic kidney disease, age-related macular degeneration, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, or rheumatoid arthritis (RA).

[0499] Embodiment 93. The use of any one of Embodiments 87 to 92, wherein the disease, disorder or condition is lupus nephritis.

[0500] Embodiment 94. The use of any one of Embodiments 87 to 93, wherein the compound is a compound targeting CFB.

[0501] Embodiment 95. The use of any one of embodiments 87 to 94, wherein the compound is a compound or a modified oligonucleotide of any one of embodiments 1 to 70 or a composition of embodiment 71 or 72.

[0502] Embodiment 96. The method or use of any one of Embodiments 73 to 95, wherein the compound or composition is administered to the subject from about once every three months to about once a year.

[0503] Embodiment 97. The method or use of any one of Embodiments 73 to 96, wherein the compound or composition is administered to the subject about once every three months, about once every six months, or about once a year.

[0504] Example

[0505] The following examples describe methods for identifying lead compounds targeting CFB. Certain compounds were found to have high potency and tolerability.

[0506] The following examples are only used to illustrate the compounds described herein and are not intended to be limited thereto. The following examples and the associated sequence table attached to this document may identify the sequence as "RNA" or "DNA"; however, as disclosed herein, these sequences may be modified with any combination of chemical modifications. It will be readily understood by those skilled in the art that, in some cases, it is arbitrary to designate a sequence as "RNA" or "DNA". For example, an oligonucleotide comprising a nucleoside containing a 2'-OH sugar moiety and a thymine base may 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 the nucleic acid sequences 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.

[0507] Each reference cited in this application is hereby incorporated by reference in its entirety.

[0508] Table 1. Chemical nomenclature

[0509] abbreviation structure ‘m’ 2'-O-methyl sugar modifications (e.g., mA, mG, mC, mU) ‘f’ 2'-F sugar modifications (e.g., fA, fG, fC, fU) ‘*’ Phosphorothioate internucleoside linkages ‘.’ Phosphate internucleoside linkages 'dQ' Inverted abasic deoxyribose ‘H1’ Formula I ‘H2’ Formula II ‘H4” Formula III ‘H6” Formula IV ‘H7’ Formula V ‘H9’ Formula VI 'Hd' Formula VII 'HL' Formula VIII 'Hi' Formula XII

[0510] The newly designed double-stranded compounds in Tables 2 and 3 below are designed as unmodified (Table 2) and modified (Table 3) compounds. The abbreviations of the chemical modifications used in Table 3 are provided in Table 1 above. IA and IS in Ref ID NO: identify them as the antisense strand or sense strand of the compound, respectively. It should be understood that the sequence shown in each SEQ ID NO contained herein is independent of any modification to the sugar moiety, internucleoside linkage or nucleobase, even if it is displayed in the context of a modified compound. The oligomeric compound cited by the compound number or Ref ID NO represents a combination of nucleobase sequence and chemical modification. "Starting site" represents the most 5' end nucleotide (relative to the most 3' end nucleoside of the antisense oligonucleotide) targeted by the compound in the human gene sequence. "Termination site" represents the most 3' nucleotide targeted by the compound in the human gene sequence, which is relative to the most 5' nucleotide of the antisense oligonucleotide. Each compound listed in Tables 2 and 3 targets human CFB mRNA, and is named SEQ ID NO:1 (GENBANK Accession No.NM_001710.6) in this article.

[0511] Table 2

[0512] Unmodified antisense and sense sequences of double-stranded compounds targeting CFB

[0513]

[0514]

[0515]

[0516] Table 3

[0517] Modified antisense and sense sequences of double-stranded compounds targeting CFB

[0518]

[0519]

[0520]

[0521]

[0522] Example 1: Inhibition of CFB in HepG2 cells

[0523] HepG2 cells (ATCC Cat#HB-8065) ​​or Hepa 1-6 cells (ATCC CRL-1830) were seeded in antibiotic-free medium at 10,000 cells / well in 96-well plates. The next day, the test CFB compound was diluted to 1.0 μM (stock solution was 10 μM). The transfection mixture was prepared according to the instructions of Dharmafect 4 transfection reagent (Dharmacon Cat#T-2004-0). The prepared transfection mixture was incubated at room temperature for 20 minutes. During this incubation period, the culture medium in the 96-well plate was replaced with 80 μl antibiotic-free culture medium. Then 20 μl of transfection mixture was added to each well, and the final concentration was 10 nM to 1 nM (tested in triplicate). CFB siRNASMARTpool (Dharmacon Cat#L-005792-00-0005, 042586-00-0005) or Silencer Thermo Fisher (ID1966 or s533333) were used as positive controls. The cells were then incubated at 37°C with 5% CO 2 Incubate for 24 hours.

