COMPOSITIONS THAT MODULATE COMPLEMENT FACTOR B AND METHODS OF USE THEREOF - Patent application

Abstract

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 can be used to reduce the expression of CFB mRNA in a cell or animal. In certain aspects, the compounds, compositions and methods of the present disclosure can be used to reduce the expression of CFB protein in a cell or animal. In certain embodiments, the animal has or is at risk for a complement pathway-related disease, disorder or condition, or a symptom thereof.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 63 / 283,177, filed November 24, 2021, U.S. Provisional Application No. 63 / 287,952, filed December 9, 2021, U.S. Provisional Application No. 63 / 302,976, filed January 25, 2022, and U.S. Provisional Application No. 63 / 339,873, filed May 9, 2022. The disclosures of each of these prior applications are deemed to be part of the disclosure of this application and are incorporated by reference in their entirety into the disclosure of this application.

[0002] Reference to Electronic Sequence Listing The contents of the electronic format of the sequence listing (A127870010WO00-SEQ-JIB.xml, size: 111,161 bytes, created on: November 22, 2022) are incorporated herein by reference in their entirety. [Background technology]

[0003] Complement factor B (CFB) is a key component of the alternative complement pathway. CFB is a serine protease secreted by the liver. It circulates in the blood as a single polypeptide chain. Upon activation of the alternative pathway, CFB is cleaved by complement factor D into the noncatalytic chain Ba and the catalytic subunit Bb. The active subunit Bb is a serine protease that combines with C3b to form the alternative pathway C3 convertase. Generation of C3 convertase leads to the formation of C5 convertase, which cleaves C5 and triggers events that lead to the formation of the lytic membrane attack complex (MAC). This membrane attack complex forms a transmembrane channel and disrupts the phospholipid bilayer of the target cell, resulting in cell lysis.

[0004] Inappropriate complement activation contributes to many different diseases, including atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), including lupus nephritis, diabetic nephropathy, membranous nephropathy, polycystic kidney disease, age-related macular degeneration, thrombotic microangiopathy, myasthenia gravis, ischemia-reperfusion injury, and rheumatoid arthritis (RA). Thus, there is a need to find effective treatments for complement-related diseases. Summary of the Invention

[0005] The present disclosure provides compounds, compositions and methods for modulating 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 a cell or animal. In certain embodiments, the compounds, compositions and methods can be used to reduce the amount of CFB protein in a cell or animal.

[0006] In certain embodiments, the animal has or is at risk of having 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 are directed to reducing tissue damage, such as ophthalmic or renal damage, associated with dysregulation of the complement pathway. Certain compounds, compositions and methods provided herein are for alleviating 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, the compounds and compositions provided herein are potent and tolerable, inhibit the expression of CFB, and can be used to treat, prevent or ameliorate, or slow the progression of, tissue damage associated with dysregulation of the complement pathway, such as eye or kidney damage. In certain embodiments, the compounds and compositions provided herein are potent and tolerable and inhibit expression of CFB and 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), including lupus nephritis, diabetic nephropathy, membranous nephropathy, polycystic kidney disease, age-related macular degeneration, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, or rheumatoid arthritis (RA).

[0007] In certain embodiments, the compounds and compositions include one or more features that are effective for enhancing efficacy. In certain embodiments, the compounds and compositions include one or more features that are effective for enhancing tolerability. In certain embodiments, the compounds and compositions include one or more features that are effective for targeting the compound or composition to a cell or tissue. In certain embodiments, the compounds and compositions are more potent or therapeutically significant than publicly disclosed compounds. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the embodiments as claimed. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0009] Any 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 records for sequence references, are expressly incorporated herein by reference in their entirety and in part as of the filing date of this application.

[0010] It is understood that the sequence set forth in each SEQ ID NO contained herein is independent of any modifications to the sugar moiety, internucleoside linkage, or nucleobase, even when presented in terms of modified compounds. Thus, a compound defined by a SEQ ID NO may independently contain one or more modifications to the sugar moiety, internucleoside linkage, or nucleobase. Oligomeric compounds referenced by compound number or reference ID number represent a combination of nucleobase sequence, chemical modifications, and motifs.

[0011] In this specification, the use of the singular includes the plural unless specifically stated otherwise. For example, the articles "a" and "an" are used herein to refer to one or more than one (i.e., at least one) of the grammatical object of the article. For example, an "element" with "an" means one element or more than one element, e.g., a plurality of elements. As used herein, the use of "or" means "and / or" unless specifically stated otherwise. In addition, the use of the term "including" and other forms, such as "includes" and "included," is not limiting and is used synonymously with the phrase "including, but not limited to."

[0012] definition Unless otherwise indicated, the following terms have the following meanings.

[0013] "Complement factor B" is used interchangeably with the term "CFB" and refers to either the 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 31946095-31952084 (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 3423522-3429511 (incorporated herein as SEQ ID NO:4). Additional examples of sequences of CFB are readily available through publicly available databases, such as GenBank, UniProt, and OMIM. Further information on CFB can be found, for example, at https: / / www.ncbi.nlm.nih.gov / gene / ?term=CFB. As used herein, CFB also refers to the diversity of the CFB gene, including variants shown in SNP databases. Numerous sequence variations within 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" refers to the mRNA that codes for the CFB protein. CFB can refer to any of the above cases or the following cases.

[0014] "CFB specific inhibitors" refers to any agent capable of specifically inhibiting 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 capable of inhibiting the expression of CFB RNA and / or CFB protein.

[0015] "2'-O-Methoxyethyl" or "2'-MOE" refers to the modification 2'-O(CH2)2-OCH3. A 2'-O-methoxyethyl modified sugar is a modified sugar that has a 2'-O(CH2)2-OCH3 in place of the 2'-OH group of the ribosyl ring.

[0016] "5' start site" refers to the nucleotide of a target nucleic acid or target region that is complementary to the 3'-most nucleoside of an antisense oligonucleotide.

[0017] The term "3' termination site" refers to the nucleotide that is complementary to the 5'-most nucleoside of an antisense oligonucleotide among the nucleotides of a target nucleic acid or a target region.

[0018] "About" means within ±10% of a value. For example, if it is stated that "the compound inhibited CFB by about 70%," it suggests that the CFB level is inhibited within a range of 60% to 80%. When about is before a series of numbers or ranges, it is understood that "about" can modify each of the series of numbers or ranges.

[0019] "Administer" or "administering" refers to a route by which a compound or composition provided herein is introduced into an individual to perform its intended function. Examples of administration routes that can be used include, but are not limited to, parenteral administration, such as subcutaneous, intravenous or intramuscular injection or infusion.

[0020] "Ameliorate" refers to the improvement or reduction of at least one of the indicators, signs or symptoms of the relevant disease, disorder or condition. In certain embodiments, improvement includes the delay or slowing down of the progression or severity of one or more indicators of the condition or disease. The progression or severity of an indicator may be determined by subjective or objective measures, which are known to those skilled in the art.

[0021] "Animal" refers to a human or non-human animal, including, but not limited to, mice, rats, rabbits, dogs, cats, pigs and non-human primates, including, but not limited to, monkeys and chimpanzees.

[0022] By "antisense oligonucleotide" or "antisense strand" is meant an oligonucleotide that contains a region that is complementary to a target nucleic acid, e.g., CFB RNA, or a region thereof.

[0023] "Complementary" refers to a nucleobase sequence that is complementary to one or more nucleobase sequences of another oligonucleotide or nucleic acid or region thereof when the nucleobase sequence of the oligonucleotide or region is aligned in the opposite direction to the other oligonucleotide or nucleic acid or region thereof. Complementary nucleobases as described herein are limited to the combinations of adenine (A) and thymine (T), adenine (A) and uracil (U), and cytosine (C) and guanine (G), unless otherwise indicated. Complementary oligonucleotides and / or nucleic acids need not have nucleobase complementarity at each nucleoside and may contain one or more nucleobase mismatches. In contrast, "fully complementary" or "100% complementary" refers to an oligonucleotide in which there is a nucleobase match at each nucleoside and no nucleobase mismatches.

[0024] "Composition" or "pharmaceutical composition" refers to 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.

[0025] "Co-administration" means administering two or more compounds in any manner such that both pharmacological actions of the compounds are experienced in a patient. Co-administration does not require that both compounds be administered in one pharmaceutical composition, in the same dosage form, by the same route of administration, or at the same time. The actions of both compounds need not be experienced simultaneously. Their actions need only overlap over a period of time, but not for an extended period of time. Co-administration includes concurrent or sequential administration of one or more compounds.

[0026] "Conjugate group" refers to a group of atoms attached to an oligonucleotide. The conjugate group is optionally attached to the oligonucleotide via a conjugate linker. The conjugate group may, for example, change the distribution, targeting or half-life of the compound in which it is incorporated. The conjugate group includes a targeting moiety.

[0027] "Conjugate linker" means a group of atoms that includes at least one bond that connects a linking moiety to an oligonucleotide.