[0524] Cell lysis was performed according to the Cells-To-CT 1Step TaqMan kit instructions. After cell lysis, the 96-well plate was placed on ice while preparing the qRT-PCR reaction. 2 μl of cell lysate was added to a reaction mixture in a MicroAmp optical 96-well plate (0.2 mL), containing 5 μl of TaqMan 1-Step qRT-PCR mixture, 1 μl of CFB (FAM) TaqMan Gene Expression Assay (Hs00156060_m1 or Mm00433909_m1), 1 μl of GAPDH (VIC) TaqMan Gene Expression Assay (Hs02786624_g1 or Mm99999915_g1) and 11 μl of RT-PCR grade nuclease-free water. qPCR was performed using a QuantStudio3 qPCR machine under the following cycles: 50°C for 1 minute, 95°C for 20 seconds, and 40 cycles at 95°C for 15 seconds and 60°C for 1 minute. The results are presented in the table below as percent inhibition of CFB relative to untreated control cells (Table 4).

[0525] Table 4. Inhibition of CFB mRNA by double-stranded compounds targeting SEQ ID NO: 1

[0526]

[0527] Example 2: Effects of compounds targeting human CFB in mice

[0528] Evaluate the modified compounds RD1706, RD1707, RD1727, RD1708, RD1705 and RD1726 as in Table 3 in C57Bl / 6 mice.Before the study, mice were raised in the animal breeding house (vivarium) of IACUC approval placement.On the 0th day of the study, mice were injected with a single 5mg / kg subcutaneous dose of oligonucleotide.During the study period, the disease or painful signs of mice were observed every day.Blood was taken from animals at the 0th and 8th, 15th, 22nd, 29th and 35th days.

[0529] Immunoblotting was used to evaluate the level of complement factor B (CFB) in mouse (C57Bl / 6) serum. After serum collection, serum was diluted in 1×PBS buffer and mixed with SDS-PAGE compatible loading buffer and reducing agent. The samples were heated to 70°C for ten minutes and resolved by SDS-PAGE. After the samples were migrated by PAGE, the proteins were transferred to nitrocellulose or other compatible membranes. The membrane was stained with Revert 700 and the total protein of each sample was quantified using the Odyssey CLx detection system.

[0530] Use the membrane The cells were blocked with blocking buffer (P / N: 927-60001) and then probed with a primary antibody specific for CFB (Invitrogen #27924). After incubation of the membrane with the primary antibody, the membrane was washed and then probed with a secondary antibody (IgG P / N: 926-32211). The samples were diluted in antibody diluent (P / N: 927-75001). The membranes were then analyzed on the Odyssey CLx detection system to determine the level of CFB in each sample. The data for each sample was normalized to the total protein loaded into each lane, and CFB levels were quantified using Image Studio Lite. The CFB inhibition data in Table 5 are expressed as a percentage change relative to pre-dose levels.

[0531] Table 5. Average CFB Suppression

[0532]

[0533] Example 3: Effects of compounds targeting human CFB in mice

[0534] The modified compounds RD2401, RD2402, RD2403, RD2404, RD2405, RD2406, RD2407, RD2408 and RD2409 in Table 3 were evaluated in C57Bl / 6 mice. Before the study, mice were kept in an animal breeding facility approved by IACUC. On the 0th day of the study, mice were injected with a single 5mg / kg subcutaneous dose of oligonucleotide. During the study period, the disease or painful signs of mice were observed every day. Blood was taken from animals on the 0th, 8th, 15th, 22nd, 29th and 36th days. Immunoblotting was used to evaluate the level of complement factor B (CFB) in mouse (C57Bl / 6) serum, as described in Example 2. The CFB inhibition data in Table 6 are expressed as a percentage change relative to the pre-dose level.

[0535] Table 6. Average CFB Suppression

[0536]

[0537] Example 4: Effects of compounds targeting human CFB in mice

[0538] Evaluate the modified compounds RD2392, RD2393, RD2394, RD2395 and RD2396 as in Table 3 in C57Bl / 6 mice.Before the study, mice were housed in an animal breeding facility approved by IACUC.On the 0th day of the study, mice were injected with a single 5mg / kg subcutaneous dose of oligonucleotide.During the study period, mice were observed for signs of disease or pain every day.Blood was taken from animals on the 0th and 7th, 14th, 21st, 28th and 35th days.Immunoblotting was used to evaluate the level of complement factor B (CFB) in mouse (C57Bl / 6) serum, as described in Example 2.The CFB inhibition data in Table 7 are expressed as percentage changes relative to pre-dose levels.

[0539] Table 7. Average CFB Suppression

[0540]

[0541] Example 5: Effects of compounds targeting human CFB in mice

[0542] Evaluate the modified compounds RD1701, RD2501, RD2502, RD2503, RD2504, RD2505, RD2506, RD2507, RD2508, RD2509, RD2512, RD2518 and RD2519 in C57Bl / 6 mice.Before the study, mice were kept in an animal breeding house approved by IACUC.On the 0th day of the study, mice were injected with a single 5mg / kg subcutaneous dose of oligonucleotide.During the study period, the disease or painful signs of mice were observed every day.Blood was taken from animals on the 0th, 7th, 15th, 22nd, 28th and 35th days.The data of the 7th, 15th and 22nd days are as follows.Use immunoblotting to evaluate the level of complement factor B (CFB) in mouse (C57Bl / 6) serum, as described in Example 2.The CFB inhibition data in Table 8 are expressed as percentage changes relative to the pre-dose level.

[0543] Table 8. Average CFB Suppression

[0544]

[0545] Example 6: Effects of compounds targeting human CFB in rats

[0546] The modified compounds RD1709, RD1710, RD1711, RD1712 and RD1713 in Table 3 were evaluated in Sprague-Dawley or Lewis rats. Before the study, rats were kept in an animal breeding facility approved by IACUC. On the 0th day of the study, a single 5 mg / kg subcutaneous dose of oligonucleotide was injected into the rats. During the study period, the disease or painful signs of the rats were observed every day. Blood was taken from the animals at the 0th and 8th, 15th, 22nd, 29th and 36th days. The data of the 8th, 15th and 22nd days are as follows.

[0547] Immunoblotting was used to evaluate the level of complement factor B (CFB) in rat (Sprague-Dawley and Lewis) serum. After serum collection, serum was diluted in 1×PBS buffer and mixed with SDS-PAGE compatible loading buffer and reducing agent. The samples were heated to 70°C for ten minutes and resolved by SDS-PAGE. After the samples were migrated by PAGE, the proteins were transferred to nitrocellulose or other compatible membranes. The membrane was stained with Revert 700 and the total protein of each sample was quantified using the Odyssey CLx detection system.

[0548] Use the membrane The cells were blocked with blocking buffer (P / N: 927-60001) and then probed with a primary antibody specific for CFB (Invitrogen #27924). After incubation of the membrane with the primary antibody, the membrane was washed and then probed with a secondary antibody (IgG P / N: 926-32211). The samples were diluted in antibody diluent (P / N: 927-75001). The membranes were then analyzed on the Odyssey CLx detection system to determine the level of CFB in each sample. The data for each sample was normalized to the total protein loaded into each lane, and CFB levels were quantified using Image Studio Lite. The CFB inhibition data in Table 9 are expressed as a percentage change relative to pre-dose levels.

[0549] Table 9. Average CFB Suppression

[0550]

[0551] Example 7: Effects of compounds targeting human CFB in rats

[0552] The modified compounds RD1709, RD1710, RD1711 and RD1712 in Table 3 were evaluated in Sprague-Dawley or Lewis rats. Prior to the study, rats were housed in an animal breeding facility approved by IACUC. On day 0 of the study, rats were injected with a single 5 mg / kg subcutaneous dose of oligonucleotide. During the study period, rats were observed for signs of disease or pain every day. Blood was taken from animals on days 0 and 12. The data for day 12 are as follows. Immunoblotting was used to evaluate the level of complement factor B (CFB) in rat (Sprague-Dawley and Lewis) serum, as described in Example 6. The CFB inhibition data in Table 10 are expressed as percentage changes relative to pre-dose levels.

[0553] Table 10. Average CFB Suppression

[0554] Number of days Compound 12 RD1709 71 RD1710 62 RD1711 55 RD1712 60

[0555] Example 8: Effects of compounds targeting human CFB in rats

[0556] The modified compounds RD2380, RD2381, RD2382, RD2383, RD2384 and RD2385 in Table 3 were evaluated in Sprague-Dawley or Lewis rats. Prior to the study, rats were housed in an animal breeding facility approved by IACUC. On the 0th day of the study, rats were injected with a single 5 mg / kg subcutaneous dose of oligonucleotide. During the study period, rats were observed for signs of disease or pain every day. Blood was taken from animals on days 0, 4, 8, 15, 22, 29 and 36 in other groups. Immunoblotting was used to evaluate the level of complement factor B (CFB) in rat (Sprague-Dawley and Lewis) serum, as described in Example 6. The CFB inhibition data in Table 11 are expressed as percentage changes relative to pre-dose levels.

[0557] Table 11. Average CFB Suppression

[0558]

[0559] Example 9: Effects of compounds targeting human CFB in rats

[0560] The modified compounds RD1709, RD1711, RD2386, RD2388, RD2390, RD2391, RD2513 and RD2520 in Table 3 were evaluated in Sprague-Dawley or Lewis rats. Prior to the study, rats were housed in an animal breeding facility approved by IACUC. On the 0th day of the study, rats were injected with a single 5 mg / kg subcutaneous dose of oligonucleotide. During the study period, rats were observed for signs of disease or pain every day. Blood was taken from animals on the 0th, 4th, 8th, 15th, 22nd, 29th and 36th days. Immunoblotting was used to evaluate the level of complement factor B (CFB) in rat (Sprague-Dawley and Lewis) serum, as described in Example 6. The CFB inhibition data in Table 12 are expressed as percentage changes relative to pre-dose levels.

[0561] Table 12. Average CFB Suppression

[0562]

[0563]

[0564] Example 10: Effects of compounds targeting human CFB in cynomolgus monkeys

[0565] Evaluate the modified compounds RD2273, RD2275, RD2276, RD2277, RD2278, RD2279, RD2533 and RD2534 as in Table 3 in cynomolgus monkeys.Before the study, the monkeys were kept isolated and the general health of the animals was observed every day during the isolation period.On the 1st day of the study, eight groups of cynomolgus monkeys (2 in each group) were each injected with a single 6mg / kg subcutaneous dose of oligonucleotide.During the study period, the disease or painful signs of monkeys were observed every day.Blood was taken from animals on -6 days and the 1st day (before administration), the 8th day and the 15th, 22nd, 29th, 36th, 43rd, 50th, 57th and 64th days.