[0028] "Identity" refers to, in relation to an oligonucleotide, the nucleic acid base sequence of one or more of the nucleic acid bases of the oligonucleotide or its region that matches the nucleic acid base sequence of another oligonucleotide or nucleic acid or its region. The identity of an oligonucleotide to another oligonucleotide or nucleic acid does not necessarily have to match each nucleic acid base, but may include one or more different nucleic acid bases. In contrast, "completely identical" or "100% identity" refers to, in relation to an oligonucleotide, that the oligonucleotide has the same nucleic acid bases as the other oligonucleotide or nucleic acid at each corresponding position and over its length.

[0029] "Individual" means a human or non-human animal selected to be the subject of treatment or therapy.

[0030] "Inhibiting expression or activity," with respect to a target nucleic acid or target protein, means reducing or blocking the expression or activity of the target relative to the expression or activity in an untreated or control sample, and does not necessarily indicate a complete abolition of expression or activity.

[0031] As used herein, the term "internucleoside bond" refers to the covalent bond between adjacent nucleosides in an oligonucleotide.As used herein, "modified internucleoside bond" refers to any internucleoside bond other than phosphodiester internucleoside bond."Phosphorothioate internucleoside bond" refers to the modified internucleoside bond in which one of the non-bridging oxygen atoms of phosphodiester internucleoside bond is replaced with a sulfur atom.

[0032] Representative internucleoside linkages with chiral centers include, but are not limited to, alkylphosphonates and phosphorothioates.Modified oligonucleotides containing internucleoside linkages with chiral centers can be prepared as a population of modified oligonucleotides containing stereorandom internucleoside linkages or as a population of modified oligonucleotides containing phosphorothioate linkages of specific stereochemical configuration, as described further below.Unless otherwise indicated, the chiral internucleoside linkages of the modified oligonucleotides described herein can be stereorandom or of specific stereochemical configuration.

[0033] The compounds of the present disclosure may contain proportions of atomic isotopes not found in nature at one or more of the atoms that constitute such compounds. For example, the compounds may contain radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I) or carbon-14( 14 C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure.

[0034] The term "isotopic variant" refers to a therapeutic agent (e.g., a compound and / or modified oligonucleotide disclosed herein) that contains a proportion of an isotope not found in nature at one or more of the atoms that constitute such therapeutic agent. In certain embodiments, an "isotopic variant" of a therapeutic agent contains one or more isotopes not found in nature, including 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( 131In certain embodiments, an "isotopic variant" of a therapeutic agent includes one or more isotopes in a ratio not found in nature, 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) are included, but are not limited to these.

[0035] For example, where feasible according to the judgment of one of skill in the art, in a therapeutic agent (e.g., a compound and / or modified oligonucleotide disclosed herein), any hydrogen may be, e.g., 2H or any carbon can be, e.g. 13 C, or any nitrogen can be, e.g. 15 It can also be N, or any oxygen can be, for example, 18 It will be understood that the isotopic variant can also be O. In certain embodiments, an "isotopic variant" of a therapeutic agent contains deuterium (D) in a proportion not found in nature.

[0036] "Mismatched" or "non-complementary" refers to a nucleobase of a first oligonucleotide or nucleic acid that is not complementary to the corresponding nucleobase of a second oligonucleotide or nucleic acid when the first oligonucleotide / nucleic acid and the second oligonucleotide / nucleic acid are aligned in an antiparallel orientation. For example, a nucleobase (including but not limited to the universal nucleobases inosine and hypoxanthine) can hybridize with at least one nucleobase, but remains mismatched or non-complementary to the nucleobase to which it hybridizes. As another example, a nucleobase of a first oligonucleotide / nucleic acid that cannot hybridize to the corresponding nucleobase of a second oligonucleotide / nucleic acid when the first oligonucleotide / nucleic acid and the second oligonucleotide are aligned in an antiparallel orientation is a mismatched or non-complementary nucleobase.

[0037] "Modified oligonucleotide" refers to 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.

[0038] "Modulation" refers to the alteration or adjustment of the characteristics of a cell, tissue, organ, or organism. For example, modulation of CFB RNA can mean increasing or decreasing the levels of CFB RNA and / or CFB protein in a cell, tissue, organ, or organism. A "modulator" produces a change in a cell, tissue, organ, or organism. For example, a CFB compound can be a modulator that decreases the amount of CFB RNA and / or CFB protein in a cell, tissue, organ, or organism.

[0039] By "motif" is meant the pattern of unmodified and modified sugar moieties, nucleobases and / or internucleoside linkages in an oligonucleotide.

[0040] "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 acids, and double-stranded nucleic acids.

[0041] "Nucleobase" refers to a heterocyclic moiety that can pair with a base of another nucleic acid. As used herein, "natural nucleobase" refers to adenine (A), thymine (T), cytosine (C), uracil (U) and guanine (G). "Modified nucleobase" refers to a natural nucleobase that has been chemically modified. "Universal base" or "universal nucleobase" refers to a nucleobase other than natural and modified nucleobases, which can pair with any nucleobase.

[0042] "Nucleobase sequence" means the order of contiguous nucleobases in a nucleic acid or oligonucleotide, regardless of any sugar or internucleoside linkages.

[0043] "Nucleoside" refers to a compound comprising a nucleobase and a sugar moiety, each of which is independently unmodified or modified. "Modified nucleoside" refers to a nucleoside comprising a modified nucleobase and / or a modified sugar moiety. Modified nucleosides include abasic nucleosides in which the nucleobase is missing.

[0044] "Oligomeric compounds" refers to compounds that include one or more oligonucleotides and, optionally, one or more additional features, such as conjugate groups or terminal groups. Examples of oligomeric compounds include single-stranded and double-stranded compounds, such as oligonucleotides, antisense oligonucleotides, interfering RNA compounds (RNAi compounds), oligonucleotides that target microRNAs, occupancy-based compounds (e.g., compounds that block mRNA processing or translation, and splicing compounds). RNAi compounds include double-stranded compounds (e.g., small interfering RNA (siRNA) and double-stranded RNA (dsRNA)), as well as 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, which causes sequence-specific degradation and / or sequestration of target nucleic acids through a process known as RNA interference (RNAi). The term "RNAi compound" is meant to be synonymous with other terms used to describe nucleic acid compounds capable of mediating sequence-specific RNA interference, such as interfering RNA (iRNA), iRNA agent, RNAi agent, short interfering oligonucleotide, short interfering nucleic acid, short interfering modified oligonucleotide, chemically modified siRNA, etc. In addition, the term "RNAi" is meant to be synonymous with other terms used to describe sequence-specific RNA interference.

[0045] "Oligonucleotide" means a polymer of linked nucleosides, each of which, independent of one another, can be modified or unmodified.

[0046] The term "oligomeric duplex" refers to a duplex formed by two oligomeric compounds having complementary nucleobase sequences. Each oligomeric compound of an oligomeric duplex may also be referred to as a "duplex-forming oligomeric compound." The oligonucleotides of each oligomeric compound of an oligomeric duplex may contain non-complementary overhang-forming nucleosides. In some embodiments, the terms "duplex-forming oligomeric compound" and "modified oligonucleotide" are used interchangeably. In another embodiment, the terms "oligomeric duplex" and "compound" are used interchangeably.

[0047] "Parenteral administration" means administration by injection or infusion. Parenteral administration includes subcutaneous, intravenous, intramuscular, intraarterial, intraperitoneal, or intracranial, e.g., intrathecal or intraventricular, administration.

[0048] "Pharmaceutically acceptable carrier or diluent" means any substance suitable for use in administration to an individual. In certain embodiments, a pharma-ceutically acceptable carrier or diluent can be included in the compositions of the present disclosure, which aids in the administration and absorption of the compound by an individual, and does not cause significant adverse toxic effects to the patient. Non-limiting examples of pharma-ceutically acceptable excipients include water, NaCl, saline, and the like. For example, the pharma-ceutically acceptable carrier can be a sterile aqueous solution, such as PBS or water for injection. Those skilled in the art will recognize that other pharmaceutical excipients are also useful in the present disclosure.

[0049] "Pharmaceutically acceptable salt" means or refers to a physiologically and pharma- ceutically acceptable salt of a compound, e.g., an oligomeric compound or an oligonucleotide, i.e., a salt that retains the desired biological activity of the parent compound and does not impart undesired toxic effects. As used herein, a pharma-ceutically acceptable salt is any salt of a compound provided by the present invention that retains its biological properties and is not toxic or otherwise undesirable for pharmaceutical use. Pharmaceutically acceptable salts of the therapeutic agents described herein include salts prepared with relatively non-toxic acids or bases, depending on the specific substituents found in the compounds or modified oligonucleotides described herein.

[0050] When a compound of the present disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent.

[0051] When a compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.

[0052] That is, the compounds of the present disclosure may exist as salts, for example, salts with pharma- ceutically acceptable acids. Such salts may be derived from a variety of organic and inorganic counterions well known in the art. Such salts include (1) salts of 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.or (2) acid addition salts formed with acids such as 2-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, benzoic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylsulfamic acid, quinic acid, muconic acid, or (3) acid addition salts formed with acids such as 2-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, benzoic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylsulfamic acid, quinic acid, muconic acid, or (4) acid addition salts formed with acids such as 2-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, benzoic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylsulfamic acid, quinic acid, muconic acid, or (5) acid addition salts formed with acids such as 2-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, benzoic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylsulfamic acid, quinic acid, muconic acid, or (6) acid addition salts formed with acids such as 2-oct-2-ene-1-carboxylic acid, glucoh or (b) is coordinated 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'-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, N-methylglucamine piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, and the like (see, for example, Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19).