[0566] Abcam (ab137973) ELISA kit was used to determine CFB levels in cynomolgus monkey serum. The Abcam antibody has <5% cross-reactivity with monkey CFB. The protocol used was that described by the manufacturer. All reagents, standards, and samples were prepared as directed in the manual. Standards or samples were added to the wells and incubated at room temperature. The wells were washed and biotin antibody was added to each well and incubated at room temperature. After incubation, the wells were washed and streptavidin-peroxidase conjugate was added to the wells and incubated with the samples at room temperature. The chromogenic substrate was added to each well and incubated with the samples at room temperature. Stop solution was added to each well and used immediately. The plate was read by a plate reader. CFB inhibition data are expressed as percent change relative to pre-dose levels. Data for days 8, 15, 22, 29, 36, and 43 are shown in Table 13 below.

[0567] Table 13. Average CFB Inhibition (ELISA)

[0568]

[0569] Immunoblotting was also used to evaluate the level of complement factor B (CFB) in cynomolgus monkey serum. After serum collection, the serum was diluted in 1×PBS buffer and mixed with SDS-PAGE compatible loading buffer and reducing agent. The samples were heated to 70°C for ten minutes and resolved by SDS-PAGE. After the samples were migrated by PAGE, the proteins were transferred to nitrocellulose or other compatible membranes. The membrane was stained with Revert 700, and the total protein of each sample was quantified using the Odyssey CLx detection system.

[0570] Use the membrane The cells were blocked with blocking buffer (P / N: 927-60001) and then probed with a primary antibody specific for CFB (ProteinTech, Cat. No. 10170-1-AP). After incubation of the membrane with the primary antibody, the membrane was washed and then probed with a secondary antibody (IgG P / N: 926-32211). The antibody diluent (P / N:927-75001) was diluted. The membrane was then analyzed on the OdysseyCLx detection system to determine the level of CFB in each sample. The data of each sample were normalized relative to the total protein loaded into each lane, and Image Studio Lite was used to quantify the CFB level. CFB inhibition data are expressed as a percentage change relative to the pre-administration level. The data for the 8th, 15th, 22nd, 29th, 36th, 43rd, 50th, 57th and 64th days are shown in Table 14 below. In a second group of experiments, blood was taken from some animals for serum collection and analysis at the first 6 days and the 1st day (before administration), the 8th day and the 15th, 22nd, 29th, 36th, 43rd, 50th, 57th, 64th, 71st, 78th, 85th and 92nd days, and the data are shown in Table 15 below.

[0571] Table 14. Average CFB Suppression (Western)

[0572] Compound Day 8 Day 15 Day 22 Day 29 Day 36 Day 43 Day 50 Day 57 Day 64 RD2273 85 91 89 87 77 65 60 49 RD2275 86 91 92 91 90 86 77 71 RD2276 45 70 79 81 77 80 80 82 80 RD2533 47 72 80 75 79 75 71 73 68 RD2277 12 36 44 34 RD2278 44 47 59 53 RD2279 18 22 25 21 RD2534 46 58 60 60

[0573] Table 15. Average CFB Suppression (Western)

[0574]

[0575]

[0576] Example 11: Effects of compounds targeting human CFB in cynomolgus monkeys

[0577] Evaluate the modified compounds RD2557, RD2558, RD2559 and RD2560 as in Table 3 in cynomolgus monkeys.Before the study, the monkeys were kept in isolation, and the general health of the animals was observed every day during the isolation period.On the 1st day of the study, eight groups of cynomolgus monkeys (2 in each group) were each injected with a single 6mg / kg subcutaneous dose of oligonucleotide.During the study period, the disease or painful signs of the monkeys were observed every day.Blood was taken from the animals on the first 6 days and the 1st day (before administration), the 4th, 8th day and the 15th, 22nd, 29th, 36th, 43rd, 50th, 57th and 64th day.

[0578] ELISA was used to evaluate the levels of complement factor B (CFB) in cynomolgus monkey serum as described in Example 10. CFB inhibition data are expressed as percent change relative to pre-dose levels. Data for days 8, 15, 22, and 29 are shown in Table 16 below.

[0579] Table 16. Average CFB Inhibition (ELISA)

[0580]

[0581] Immunoblot was also used to evaluate the level of complement factor B (CFB) in cynomolgus monkey serum, as described in Example 10. CFB inhibition data are expressed as a percentage change relative to pre-dose levels. Data for days 8, 15, 22, 29, 36 and 43 are shown in Table 17 below. In a second set of experiments, blood was taken from certain animals at the first 6 days and day 1 (before dosing), day 4, 8 and day 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, 85 and 92 for serum collection and analysis, and the data are shown in Table 18 below.

[0582] Table 17. Average CFB Suppression (Western)

[0583] Compound Day 8 Day 15 Day 22 Day 29 Day 36 Day 43 RD2557 51 68 72 80 80 61 RD2558 83 92 89 88 87 81

[0584] Compound Day 8 Day 15 Day 22 Day 29 Day 36 Day 43 RD2559 0 5 22 18 13 0 RD2560 55 84 89 85 84 76

[0585] Table 18. Average CFB Suppression (Western)

[0586]

[0587] Example 12: Effects of compounds targeting human CFB in cynomolgus monkeys

[0588] Evaluate the modified compounds RD1714, RD1715 and RD2262 as in Table 3 in cynomolgus monkeys.Before the study, the monkeys were kept in isolation, and the general health of the animals was observed every day during the isolation period.On the 1st day of the study, eight groups of cynomolgus monkeys (2 in each group) were each injected with a single 3mg / kg or 6mg / kg subcutaneous dose of oligonucleotide.During the study period, the disease or painful signs of the monkeys were observed every day.Blood was taken from the animals on days -6 and 1 (before administration), 8th, 15th, 22nd, 29th, 36th, 43rd, 50th, 57th and 64th.ELISA was used to evaluate the level of complement factor B (CFB) in cynomolgus monkey serum, as described in Example 10.CFB inhibition data are expressed as a percentage change relative to pre-administration levels.Immunoblotting was also used to evaluate the level of complement factor B (CFB) in cynomolgus monkey serum, as described in Example 10.The ELISA data of days 8, 15th, 22nd, 29th and 36th are shown in Table 19 below.

[0589] Table 19. Average CFB Inhibition (ELISA)

[0590]

[0591] Example 13: Effects of compounds targeting human CFB in complement pathway assays

[0592] The level of active C5b-9 formation was determined using the Wieslab complement alternative pathway assay (COMPL AP330 RUO, SVAR) and the Wieslab complement classical pathway assay (COMPL CL310 RUO, SVAR) according to the manufacturer's instructions to assess alternative complement pathway activity and classical complement pathway activity. The serum from monkeys administered with RD2273, RD2275 and RD2276 of Example 10 was tested, and the data from the Wieslab complement alternative pathway assay are shown in Table 20 below. The Wieslab complement classical pathway assay showed no effect, as expected. The serum from monkeys administered with RD2558 and RD2560 of Example 11 was also tested, and the data from the Wieslab complement alternative pathway assay are shown in Table 21 below. The Wieslab complement classical pathway assay showed no effect, as expected. In a separate study, sera from monkeys dosed with RD2558 and RD256 of Example 11 were tested, and the data from the Wieslab complement alternative pathway assay are shown in Table 22 below. The Wieslab complement classical pathway assay showed no effect, as expected. Sera from monkeys dosed with RD2558 and RD2560 of Example 11 were also tested in the hemolytic assay to determine alternative hemolytic activity, and the data are shown in Table 23.

[0593] The alternative hemolytic activity was determined as follows. NHP serum (5.6%) was added to 5mM EGTA and GVB° (Complement Technology, Tyler, Texas) in the presence of 25% rabbit erythrocytes (Er, Complement Technology, Tyler, Texas). The samples were incubated at 37°C with intermittent shaking for 1 hour. Hemolysis was terminated by adding GVBE (Complement Technology, Tyler, Texas) to the samples at a ratio of 1:1. The samples were then centrifuged and the supernatant was transferred to a new 96-well plate. The absorbance was measured at 412nm. The alternative hemolytic activity was measured by subtracting the OD value of the negative control sample (buffer and Er only) and normalizing each sample to the positive control sample (water and Er only). The single time point samples were then normalized to their average pre-dose samples.

[0594] Table 20. % Inhibition of Alternative Pathways

[0595] Compound Day 22 Day 29 Day 36 Day 43 Day 50 Day 57 Day 64 RD2273 88 91 88 66 49 9 3 RD2275 86 89 82 84 74 48 48 RD2276 44 53 59 55 49 46

[0596] Table 21. % Inhibition of Alternative Pathways

[0597] Compound Day 8 Day 15 Day 22 Day 36 Day 43 RD2558 80 96 93 88 32 RD2560 30 72 80 64 26

[0598] Table 22. % Inhibition of Alternative Pathways

[0599]

[0600] Table 23. % Inhibition of Alternative Pathway Hemolysis

[0601]

[0602] Example 14: Effects of compounds targeting human CFB in cynomolgus monkeys

[0603] Compounds RD2794, RD2795 and RD2796 were designed using the parent compound RD2558 as a starting point, as shown in Tables 24 and 25 below. The modified compounds shown in Table 25 were evaluated in cynomolgus monkeys. Monkeys were administered with a 4 mg / kg subcutaneous dose of oligonucleotides according to the protocol in Example 10 on Day 1 of the study. ELISA will be used to evaluate the level of complement factor B (CFB) in cynomolgus monkey serum, as described in Example 10. Immunoblot will also be used to evaluate the level of complement factor B (CFB) in cynomolgus monkey serum, as described in Example 10. CFB inhibition data are expressed as a percentage change relative to pre-dose levels. Data for days 4, 8, 15, 22, 29 and 36 are shown in Table 26 below. In a second set of experiments, CFB inhibition data were collected for RD2795 and RD2796 at days 4, 8, 15, 22, 29, 36, 43, 50, 57 and 64, and additionally for RD2794 at days 71, 78, 85 and 96, as shown in Table 27 below. Inhibition of alternative complement pathway activity was assessed using the WIESLAB assay (COMPLAP330) following the manufacturer's recommended protocol, as described above. The data are shown in Table 28 below. Inhibition of alternative hemolysis was assessed using 5.6% serum, 25% Er (Complement Technologies, Inc.) and buffer GVB°+MgEDTA, as described above. The data are shown in Table 29 below. The assay for the classical pathway showed no effect, as expected (not shown).