[0053] Pharmaceutically acceptable salts further include salts of sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like, and, when the compound contains a basic functional group, salts of non-toxic organic or inorganic acids, such as hydrohalides, e.g., hydrochlorides and hydrobromides, sulfates, phosphates, sulfamate, nitrates, acetates, trifluoroacetates, trichloroacetates, propionates, hexanoates, cyclopentylpropionates, glycolates, glutarates, pyruvates, lactates, malonates, succinates, sorbates, ascorbates, malates, maleates, fumarates, tartrates, citrates, benzoates, 3-(4-hydroxybenzoyl)benzoates, picrates, cinnamates, mandelates, phthal ... Examples of suitable salts include, but are not limited to, phosphate, laurate, methanesulfonate (mesylate), ethanesulfonate, 1,2-ethane-disulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (besylate), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphorsulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, glucoheptonate, 3-phenylpropionate, trimethylacetate, tert-butylacetate, lauryl sulfate, gluconate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylsulfamate, quinate, muconate, and the like. In some embodiments, the pharma- ceutically acceptable salts of the compounds and modified oligonucleotides disclosed herein are sodium or potassium salts. In some embodiments, the pharma- ceutically acceptable salts of the compounds and modified oligonucleotides disclosed herein are sodium salts.

[0054] The neutral form of the compound is preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents. In embodiments, the compounds of the present disclosure contain both basic and acidic functional groups that allow the compounds to be converted into either base or acid addition salts. The neutral form of the compound may be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents, but unless otherwise indicated, the salts disclosed herein are equivalent to the parent form of the compound for the purposes of this disclosure.

[0055] By "pharmaceutical agent" is meant a chemical compound that produces a therapeutic effect when administered to an individual.

[0056] By "phosphorothioate linkage" is meant a modified phosphate linkage in which one of the non-bridging oxygen atoms is replaced with a sulfur atom.

[0057] "Part" refers to a certain number of consecutive (i.e. linked) nucleobases of a nucleic acid. In certain embodiments, a part is a certain number of consecutive nucleobases of a target nucleic acid. In certain embodiments, a part is a certain number of consecutive nucleobases of an oligonucleotide.

[0058] "Preventing" refers to delaying or forestalling the onset, development or progression of a disease, disorder or condition for a period of time.

[0059] "RNA interference compound" or "RNAi compound" refers to a compound that regulates a target nucleic acid and / or a target protein encoded by a target nucleic acid by acting, 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).

[0060] By "sense oligonucleotide" or "sense strand" is meant the strand of a double-stranded compound that includes a region that is substantially complementary to a region of the antisense strand of the compound.

[0061] "Specifically inhibit," with respect to a target nucleic acid or protein, means to reduce or block the expression or activity of the target nucleic acid or protein while minimizing or eliminating effects on non-target nucleic acids or proteins.

[0062] "Subunit", with respect to an oligonucleotide, means a nucleotide, nucleoside, nucleobase or sugar, or a modified nucleotide, nucleoside, nucleobase or sugar, as provided herein.

[0063] "Target nucleic acid," "target RNA," and "nucleic acid target" all refer to a nucleic acid that can be targeted by the compounds described herein.

[0064] "Target region" means a portion of a target nucleic acid to which one or more compounds are targeted.

[0065] By "targeting moiety" is meant a conjugate group that confers increased affinity for a given target, e.g., a molecule, a cell or cell type, a compartment, e.g., a cellular or organ compartment, a tissue, an organ, or a region of the body, e.g., compared to a compound lacking such a moiety.

[0066] "Terminal group" means a chemical group or group of atoms that is covalently attached to the end of an oligonucleotide.

[0067] "Therapeutically effective amount" or "effective amount" refers to an amount of a compound, pharmaceutical agent, or composition that provides a therapeutic effect to an individual. A "therapeutically effective amount" or "effective amount" is an amount of a compound sufficient to achieve its stated purpose (e.g., to treat, prevent, or ameliorate a disease, or to exert the action of administering the compound to alleviate one or more symptoms of a disease or condition) compared to the absence of the compound. An example of a "therapeutically effective amount" or "effective amount" is an amount sufficient to contribute to the treatment, prevention, amelioration, or alleviation of one or more symptoms of a disease. "Alleviation" of one or more symptoms (and grammatical equivalents of this phrase) means reducing the severity or frequency of the symptom(s) or eliminating the symptom(s). A "prophylactically effective amount" of a drug is an amount of drug that, when administered to a subject, has an intended prophylactic effect, e.g., prevents or delays the onset (or recurrence) of an injury, disease, condition or pathology, or reduces the likelihood of the onset (or recurrence) of an injury, disease, condition or pathology, or a symptom thereof. The term "therapeutically effective amount," as used herein, refers to an amount of a therapeutic agent sufficient to provide a therapeutic effect to an individual, e.g., to treat, prevent, or ameliorate a disease or disorder, or a symptom thereof, 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%. Therapeutic efficacy can also be expressed as a "fold" improvement or a "fold" decrease. For example, a therapeutically effective amount can be at least 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more, in effect, than a control.

[0068] The term "treating" or "treatment" refers to any objective or subjective parameter, such as relief, remission, reduction of symptoms, or any indication of successful treatment or improvement of an injury, disease, condition, or disease state, including making the injury, disease state, or disease state tolerable to the patient, slowing the rate of deterioration or decline, making the end point of deterioration less debilitating, improving the patient's physical or mental well-being. Treatment or improvement of symptoms can be based on objective or subjective parameters, including the results of a physical exam. The term "treating" and its variants may include prevention of an injury, disease state, condition, or disease. In an embodiment, treating is preventing. In an embodiment, treating does not include preventing.

[0069] "Treating" or "treatment", as used herein (and as well understood in the art), broadly includes any approach to obtain beneficial or desired results, including clinical results, in a subject's condition. Beneficial or desired clinical results may include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, reduction in the extent of the disease, stabilization of the condition (i.e., not worsening), prevention of the spread or spread of the disease, delay or slowing of the progression of the disease, improvement or mitigation of the condition, reduction in recurrence of the disease, and remission (whether partial or complete, detectable or undetectable). In other words, "treatment", as used herein, includes either curing, ameliorating, or preventing the disease. Treatment may prevent the onset of the disease, inhibit the spread of the disease, reduce the symptoms of the disease, completely or partially eliminate the underlying cause of the disease, shorten the duration of the disease, or a combination of these.

[0070] "Treating" and "treatment" as used herein include preventive treatment. The treatment method includes administering to a subject a therapeutically effective amount of a compound described herein. The administering step may consist of a single administration or may include a series of administrations. The length of the treatment period will depend on various 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 will also be apparent that the effective dosage of the agent used in the treatment or prevention may increase or decrease over a particular treatment or prevention regime. In some cases, chronic administration may be required. For example, the composition is administered to a subject in an amount and for a period sufficient to treat the patient.

[0071] "Treating" refers to the administration of a compound or pharmaceutical composition to an animal to alter or ameliorate a disease, disorder, or condition in the animal.

[0072] Certain compounds of the present disclosure have asymmetric carbon atoms (optical or chiral centers) or double bonds, and their enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomers that may be defined in terms of absolute stereochemistry as (R) or (S) forms, or in the case of amino acids as (D) or (L) forms, and individual isomers are included within the scope of the present disclosure. The compounds of the present disclosure do not include isomers that are known in the art to be highly unstable and cannot be synthesized and / or isolated. The present disclosure is intended to include the compounds in racemic and optically pure form. Optically active (R) and (S) forms, or (D) and (L) forms, may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When a compound described herein contains an olefinic bond or other geometrically asymmetric center, and unless otherwise specified, the compound is intended to include both the E and Z geometric isomers.

[0073] As used herein, the term "isomers" refers to compounds that have the same number and kinds of atoms, i.e., the same molecular weight, but differ in structural organization or arrangement of the atoms.

[0074] The term "tautomer," as used herein, refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

[0075] It will be apparent to one of ordinary skill in the art that certain compounds of the present disclosure may exist in tautomeric forms, and all such tautomeric forms of the compounds are within the scope of the present disclosure.

[0076] Unless otherwise indicated, structures depicted herein are intended to include all stereochemical forms of the structure (i.e., the R and S configurations at each asymmetric center). Thus, single stereochemical isomers, as well as enantiomeric and diastereomeric mixtures of the compounds of the present disclosure, are included within the scope of the present disclosure.

[0077] As used herein, "chirally enriched population" refers to a plurality of molecules of the same molecular formula, in which the number or percentage of molecules in the population that contain a particular stereochemical configuration at a particular chiral center is greater than the number or percentage of molecules in the population that would be expected to contain the same particular stereochemical configuration at the same particular chiral center if the particular chiral center were stereorandom. A chirally enriched population of molecules that has multiple chiral centers in each molecule may contain one or more stereorandom chiral centers. In certain embodiments, the molecule is a modified oligonucleotide. In certain embodiments, the molecule is a compound that includes a modified oligonucleotide.

[0078] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, hydrogen has been replaced by deuterium or tritium, or carbon has been replaced by 13 C or 14 Compounds having the structures of the present invention except for the substitution of a C-rich carbon are within the scope of this disclosure.

[0079] As used herein, "stereorandom chiral center" refers to a chiral center that has random stereochemical configuration with respect to a population of molecules of the same molecular formula. For example, in a population of molecules that includes stereorandom chiral centers, the number of molecules that have stereorandom chiral centers in the (S) configuration may be, but is not necessarily, the same as the number of molecules that have stereorandom chiral centers in the (R) configuration. The stereochemical configuration of a chiral center is considered random when it is the result of a synthetic method that is not designed to control the stereochemical configuration. In certain embodiments, the stereorandom chiral center is a stereorandom phosphorothioate internucleoside linkage.

[0080] Specific Embodiments 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, expression of CFB is inhibited. In certain embodiments, translation of CFB is inhibited. In certain embodiments, activity of CFB is inhibited. In certain embodiments, expression, translation or activity of CFB is reduced by at least 10% compared to expression, translation or activity in an untreated sample or a control sample. For example, in certain embodiments, expression, translation or activity of CFB is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, 10-50%, 25-50%, 25-75%, 50-75%, 50-99% or 75-99% compared to expression, translation or activity in an untreated sample or a control sample. In certain embodiments, CFB expression, translation or activity is decreased 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).

[0081] In certain aspects, the disclosure relates to compounds that target CFB nucleic acids. In certain embodiments, the CFB nucleic acid has the sequence shown in GenBank Accession No. NM_001710.6 (herein incorporated as SEQ ID NO: 1), GenBank Accession No. NC_000006.12, nucleotides 31946095-31952084 (herein incorporated as SEQ ID NO: 2), GenBank Accession No. NM_001710.6 (herein incorporated as SEQ ID NO: 3), and GenBank Accession No. NT_113891.3, nucleotides 3423522-3429511 (herein incorporated as SEQ ID NO: 4).

[0082] 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.

[0083] Certain embodiments provide compounds comprising modified oligonucleotides (e.g., modified oligonucleotides having a length of 14 to 30, e.g., 14 to 23 nucleosides linked together) 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 modified oligonucleotides (e.g., modified oligonucleotides having a length of 14 to 30, e.g., 14 to 23 nucleosides linked together) having a nucleobase sequence comprising any one of the nucleobase sequences of SEQ ID NOs: 11 to 44 and 96 to 102.

[0084] 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.

[0085] 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.

[0086] Certain embodiments provide a compound comprising a first modified oligonucleotide (e.g., a first modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 nucleosides linked together) having a nucleobase sequence including 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 NOs: 11 to 110, and a second modified oligonucleotide (e.g., a second modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 nucleosides linked together) having a region complementary to the first modified oligonucleotide.

[0087] In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., a first modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 linked nucleosides) having a nucleobase sequence that includes 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 shown in Tables 2 and 3, and a second modified oligonucleotide (e.g., a second 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.

[0088] Certain embodiments provide a compound comprising a first modified oligonucleotide having a nucleobase sequence including any one of SEQ ID NOs: 11 to 110 (e.g., a first modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23, nucleosides linked together) and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (e.g., a second modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23, nucleosides linked together).

[0089] 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: 11-110, and a second modified oligonucleotide having a length of 19 to 23 linked nucleosides, the second modified oligonucleotide having a region complementary to the first modified oligonucleotide.

[0090] In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 linked nucleosides) having a nucleobase sequence that includes 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 NOs: 96, 97, 100, or 101. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 linked nucleosides) having a nucleobase sequence that includes 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 the nucleobase sequence of SEQ ID NOs: 93, 106, 109, or 110. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequences 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 sequences 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.

[0091] In certain embodiments, the modified oligonucleotide or the first modified oligonucleotide of any of the compounds of the invention has a nucleobase sequence that is at least 80%, at least 85%, at least 90% or at least 95% complementary or identical over its length to the nucleobase sequence of SEQ ID NO: 1 or 3. In certain embodiments, the modified oligonucleotide or the first modified oligonucleotide has a nucleobase sequence that has at least one, at least two or at least three mismatches to a region of the nucleobase sequence of SEQ ID NO: 1 or 3. In certain embodiments, the region of complementarity between the first strand and the second strand is 14-30 linked nucleosides in length. In certain embodiments, the region of complementarity between the first modified oligonucleotide, i.e., the first strand, and the second modified oligonucleotide, i.e., the second strand, is 14-23 linked nucleosides in length. In certain embodiments, the complementary region between the first modified oligonucleotide, i.e., the first strand, and the second modified oligonucleotide, i.e., the second strand, is 19-23 nucleosides long. In certain embodiments, the complementary region between the first modified oligonucleotide, i.e., the first strand, and the second modified oligonucleotide, i.e., the second strand, is 21-23 nucleosides long. In certain embodiments, the first modified oligonucleotide is fully complementary to the second modified oligonucleotide.

[0092] In certain embodiments, the first modified oligonucleotide of any of the above compounds or other compounds of the invention 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 above 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 or second modified oligonucleotide or at the 5' end of the first modified oligonucleotide. In certain embodiments, the modified sugar comprises a modification selected from a halogen, an alkoxy group, and a bicyclic sugar. In certain embodiments, the modified sugar comprises a 2'-F modification. In certain embodiments, the modified sugar comprises a 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 a halogen, an alkoxy group, and a bicyclic sugar, or a combination thereof. 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 comprises 10 or fewer 2'-F sugar modifications. In certain embodiments, the second modified oligonucleotide comprises 5 or fewer 2'-F sugar modifications.

[0093] In certain embodiments, the compound of any of the above embodiments comprises a conjugate group. In certain embodiments, the conjugate group is attached to the 5' end of the modified oligonucleotide. In certain embodiments, the conjugate 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, the one or more GalNAc are attached to the 2' or 3' position of the ribosyl ring. In certain embodiments, the one or more GalNAc are attached 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, where R is a portion of the modified oligonucleotide other than the 5' nucleoside. [ka] [ka] [ka] [ka] [ka]

[0094] In certain embodiments, the conjugate group according to formula III is represented by the formula: [ka]

[0095] In certain embodiments, the conjugate group according to formula V is represented by the formula: [ka]

[0096] In certain embodiments, the conjugate group according to formula VIII is represented by the formula: [ka]

[0097] In certain embodiments, R' is OH. In certain embodiments, R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula I and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula I and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula II and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula II and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula III and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula III and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula IV and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula IV and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula V and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula V and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VI and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VI and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VII and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VII and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VIII and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VIII and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula XII and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula XII, where R' is SH.

[0098] In certain embodiments, R' is OH. In certain embodiments, R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula I and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula I and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula II and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula II and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula III and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula III and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula IV and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula IV and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula V and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula V and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VI and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VI and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VII and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VII and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VIII and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VIII and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula XII and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula XII, where R' is SH.

[0099] In certain embodiments, R' is O. In certain embodiments, R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula I and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula I and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula II and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula II and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula III and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula III and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula IV and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula IV and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula V and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula V and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VI and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VI and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VII and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VII and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VIII and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VIII and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula XII and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula XII and R' is S.

[0100] Certain embodiments are described with reference ID numbers IA0478-490, IA0840, IA0842-846, IA0852-862, IA0872-882, IA0887-890, IA1010-1012, IA1015-1018, IS0570-587, IS0969, IS0972-977, IS1023-1027, IS1029, IS1031-1037, IS1042-1046, IS1082, IS1085, I The present invention provides a compound comprising a first modified oligonucleotide selected from any one of IS1086, IS1091-1095, IS1108-1111, IS1236-1239, IS1242, IS1249, and IS1251-1254, and a second modified oligonucleotide having a length of 14 to 21 nucleosides linked thereto, the second modified oligonucleotide being completely complementary to the first modified oligonucleotide.

[0101] Certain embodiments comprise a first modified oligonucleotide selected from any one of reference ID numbers 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 reference ID numbers IS0570-587, IS0969, IS0972-977 and a second modified oligonucleotide selected from any one of IS1023-1027, IS1029, IS1031-1037, IS1042-1046, IS1082, IS1085, IS1086, IS1091-1095, IS1108-1111, IS1236-1239, IS1242, IS1249, and IS1251-1254.

[0102] Certain embodiments provide a compound comprising a first modified oligonucleotide that is IA0840 and a second modified oligonucleotide that is IS0972.

[0103] Certain embodiments provide a compound comprising a first modified oligonucleotide that is IA0842 and a second modified oligonucleotide that is IS0974.

[0104] Certain embodiments provide a compound comprising a first modified oligonucleotide that is IA0888 and a second modified oligonucleotide that is IS1109.

[0105] Certain embodiments provide a compound comprising a first modified oligonucleotide that is IA0888 and a second modified oligonucleotide that is IS1236.

[0106] Certain embodiments provide a compound comprising a first modified oligonucleotide that is IA1010 and a second modified oligonucleotide that is IS1109.

[0107] Certain embodiments provide a compound comprising a first modified oligonucleotide that is IA1011 and a second modified oligonucleotide that is IS1239.