[0604] Table 24

[0605] Unmodified antisense and sense sequences of double-stranded compounds targeting CFB

[0606]

[0607] Table 25

[0608] Modified antisense and sense sequences of double-stranded compounds targeting CFB

[0609]

[0610] Table 26. Average CFB Suppression (Western)

[0611] Compound Day 4 Day 8 Day 15 Day 22 Day 29 Day 36 RD2794 31 67 87 89 89 81 RD2795 36 72 89 91 93 88 RD2796 31 70 82 82 79 65

[0612] Table 27. Average CFB Suppression (Western)

[0613]

[0614] Table 28. Average Alternative Pathway Inhibition (WIESLAB COMPL AP330)

[0615]

[0616] Table 29. Mean surrogate hemolysis inhibition

[0617]

[0618] Example 15: Effects of compounds targeting human CFB in cynomolgus monkeys

[0619] The parent compounds RD2273, RD2275, RD2558, RD2560 and RD2276 were used as starting points to design compounds RD2797, RD2829, RD2798, RD2801, RD2830, RD2821, RD2831 and RD2832, as shown in Tables 30 and 31 below. The modified compounds shown in Table 31 were evaluated in cynomolgus monkeys. Monkeys were dosed with a 4 mg / kg subcutaneous dose of the oligonucleotides on day 1 of the study according to the protocol in Example 10. ELISA will be used to evaluate the levels of complement factor B (CFB) in cynomolgus monkey serum, as described in Example 10. Immunoblot will also be used to evaluate the levels of complement factor B (CFB) in cynomolgus monkey serum, as described in Example 10. CFB inhibition data are expressed as a percentage change relative to pre-dose levels. Data for RD2798, RD2801, RD2821, RD2830, and RD2832 at 8, 15, 22, and 29 days are shown in Table 32 below. In a second set of experiments, CFB inhibition data for RD2821 and RD2832 at 8, 15, 22, 29, 36, 43, 50, 57, and 64 days were collected, and additionally CFB inhibition data for RD2798 and RD2801 at 71, 78, and 85 days, and additionally CFB inhibition data for RD2830 at 96 days were collected, as shown in Table 33 below. In a third set of experiments, CFB inhibition data for RD2797, RD2829, and RD2831 at 8, 15, 22, 29, 36, 43, 50, 57, 64, and 71 days were collected, as shown in Table 34 below. The inhibition of alternative complement pathway activity was evaluated using the WIESLAB assay (COMPL AP330) following the manufacturer's recommended protocol, as shown above. The data are shown in Table 35 below. The inhibition of alternative hemolysis was evaluated using 5.6% serum, 25% Er (Complement Technologies, Inc.) and buffer GVB + MgEDTA, as shown above. The data are shown in Table 36 below.

[0620] Table 30

[0621] Unmodified antisense and sense sequences of double-stranded compounds targeting CFB

[0622]

[0623]

[0624] Table 31

[0625] Modified antisense and sense sequences of double-stranded compounds targeting CFB

[0626]

[0627] Table 32. Average CFB Suppression (Western)

[0628] Compound Day 8 Day 15 Day 22 Day 29 RD2798 72 82 92 81 RD2801 73 82 89 86 RD2821 68 64 62 47 RD2830 64 81 89 85 RD2832 40 48 71 60

[0629] Table 33. Average CFB Suppression (Western)

[0630]

[0631] Table 34. Average CFB Suppression (Western)

[0632]

[0633] Table 35. Average Alternative Pathway Inhibition (WIESLAB COMPL AP330)

[0634]

[0635] Table 36. Mean surrogate hemolysis inhibition

[0636]

[0637] Example 16: Effects of compounds targeting human CFB in Sprague Dawley rats

[0638] Sprague Dawley rats (3 / sex / main group (Groups 1 to 5), 1 / sex / toxicokinetic group (Groups 6 to 9)), 8 to 9 weeks old) were administered vehicle control (Group 1) or 30, 60, 150 or 300 mg / kg / dose RD2830 (Groups 2 and 6, 3 and 7, 4 and 8, or 5 and 9, respectively) by SC injection at a dosing volume of 5 mL / kg on Days 1 and 21.

[0639] Observations included cage-side observations (general signs of toxicity, including feces and urine quality), physical examination (pre-dose), body weights (Days 1, 5, 8, 12, 15, 19, 21 (toxicokinetics), and Day 26 (primary)), and quantified food intake (weekly). Blood samples were collected on Day 26 for clinical biochemistry, hematology, and coagulation. Termination was on Day 26. Necropsy included visual inspection for external abnormalities, abdominal, thoracic, and cranial cavities. Organ weights were recorded (heart, kidney, liver, spleen, and thymus). Histology and microscopic pathology were performed (heart, kidney, lesions, liver, lung, lymph nodes, injection sites, skin, spleen, and thymus).

[0640] RD2830 administered as a single SC dose on days 1 and 21 at 30, 60, 150 and 300 mg / kg / dose was considered generally tolerated by male and female rats.