[0108] Certain embodiments provide compounds comprising a first modified oligonucleotide that is IA1012 and a second modified oligonucleotide that is IS1242. Certain embodiments provide compounds comprising a first modified oligonucleotide that is IA1016 and a second modified oligonucleotide that is IS1252.

[0109] Certain embodiments provide a compound comprising a first modified oligonucleotide that is IA1017 and a second modified oligonucleotide that is IS1253.

[0110] In certain embodiments, the compound of any of the above embodiments is in the form of a pharma- ceutically acceptable salt. In certain embodiments, the pharma- ceutically acceptable salt is a sodium salt. In certain embodiments, the pharma- ceutically acceptable salt is a potassium salt.

[0111] Certain embodiments provide compounds of any of the above embodiments that are stereoisomers.

[0112] An embodiment provided by the present invention is a modified oligonucleotide according to the chemical structure: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, reference ID number IA1016 is a modified oligonucleotide according to the above chemical structure, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0113] An embodiment provided by the present invention is a modified oligonucleotide according to the chemical structure: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, Reference ID No. IS1252 is a modified oligonucleotide according to the above chemical structure, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0114] An embodiment provided by the present invention is a modified oligonucleotide according to the chemical structure: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, reference ID number IA1017 is a modified oligonucleotide according to the above chemical structure, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0115] An embodiment provided by the present invention is a modified oligonucleotide according to the chemical structure: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, Reference ID No. IS1253 is a modified oligonucleotide according to the above chemical structure, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0116] An embodiment provided by the present invention is a modified oligonucleotide according to the chemical structure: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, reference ID number IA1010 is a modified oligonucleotide according to the above chemical structure, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0117] An embodiment provided by the present invention is a modified oligonucleotide according to the chemical structure: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, Reference ID No. IS1109 is a modified oligonucleotide according to the above chemical structure, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0118] An embodiment provided by the present invention is a modified oligonucleotide according to the chemical structure: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, reference ID number IA1011 is a modified oligonucleotide according to the above chemical structure, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0119] An embodiment provided by the present invention is a modified oligonucleotide according to the chemical structure: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, Reference ID No. IS1239 is a modified oligonucleotide according to the above chemical structure, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0120] An embodiment provided herein is a sodium salt of a modified oligonucleotide according to the following chemical structure: [ka] or a stereoisomer thereof. In certain embodiments, reference ID number IA1016 is a modified oligonucleotide according to the above chemical structure or a stereoisomer thereof.

[0121] An embodiment provided herein is a sodium salt of a modified oligonucleotide according to the following chemical structure: [ka] or a stereoisomer thereof. In certain embodiments, Reference ID No. IS1252 is a modified oligonucleotide according to the above chemical structure or a stereoisomer thereof.

[0122] An embodiment provided herein is a sodium salt of a modified oligonucleotide according to the following chemical structure: [ka] or a stereoisomer thereof. In certain embodiments, reference ID number IA1017 is a modified oligonucleotide according to the above chemical structure or a stereoisomer thereof.

[0123] An embodiment provided herein is a sodium salt of a modified oligonucleotide according to the following chemical structure: [ka] or a stereoisomer thereof. In certain embodiments, Reference ID No. IS1253 is a modified oligonucleotide according to the above chemical structure or a stereoisomer thereof.

[0124] An embodiment provided herein is a sodium salt of a modified oligonucleotide according to the following chemical structure: [ka] or a stereoisomer thereof. In certain embodiments, reference ID number IA1010 is a modified oligonucleotide according to the above chemical structure or a stereoisomer thereof.

[0125] An embodiment provided herein is a sodium salt of a modified oligonucleotide according to the following chemical structure: [ka] or a stereoisomer thereof. In certain embodiments, Reference ID No. IS1109 is a modified oligonucleotide according to the above chemical structure or a stereoisomer thereof.

[0126] An embodiment provided herein is a sodium salt of a modified oligonucleotide according to the following chemical structure: [ka] or a stereoisomer thereof. In certain embodiments, reference ID number IA1011 is a modified oligonucleotide according to the above chemical structure or a stereoisomer thereof.

[0127] An embodiment provided herein is a sodium salt of a modified oligonucleotide according to the following chemical structure: [ka] or a stereoisomer thereof. In certain embodiments, Reference ID No. IS1239 is a modified oligonucleotide according to the above chemical structure or a stereoisomer thereof.

[0128] An embodiment provided herein is a compound according to the chemical structure: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, compound number RD2830 is a compound according to the above chemical structure, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0129] An embodiment provided herein is a compound according to the chemical structure: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, compound number RD2831 is a compound according to the above chemical structure, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0130] An embodiment provided herein is a compound according to the chemical structure: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, compound number RD2795 is a compound according to the above chemical structure, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0131] An embodiment provided herein is a compound according to the chemical structure: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, compound number RD2798 is a compound according to the above chemical structure, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0132] An embodiment provided herein is a sodium salt of a compound according to the following chemical structure: [ka] or a stereoisomer thereof. In certain embodiments, compound number RD2830 is a compound according to the above chemical structure, or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0133] An embodiment provided herein is a sodium salt of a compound according to the following chemical structure: [ka] or a stereoisomer thereof. In certain embodiments, compound number RD2831 is a compound according to the above chemical structure, or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0134] An embodiment provided herein is a sodium salt of a compound according to the following chemical structure: [ka] or a stereoisomer thereof. In certain embodiments, compound number RD2795 is a compound according to the above chemical structure, or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0135] An embodiment provided herein is a sodium salt of a compound according to the following chemical structure: [ka] or a stereoisomer thereof. In certain embodiments, compound number RD2798 is a compound according to the above chemical structure, or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0136] In certain embodiments, the present invention provides a population of modified oligonucleotides, in which any of the phosphorothioate internucleoside linkages of the modified oligonucleotides are stereorandom. In certain embodiments, the present invention provides a population of compounds in which any of the phosphorothioate internucleoside linkages of the modified oligonucleotides are stereorandom.

[0137] Certain embodiments provide a composition comprising a compound of any of the above embodiments and a pharma- ceutically acceptable carrier.

[0138] Certain embodiments provide a composition comprising a compound of any of the above embodiments for use in therapy.

[0139] 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.

[0140] In certain embodiments, the compound or composition of any of the above 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, reduces or ameliorates atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), including 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.

[0141] In certain embodiments, a compound of any of the above embodiments, or a composition comprising the compound, is administered to an individual in a therapeutically effective amount. In certain embodiments, a composition comprising the compound of any of the above embodiments is administered to an individual at a dosage level sufficient to deliver about 1-100 mg per kg of body weight of the individual. In certain embodiments, a compound of any of the above 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 the individual one or more times per day, up to that dosage level or dose.

[0142] In certain embodiments, a composition comprising a compound of any of the above embodiments is administered to an individual once a day, once a week, once a month, once a quarter, or once a year. In certain embodiments, a compound of any of the above embodiments, or a composition comprising the compound, is administered to an individual about once a quarter (i.e., once every three months) to about once a year. In certain embodiments, a compound of any of the above embodiments, or a composition comprising the compound, is administered to an individual about once a quarter, about once every six months, or about once a year.

[0143] Certain embodiments provide a method for inhibiting the expression of CFB in a cell, comprising contacting the cell with a compound that targets 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 is or is at risk of developing 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).

[0144] Certain embodiments relate to 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), e.g., 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 an individual, comprising administering a compound that targets CFB to the individual. By administering to the individual, atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), e.g., 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, are alleviated or inhibited in the individual. In certain embodiments, the individual is or is at risk of developing 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 of the above conditions. In certain embodiments, the compound is a compound that targets CFB. In certain embodiments, the compound is any of the above compounds. In certain embodiments, the compound or composition is administered parenterally.

[0145] Certain embodiments provide for the use of a compound that targets CFB in the treatment, prevention or amelioration of 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 that targets CFB.In certain embodiments, the compound is any of the above-mentioned compounds.

[0146] Certain embodiments provide for the use of a compound that targets CFB in the manufacture of a medicament 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 that targets CFB.In certain embodiments, the compound is any of the above-mentioned compounds. Certain Indications

[0147] In certain aspects, the present disclosure relates to a method for inhibiting the expression of CFB, which may be useful for treating, preventing or ameliorating diseases, disorders or conditions associated with CFB in an individual by administering a compound that targets CFB.In certain embodiments, the compound can be a CFB-specific inhibitor.In certain embodiments, the compound can be an antisense oligonucleotide, oligomeric compound or oligonucleotide that targets CFB.

[0148] In certain aspects, the disclosure relates to treating, preventing or ameliorating a disease, disorder or condition associated with CFB. In certain embodiments, the disease, disorder or condition associated with CFB that can be treated, prevented and / or ameliorated by the methods provided herein includes atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), including 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 are directed to compounds and compositions that alleviate atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), including 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, in an animal.

[0149] In certain embodiments, the method of 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 having or at risk of having a disease, disorder or condition associated with CFB. In certain embodiments, the disease, disorder or condition is a liver disease, a kidney disease or an eye disease. In certain embodiments, the compound comprises an antisense oligonucleotide that targets CFB. In certain embodiments, the compound comprises an oligonucleotide that targets CFB. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleobases of any of the nucleobase sequences of SEQ ID NOs: 11-44 and 96-102 (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 nucleosides linked together). In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising any one of the nucleobase sequences of SEQ ID NOs: 11-44 and 96-102 (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 nucleosides linked together). 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: 11-44 and 96-102. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising any one of the nucleobase sequences of SEQ ID NOs: 24, 25, 42, 96, 97, 98, and 100 (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 linked nucleosides). 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 above embodiments, the compound can be single-stranded or double-stranded. In certain embodiments, the single-stranded compound can be 14-30, 14-23, 14-20, 16-20, or 14-16 linked nucleosides in length. In certain embodiments, the 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 length. In certain embodiments, the double-stranded compound can include two oligonucleotides of the same or different length, as described elsewhere herein. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 linked nucleosides) having a nucleobase sequence that includes 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 the 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 having a length of 14-30, e.g., 14-23 linked nucleosides) having a nucleobase sequence that includes 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 the 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 sequences 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 sequences 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 above embodiments, the compound can be an antisense oligonucleotide or an oligomeric compound. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence including 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 NOs: 11-110 (e.g., a first modified oligonucleotide having a length of 14-30, e.g., 14-23, nucleosides linked together), and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (e.g., a second modified oligonucleotide having a length of 14-30, e.g., 14-23, nucleosides linked together). In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence including any one of SEQ ID NOs: 11-110 (e.g., a first modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23, nucleosides linked together) and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (e.g., a second modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23, nucleosides linked together).In certain embodiments, the compound includes a first modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 11-110, and a second modified oligonucleotide having a length of 19-23 nucleosides linked thereto, the second modified oligonucleotide having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound is administered parenterally to the individual. 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 symptoms thereof in an animal.

[0150] In certain embodiments, the 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), e.g., lupus nephritis, diabetic nephropathy, membranous nephropathy, polycystic kidney disease, age-related macular degeneration, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, rheumatoid arthritis (RA), or a symptom of any thereof, in an animal, comprises administering to the individual a CF The present invention includes administering a compound that comprises a B-specific inhibitor to treat, prevent or ameliorate 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 of the symptoms thereof. In certain embodiments, the compound comprises an antisense oligonucleotide that targets CFB. In certain embodiments, the compound comprises an oligonucleotide that targets CFB. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleobases of any one of the nucleobase sequences of SEQ ID NOs: 11-44 and 96-102 (e.g., a modified oligonucleotide having a length of 14-30, e.g., a modified oligonucleotide having a length of 14-30, e.g., a modified oligonucleotide having a length of 14-23 nucleosides linked together). In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising any one of the nucleobase sequences of SEQ ID NOs: 11-44 and 96-102 (e.g., a modified oligonucleotide having a length of 14-30, e.g., a modified oligonucleotide having a length of 14-23 nucleosides linked together). 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: 11-44 and 96-102.In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 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 above embodiments, the compound can be single-stranded or double-stranded. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 linked nucleosides) having a nucleobase sequence that includes 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 the 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 having a length of 14-30, e.g., 14-23 linked nucleosides) having a nucleobase sequence that includes 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 the nucleobase sequence of SEQ ID NO: 93, 106, 109, or 110. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequences of SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 100, and SEQ ID NO: 101. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequences 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 the nucleobase sequence of SEQ ID NO: 96 and a second modified oligonucleotide having the 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 above embodiments, the compound can be an antisense oligonucleotide or an oligomeric compound. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence including 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 NOs: 11-110 (e.g., a first modified oligonucleotide having a length of 14-30, e.g., 14-23, nucleosides linked together), and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (e.g., a second modified oligonucleotide having a length of 14-30, e.g., 14-23, nucleosides linked together). In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence including any one of SEQ ID NOs: 11-110 (e.g., a first modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23, nucleosides linked together) and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (e.g., a second modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23, nucleosides linked together).In certain embodiments, the compound includes a first modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 11-110, and a second modified oligonucleotide having a length of 19-23 nucleosides linked thereto, the second modified oligonucleotide 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, the individual has been identified as having, or at risk for, a disease, disorder or condition associated with CFB.

[0151] In certain embodiments, the method of inhibiting the expression of CFB in an individual who is at risk of developing or has 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, administering 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 is or is at risk of developing 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 that targets CFB.In certain embodiments, the compound comprises an oligonucleotide that targets CFB. 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 that includes 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 NOs: 11-44 and 96-102.In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising any one of SEQ ID NOs: 11-44 and 96-102 (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 linked nucleosides). In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 11-44 and 96-102. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising any one of SEQ ID NOs: 24, 25, 42, 96, 97, 98, and 100 (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 linked nucleosides). In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 24, 25, 42, 96, 97, 98, and 100. In any of the above embodiments, the compound can be single-stranded or double-stranded. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 linked nucleosides) having a nucleobase sequence that includes 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 the 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 having a length of 14-30, e.g., 14-23 linked nucleosides) having a nucleobase sequence that includes 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 the 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 sequences 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 sequences 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 above embodiments, the compound can be an antisense oligonucleotide or oligomeric compound. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., a first modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 nucleosides linked together) having a nucleobase sequence including 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 NOs: 11 to 110, and a second modified oligonucleotide (e.g., a second modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 nucleosides linked together) having a region complementary to the first modified oligonucleotide.In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence comprising any one of SEQ ID NOs: 11-110 (e.g., a first modified oligonucleotide having a length of 14-30, e.g., 14-23 nucleosides linked together) and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (e.g., a second modified oligonucleotide having a length of 14-30, e.g., 14-23 nucleosides linked together). In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 11-110 and a second modified oligonucleotide having a length of 19-23 nucleosides linked together, the second modified oligonucleotide having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound is administered parenterally to the individual. 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 of the symptoms thereof. In certain embodiments, the method of inhibiting the expression of CFB 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 a cell in the liver. In certain embodiments, the cells are in the liver of an individual who has or is 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 targeting CFB. In certain embodiments, the compound comprises an oligonucleotide targeting CFB. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleobases of any one of the nucleobase sequences of SEQ ID NOs: 11-44 and 96-102 (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 nucleosides linked together). In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising any one of the nucleobase sequences of SEQ ID NOs: 11-44 and 96-102 (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 nucleosides linked together). In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 11-44 and 96-102. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising any one of SEQ ID NOs: 24, 25, 42, 96, 97, 98, and 100 (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 linked nucleosides). In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 24, 25, 42, 96, 97, 98, and 100. In any of the above embodiments, the compound can be single-stranded or double-stranded.In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 linked nucleosides) having a nucleobase sequence that includes 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 the 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 having a length of 14-30, e.g., 14-23 linked nucleosides) having a nucleobase sequence that includes 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 the 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 sequences 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 nucleobase sequences of SEQ ID NO: 93, SEQ ID NO: 106, SEQ ID NO: 109, and SEQ ID NO: 110. In certain embodiments, the compound is. , 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 above embodiments, the compound can be an antisense oligonucleotide or an oligomeric compound. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence including 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 NOs: 11-110 (e.g., a first modified oligonucleotide having a length of 14-30, e.g., 14-23, nucleosides linked together), and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (e.g., a second modified oligonucleotide having a length of 14-30, e.g., 14-23, nucleosides linked together). In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence including any one of SEQ ID NOs: 11-110 (e.g., a first modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23, nucleosides linked together) and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (e.g., a second modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23, nucleosides linked together).In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 11-110, and a second modified oligonucleotide having a length of 19 to 23 nucleosides linked together, the second modified oligonucleotide having a region complementary to the first modified oligonucleotide.

[0152] Certain embodiments are directed to treating a patient suffering from or at risk of suffering from a disease, disorder or condition associated with CFB, including 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), any symptoms thereof. Methods of reducing or inhibiting include reducing or inhibiting in an individual atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), e.g., lupus nephritis, diabetic nephropathy, membranous nephropathy, polycystic kidney disease, age-related macular degeneration, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, or rheumatoid arthritis (RA), by administering to the individual a compound comprising a CFB-specific inhibitor. In certain embodiments, the individual is or is at risk of developing 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 that targets CFB.In certain embodiments, the compound comprises an oligonucleotide that targets CFB. 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 that includes 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 NOs: 11-44 and 96-102.In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising any one of SEQ ID NOs: 11-44 and 96-102 (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 nucleosides linked together). In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 11-44 and 96-102. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising any one of SEQ ID NOs: 24, 25, 42, 96, 97, 98, and 100 (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 nucleosides linked together). In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 24, 25, 42, 96, 97, 98, and 100. In any of the above embodiments, the compound can be single-stranded or double-stranded. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 linked nucleosides) having a nucleobase sequence that includes 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 the 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 having a length of 14-30, e.g., 14-23 linked nucleosides) having a nucleobase sequence that includes 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 the 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 sequences 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 sequences 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 above embodiments, the compound can be an antisense oligonucleotide or oligomeric compound. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., a first modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 nucleosides linked together) having a nucleobase sequence including 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 NOs: 11 to 110, and a second modified oligonucleotide (e.g., a second modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 nucleosides linked together) having a region complementary to the first modified oligonucleotide.In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence comprising any one of SEQ ID NOs: 11-110 (e.g., a first modified oligonucleotide having a length of 14-30, e.g., 14-23 nucleosides linked together) and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (e.g., a second modified oligonucleotide having a length of 14-30, e.g., 14-23 nucleosides linked together). In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 11-110 and a second modified oligonucleotide having a length of 19-23 nucleosides linked together, the second modified oligonucleotide having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound is administered parenterally to the individual. In certain embodiments, the individual is identified as having or at risk for a disease, disorder, or condition associated with CFB.