[0641] SEQ ID NO: 1

[0642]

[0643] Although the disclosure has been described with reference to the above embodiments, it will be understood that modifications and variations are encompassed within the spirit and scope of the disclosure and are covered by the following claims.

Claims

1. A compound comprising a modified oligonucleotide of 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, or at least 20 consecutive nucleobases of any of the nucleobase sequences of SEQ ID NOs: 11 to 44 or 96 to 102.

2. A compound comprising a modified oligonucleotide of 14 to 23 linked nucleosides in length having a nucleobase sequence comprising any one of SEQ ID NOs: 11 to 44 or 96 to 102.

3. A compound comprising a modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 11 to 44 and 96 to 102.

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

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

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

7. A compound comprising: a first modified oligonucleotide of 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, or at least 20 consecutive nucleobases of any of the nucleobase sequences of SEQ ID NOs: 11 to 110; and a second modified oligonucleotide of 14 to 23 linked nucleosides in length having a region complementary to the first modified oligonucleotide.

8. A compound comprising: a first modified oligonucleotide of 14 to 23 linked nucleosides in length having a nucleobase sequence comprising any one of SEQ ID NOs: 11 to 110; and a second modified oligonucleotide of 14 to 23 linked nucleosides in length having a region complementary to the first modified oligonucleotide.

9. A compound comprising: a first modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 11 to 110; and a second modified oligonucleotide having a length of 19 to 23 linked nucleosides having a region complementary to the first modified oligonucleotide.

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

11. The compound of any one of claims 7 to 10, wherein the region of the core base sequence of the first modified oligonucleotide and the core base sequence of SEQ ID NO:1 or 3 has at least 1, at least 2, or at least 3 mismatches, and the region is the same length as the first modified oligonucleotide.

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

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

17. The compound of any one of claims 7 to 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 or 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 modified oligonucleotide or the second modified oligonucleotide or at the 5' end of the first modified oligonucleotide.

20. The compound of any one of claims 5, 16 or 17, wherein the modified sugar comprises a modification selected from the group consisting of a halogen, an alkoxy group, and a 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. The compound of any one of claims 7 to 15, wherein each nucleoside of the first modified oligonucleotide comprises a modified sugar.

24. The compound of any one of claims 7 to 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 a halogen, an alkoxy group, and a 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 preceding claim 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 groups 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 is 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 transamide, a carbamate, a carbonate, a urea, an alkyl group, or a heteroalkyl group; R 2 is an oligonucleotide sequence or a modified oligonucleotide; 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 n1, n3, n4 and n5 are each 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 Formulas I to VIII and XII, and wherein R' is S or SH, and R is a moiety 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 Formulas I to VIII and XII, and wherein R' is O or OH, and R is a portion of the modified oligonucleotide other than the 5' nucleoside.

38. A compound comprising a first modified oligonucleotide having any one of the nucleobase sequences selected from SEQ ID NOs: 11 to 110; and a second modified oligonucleotide having a length of 14 to 21 linked nucleosides having a portion that is fully complementary to the first modified oligonucleotide.

39. A compound comprising: a first modified oligonucleotide selected from any one of the following: Ref ID NO: IA0478-490 ， IA0840, IA0842-846, IA0852-862, IA0872-882, IA0887-890, IA1010-1012, and IA1015-1018; and a second modified oligonucleotide of 14 to 21 linked nucleosides in length that is fully complementary to the first modified oligonucleotide.

40. A compound comprising: a first modified oligonucleotide selected from any one of: Ref ID NO: IA0478-490, IA0840, IA0842-846, IA0852-862, IA0872-882, IA0887-890, IA1010-1012, and IA1015-1018, and a second modified oligonucleotide selected from any one of: Ref ID NO: IS0570-587, IS0969, IS0972-977, IS1023-1027, IS1029, IS1031-1037, IS1042-1046, IS10 82, IS1085, IS1086, IS1091-1095, ISI108-1111, IS1236-1239, IS1242.IS1249, and IS1251-1254.

41. A compound comprising: a first modified oligonucleotide selected from any one of the following: Ref ID NO: IA0840, IA0842, IA0888, IA1010-1012, and IA1016, and a second modified oligonucleotide selected from any one of the following: Ref ID NO: IS0972, IS0974, IS1109, IS1236, ISI239, ISI242 and IS1252.

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

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

44. The compound of claim 42, wherein the pharmaceutically acceptable salt is a potassium salt.

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

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

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

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

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

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

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

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

53. The modified oligonucleotide of any one of claims 45 to 52, wherein the pharmaceutically acceptable salt is a sodium salt or a potassium salt.

54. The modified oligonucleotide of claim 53, which is a sodium salt according to the following chemical structure: or a stereoisomer thereof.

55. The modified oligonucleotide of claim 53, which is a sodium salt according to the following chemical structure: or a stereoisomer thereof.

56. The modified oligonucleotide of claim 53, which is a sodium salt according to the following chemical structure: or a stereoisomer thereof.

57. The modified oligonucleotide of claim 53, which is a sodium salt according to the following chemical structure: or a stereoisomer thereof.

58. The modified oligonucleotide of claim 53, which is a sodium salt according to the following chemical structure: or a stereoisomer thereof.