[0153] Certain embodiments are directed to compounds comprising CFB specific inhibitors, and are used to treat diseases, disorders or conditions associated with CFB.In certain embodiments, the diseases, disorders or conditions are 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 compounds comprise antisense oligonucleotides that target CFB.In certain embodiments, the compounds comprise oligonucleotides that target CFB. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleobases of any of the nucleobase sequences of SEQ ID NOs: 11-44 and 96-102 (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 nucleosides linked together). In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising any one of the nucleobase sequences of SEQ ID NOs: 11-44 and 96-102 (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 nucleosides linked together). 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: 11-44 and 96-102. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising any one of SEQ ID NOs: 24, 25, 42, 96, 97, 98, and 100 (e.g., a modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 linked nucleosides.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 above embodiments, the compound can be single-stranded or double-stranded. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 linked nucleosides) having a nucleobase sequence that includes 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 the nucleobase sequence of SEQ ID NOs: 96, 97, 100, or 101. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence that includes 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 the nucleobase sequence of SEQ ID NO: 93, 106, 109, or 110 (e.g., a modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 linked nucleosides). In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequences 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 sequences 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 the nucleobase sequence of SEQ ID NO:97 and a second modified oligonucleotide having the 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 above embodiments, the compound can be an antisense oligonucleotide or an oligomeric compound. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence including 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 NOs: 11-110 (e.g., a first modified oligonucleotide having a length of 14-30, e.g., 14-23, nucleosides linked together), and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (e.g., a second modified oligonucleotide having a length of 14-30, e.g., 14-23, nucleosides linked together). In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence comprising any one of SEQ ID NOs: 11-110 (e.g., a first modified oligonucleotide having a length of 14-30, e.g., 14-23 nucleosides linked together) and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (e.g., a second modified oligonucleotide having a length of 14-30, e.g., 14-23 nucleosides linked together). In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 11-110 and a second modified oligonucleotide having a length of 19-23 nucleosides linked together, the second modified oligonucleotide having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound is administered parenterally to the individual.

[0154] Certain embodiments are directed to compounds that comprise CFB-specific inhibitors, and are used to reduce or suppress 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 of the symptoms thereof.In certain embodiments, the compounds comprise antisense oligonucleotides that target CFB.In certain embodiments, the compounds comprise oligonucleotides that target CFB. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleobases of any of the nucleobase sequences of SEQ ID NOs: 11-44 and 96-102 (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 nucleosides linked together). In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising any one of the nucleobase sequences of SEQ ID NOs: 11-44 and 96-102 (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 nucleosides linked together). 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: 11-44 and 96-102. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising any one of SEQ ID NOs: 24, 25, 42, 96, 97, 98, and 100 (e.g., a modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 linked nucleosides.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 above embodiments, the compound can be single-stranded or double-stranded. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 linked nucleosides) having a nucleobase sequence that includes 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 the nucleobase sequence of SEQ ID NOs: 96, 97, 100, or 101. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence that includes 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 the nucleobase sequence of SEQ ID NO: 93, 106, 109, or 110 (e.g., a modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 linked nucleosides). In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequences 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 sequences 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 the nucleobase sequence of SEQ ID NO:97 and a second modified oligonucleotide having the 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 above embodiments, the compound can be an antisense oligonucleotide or an oligomeric compound. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence including 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 NOs: 11-110 (e.g., a first modified oligonucleotide having a length of 14-30, e.g., 14-23, nucleosides linked together), and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (e.g., a second modified oligonucleotide having a length of 14-30, e.g., 14-23, nucleosides linked together). In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence comprising any one of SEQ ID NOs: 11 to 110 (e.g., a first modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 nucleosides linked together) and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (e.g., a second modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 nucleosides linked together). In certain embodiments, the compound comprises 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 nucleosides linked together, the second modified oligonucleotide having a region complementary to the first modified oligonucleotide.

[0155] Certain embodiments are directed to the use of a compound comprising a CFB-specific inhibitor in the manufacture or preparation of a medicament for treating a disease, disorder or condition associated with CFB. Certain embodiments are directed to the use of a compound comprising a CFB-specific inhibitor in the preparation of a medicament for treating a disease, disorder or condition 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 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: 11-44 and 96-102 (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 nucleosides linked together). In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising any one of the nucleobase sequences of SEQ ID NOs: 11-44 and 96-102 (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 nucleosides linked together). In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequences of any one of SEQ ID NOs: 11-44 and 96-102.In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 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 above embodiments, the compound can be single-stranded or double-stranded. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 linked nucleosides) having a nucleobase sequence that includes 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 the 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 having a length of 14-30, e.g., 14-23 linked nucleosides) having a nucleobase sequence that includes 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 the nucleobase sequence of SEQ ID NO: 93, 106, 109, or 110. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequences of SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 100, and SEQ ID NO: 101. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequences 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 the nucleobase sequence of SEQ ID NO: 96 and a second modified oligonucleotide having the 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 above embodiments, the compound can be an antisense oligonucleotide or an oligomeric compound. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence including 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 NOs: 11-110 (e.g., a first modified oligonucleotide having a length of 14-30, e.g., 14-23, nucleosides linked together), and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (e.g., a second modified oligonucleotide having a length of 14-30, e.g., 14-23, nucleosides linked together). In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence including any one of SEQ ID NOs: 11-110 (e.g., a first modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23, nucleosides linked together) and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (e.g., a second modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23, nucleosides linked together).In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 11-110, and a second modified oligonucleotide having a length of 19 to 23 nucleosides linked together, the second modified oligonucleotide having a region complementary to the first modified oligonucleotide.

[0156] Certain embodiments are directed to the use of a compound comprising a CFB-specific inhibitor in the manufacture or preparation of a medicament for reducing or suppressing a complement pathway-related disease, disorder or condition, or its symptoms, in an individual who has or is at risk of having 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 are directed to the use of a compound comprising a CFB-specific inhibitor in 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 that targets CFB.In certain embodiments, the compound comprises an oligonucleotide that targets CFB. 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 that includes 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 NOs: 11-44 and 96-102.In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising any one of SEQ ID NOs: 11-44 and 96-102 (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 nucleosides linked together). In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 11-44 and 96-102. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising any one of SEQ ID NOs: 24, 25, 42, 96, 97, 98, and 100 (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 nucleosides linked together). In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 24, 25, 42, 96, 97, 98, and 100. In any of the above embodiments, the compound can be single-stranded or double-stranded. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 linked nucleosides) having a nucleobase sequence that includes 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 the 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 having a length of 14-30, e.g., 14-23 linked nucleosides) having a nucleobase sequence that includes 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 the 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 sequences 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 sequences 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 above embodiments, the compound can be an antisense oligonucleotide or oligomeric compound. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., a first modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 nucleosides linked together) having a nucleobase sequence including 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 NOs: 11 to 110, and a second modified oligonucleotide (e.g., a second modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 nucleosides linked together) having a region complementary to the first modified oligonucleotide.In certain embodiments, the compound includes a first modified oligonucleotide having a nucleobase sequence including any one of SEQ ID NOs: 11 to 110 (e.g., a first modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 nucleosides linked together) and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (e.g., a second modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 nucleosides linked together). In certain embodiments, the compound includes 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 nucleosides linked together, the second modified oligonucleotide having a region complementary to the first modified oligonucleotide.

[0157] In any of the above methods or uses, the compound can be an oligomeric compound. In any of the above methods or uses, the compound can be single-stranded or double-stranded. In any of the above methods or uses, the compound can target the CFB. In certain embodiments, the compound comprises or consists of a modified oligonucleotide. In certain embodiments, the compound comprises one or more modified oligonucleotides. In certain embodiments, the compound comprises a first modified oligonucleotide and a second modified oligonucleotide. In certain embodiments, the modified oligonucleotide is 8-80 nucleosides linked in length, 10-30 nucleosides linked in length, 14-30 nucleosides linked in length, 14-23 nucleosides linked in length, or 19-23 nucleosides linked in length. In certain embodiments, a modified oligonucleotide having a nucleobase sequence is at least 80%, at least 85%, at least 90%, at least 95% or 100% complementary over its length to the nucleobase sequence shown in SEQ ID NO: 1 or 3. In certain embodiments, a 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 5-methylcytosine. In any of the above embodiments, each modified oligonucleotide is independently 12-30, 14-30, 14-25, 14-24, 14-23, 16-23, 17-23, 18-23, 19-23, 19-22, or 19-20 linked nucleosides in length. In certain embodiments, a modified oligonucleotide having a nucleobase sequence has at least 1, at least 2, or at least 3 mismatches to a nucleobase region of SEQ ID NO: 1 or 3.