59. The modified oligonucleotide of claim 53, which is a sodium salt according to the following chemical structure: or a stereoisomer thereof.

60. The modified oligonucleotide of claim 53, which is a sodium salt according to the following chemical structure: or a stereoisomer thereof.

61. The modified oligonucleotide of claim 53, which is a sodium salt according to the following chemical structure: or a stereoisomer thereof.

62. Compounds according to the following chemical structures: or a pharmaceutically acceptable salt or stereoisomer thereof.

63. Compounds according to the following chemical structures: or a pharmaceutically acceptable salt or stereoisomer thereof.

64. Compounds according to the following chemical structures: or a pharmaceutically acceptable salt or stereoisomer thereof.

65. Compounds according to the following chemical structures: or a pharmaceutically acceptable salt or stereoisomer thereof.

66. The compound of any one of claims 62 to 65, wherein the pharmaceutically acceptable salt is a sodium salt or a potassium salt.

67. The compound of claim 66 which is a sodium salt according to the following chemical structure: or a stereoisomer thereof.

68. The compound of claim 66 which is a sodium salt according to the following chemical structure: or a stereoisomer thereof.

69. The compound of claim 66 which is a sodium salt according to the following chemical structure: or a stereoisomer thereof.

70. The compound of claim 66 which is a sodium salt according to the following chemical structure: or a stereoisomer thereof.

71. A composition comprising the compound or modified oligonucleotide of any one of claims 1 to 70 and a pharmaceutically acceptable carrier.

72. A composition comprising a compound or modified oligonucleotide as claimed in any preceding claim for use in therapy.

73. A method of administering a compound or modified oligonucleotide according to any one of claims 1 to 70 or a composition according to claim 71 or 72 to a subject in need thereof.

74. A method for treating, preventing or ameliorating a disease, disorder or condition associated with complement factor B (CFB), comprising administering to a subject in need thereof a compound or modified oligonucleotide targeting CFB, thereby treating, preventing or ameliorating the disease, disorder or condition.

75. The method of claim 74, wherein the disease, disorder or condition is a complement pathway disease.

76. The method of any one of claims 73 to 75, wherein administration of the compound inhibits, alleviates and / or ameliorates the disease, disorder, condition, or symptoms thereof.

77. A method for inhibiting the expression of CFB in a cell, comprising contacting the cell with a compound or modified oligonucleotide targeting CFB, thereby inhibiting the expression of CFB in the cell.

78. The method of claim 77, wherein the cell is in the liver of the individual.

79. The method of claim 78, wherein the subject has or is at risk of having a complement pathway disease, disorder, condition, or a symptom thereof.

80. A method of reducing or inhibiting a complement pathway disease, disorder, condition, or symptom thereof, comprising administering to a subject in need thereof a compound or modified oligonucleotide targeting CFB.

81. The method of claim 80, wherein the subject has or is at risk of having a complement pathway disease, disorder or condition, or a symptom thereof.

82. The method of any one of claims 74 to 81, wherein the disease, disorder or condition is atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), diabetic nephropathy, membranous nephropathy, polycystic kidney disease, age-related macular degeneration, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, or rheumatoid arthritis (RA).

83. The method of any one of claims 74 to 82, wherein the disease, disorder or condition is lupus nephritis.

84. The method of any one of claims 74 to 83, wherein the compound is a compound that targets CFB.

85. The method of any one of claims 74 to 84, wherein the compound is a compound or modified oligonucleotide of any one of claims 1 to 70 or a composition of claim 71 or 72.

86. The method of claim 85, wherein the compound, modified oligonucleotide or composition is administered parenterally.

87. Use of a compound targeting CFB for treating, preventing or ameliorating a disease, disorder or condition associated with CFB, comprising administering a compound targeting CFB or a modified oligonucleotide to a subject in need thereof.

88. The use of claim 87, wherein the disease is a complement pathway disease, disorder, condition, or a symptom thereof.

89. The use of claim 87 or 88, wherein the compound is a compound targeting CFB.

90. The use of any one of claims 87 to 89, wherein the compound is a compound or modified oligonucleotide as described in any one of claims 1 to 70 or a composition as described in claim 71 or 72.

91. Use of a compound targeting CFB in the preparation of a medicament for treating, preventing or ameliorating a disease, disorder or condition associated with CFB.

92. The use of any one of claims 87 to 91, wherein the disease is a complement pathway disease, disorder or condition, or a symptom thereof, atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), diabetic nephropathy, membranous nephropathy, polycystic kidney disease, age-related macular degeneration, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, or rheumatoid arthritis (RA).

93. The use of any one of claims 87 to 92, wherein the disease, disorder or condition is lupus nephritis.

94. The use of any one of claims 87 to 93, wherein the compound is a compound that targets CFB.

95. The use of any one of claims 87 to 94, wherein the compound is a compound or modified oligonucleotide as described in any one of claims 1 to 70 or a composition as described in claim 71 or 72.

96. The method or use of any one of claims 73 to 95, wherein the compound or composition is administered to the subject from about once every three months to about once a year.

97. The method or use of any one of claims 73 to 96, wherein the compound or composition is administered to the subject about once every three months, about once every six months, or about once a year.

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