[0158] In any of the above methods or uses, the compound comprises a first and a second modified oligonucleotide, and there is a region of complementarity between the first modified oligonucleotide and the second modified oligonucleotide. In certain embodiments, the region of complementarity between the first and second oligonucleotides is 14-23, 19-23, or 21-23 nucleosides in length. In certain embodiments, the first modified oligonucleotide is fully complementary to the second modified oligonucleotide. In certain embodiments, the first modified oligonucleotide comprises at least one modification selected from a modified internucleoside linkage, a modified sugar, and a modified nucleobase. In certain embodiments, the second modified oligonucleotide comprises at least one modification selected from a modified internucleoside linkage, a modified sugar, and a modified nucleobase. 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'-terminus of the first or second modified oligonucleotide or at the 5'-terminus of the first or second modified oligonucleotide. In certain embodiments, the first or second modified oligonucleotide comprises one or more modified sugars. In certain embodiments, each nucleoside of the first or second modified oligonucleotide comprises a modified sugar. In certain embodiments, the modified sugar comprises a modification selected from a halogen, an alkoxy group, and a 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 or second modified oligonucleotide comprises 10 or fewer 2'-F sugar modifications. In certain embodiments, the first or second modified oligonucleotide comprises 5 or fewer 2'-F sugar modifications.

[0159] In any of the above methods or uses, the compound comprises a conjugate group. In certain embodiments, the conjugate group is attached to the 5' end of the modified oligonucleotide. In certain embodiments, the conjugate group is a targeting moiety. In certain embodiments, the targeting moiety comprises one or more GalNAcs. In certain embodiments, the one or more GalNAcs are attached to the 2' or 3' position of the ribosyl ring. In certain embodiments, the one or more GalNAcs are attached to the 5' nucleoside of the modified oligonucleotide. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is selected from Formulae I-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 of formula II and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula II and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula III and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula III and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula IV and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula IV and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula V and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula V and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VI and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula VI and R' is S.In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VII and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VII and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VIII and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VIII and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of 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 of formula XII and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula XII and R' is S.

[0160] In any of the above methods or uses, the compound comprises a first modified oligonucleotide selected from any one of IA0478-490, IA0840, IA0842-846, IA0852-862, IA0872-882, IA0887-890, IA1010-1012 and IA1015-1018, and a second modified oligonucleotide having a length of 14 to 21 nucleosides linked together, said second modified oligonucleotide being completely complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide selected from IA0478-490, IA0840, IA0842-846, IA0852-862, IA0872-882, IA0887-890, IA1010-1012, and IA1015-1018, and a second modified oligonucleotide selected from 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. Certain embodiments provide a compound comprising a first modified oligonucleotide that is IA0840 and a second modified oligonucleotide that is IS0972. Certain embodiments provide a compound comprising a first modified oligonucleotide that is IA0842 and a second modified oligonucleotide that is IS0974. Certain embodiments provide a compound comprising a first modified oligonucleotide that is IA0888 and a second modified oligonucleotide that is IS1109. Certain embodiments provide a compound comprising a first modified oligonucleotide that is IA0888 and a second modified oligonucleotide that is IS1236. Certain embodiments provide a compound comprising a first modified oligonucleotide that is IA1010 and a second modified oligonucleotide that is IS1109. Certain embodiments provide a compound comprising a first modified oligonucleotide that is IA1011 and a second modified oligonucleotide that is IS1239.Certain embodiments provide compounds comprising a first modified oligonucleotide that is IA1012 and a second modified oligonucleotide that is IS1242. Certain embodiments provide compounds comprising a first modified oligonucleotide that is IA1016 and a second modified oligonucleotide that is IS1252. Certain embodiments provide compounds comprising a first modified oligonucleotide that is IA1017 and a second modified oligonucleotide that is IS1253.

[0161] 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 the compound of any one of the above embodiments and a pharmaceutically acceptable carrier.

[0162] In any of the above methods or uses, the compound of any of the above embodiments, or a composition comprising the compound, is administered to the individual in a therapeutically effective amount. In certain embodiments, the compound of any of the above embodiments, or a composition comprising the compound, is administered to the individual at a dosage level sufficient to deliver about 1-100 mg per kg of the individual's body weight. In certain embodiments, the compound of any of the above embodiments, or a composition comprising the compound, is administered to the individual at a fixed dose of about 25 mg to about 1,000 mg. In certain embodiments, the composition is administered to the individual one or more times per day, up to that dosage level or dose.

[0163] In any of the above methods or uses, the compound of any of the above embodiments, or a composition comprising the compound, is administered to an individual once a day, once a week, once a month, once a quarter, or once a year. In certain embodiments, the compound of any of the above embodiments, or a composition comprising the compound, is administered to an individual about once a quarter (i.e., once every three months) to about once a year. In certain embodiments, the compound of any of the above embodiments, or a composition comprising the compound, is administered to an individual about once a quarter, about once every six months, or about once a year.

[0164] Certain compounds In certain aspects, the present disclosure relates to compounds that comprise or consist of oligomeric compounds, hi certain embodiments, the oligomeric compounds comprise a nucleobase sequence that is complementary to the nucleobase sequence of a target nucleic acid or a portion thereof.

[0165] In certain aspects, the present disclosure relates to compounds that comprise or consist of modified oligonucleotides, which in certain embodiments have a nucleobase sequence that is complementary to the nucleobase sequence of a target nucleic acid, or a portion thereof.

[0166] In certain aspects, the disclosure relates to compounds that comprise or consist of antisense oligonucleotides, which in certain embodiments have a nucleobase sequence that is complementary to the nucleobase sequence of a target nucleic acid, or a portion thereof.

[0167] In certain aspects, the disclosure relates to compounds that are single-stranded compounds. In certain embodiments, the single-stranded compounds comprise or consist of oligomeric compounds. In certain embodiments, such oligomeric compounds comprise or consist of oligonucleotides and, optionally, conjugate groups. In certain embodiments, the oligonucleotides are modified oligonucleotides. In certain embodiments, the oligonucleotides are antisense oligonucleotides. In certain embodiments, the oligonucleotides or modified oligonucleotides of the single-stranded compounds comprise self-complementary nucleobase sequences. In certain aspects, the disclosure relates to compounds that are double-stranded compounds. In certain embodiments, the double-stranded compounds comprise or consist of oligomeric compounds. In certain embodiments, the double-stranded compounds comprise a first oligonucleotide and a second oligonucleotide. In certain 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 certain embodiments, the double-stranded compounds comprise modified oligonucleotides. In certain embodiments, the modified oligonucleotide has a region complementary to the target nucleic acid. In certain embodiments, the double-stranded compound comprises a first modified oligonucleotide and a second modified oligonucleotide. In certain embodiments, the first modified oligonucleotide has 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 with a uracil nucleobase.

[0168] In certain embodiments, the compounds described herein comprise a conjugate group.In certain embodiments, the first oligonucleotide or the first modified oligonucleotide of the double-stranded compound comprises a conjugate group.In certain embodiments, the second oligonucleotide or the second modified oligonucleotide of the double-stranded compound comprises a conjugate 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 conjugate group.

[0169] In certain embodiments, the compound is 14-30 linked nucleosides in length. In certain embodiments, the first oligonucleotide or the first modified oligonucleotide of the double-stranded compound is 14-30 linked nucleosides in length. In certain embodiments, the second oligonucleotide or the second modified oligonucleotide is 14-30 linked nucleosides in length. In certain embodiments, the oligonucleotide or the modified oligonucleotide of the double-stranded compound has a blunt end at one or both ends of the compound. In certain embodiments, the oligonucleotide or the modified oligonucleotide of the double-stranded compound includes non-complementary overhang-forming nucleosides at one or both ends of the compound.

[0170] In certain embodiments, the compound has a nucleobase sequence that includes at least 14 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 11-44 and 96-102. In certain embodiments, one of the oligonucleotides or modified oligonucleotides of the double-stranded compound has a nucleobase sequence that includes at least 14 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 11-44 and 96-102.

[0171] Examples of single-stranded and double-stranded compounds include, but are not limited to, oligonucleotides, antisense oligonucleotides, siRNAs, oligonucleotides targeting microRNAs, occupancy-based compounds (e.g., compounds that block mRNA processing or translation, and splicing compounds), and single-stranded RNAi compounds (e.g., small hairpin RNAs (shRNAs), single-stranded siRNAs (ssRNAs), and microRNA mimics).

[0172] In certain embodiments, the compounds described herein, when written in the 5'→3' orientation, have a nucleobase sequence that comprises the reverse complement of a target region of a target nucleic acid to which the compound is targeted.

[0173] In certain embodiments, the compounds described herein include oligonucleotides having a length of 12-30 linked subunits. In certain embodiments, the compounds described herein include oligonucleotides having a length of 12-23 linked subunits. In certain embodiments, the compounds described herein include oligonucleotides having a length of 14-30 linked subunits. In certain embodiments, the compounds described herein include oligonucleotides having a length of 14-23 linked subunits. In certain embodiments, the compounds described herein include oligonucleotides having a length of 15-30 linked subunits. In certain embodiments, the compounds described herein include oligonucleotides having a length of 15-23 linked subunits. In certain embodiments, the compounds described herein include oligonucleotides having a length of 16-30 linked subunits. In certain embodiments, the compounds described herein include oligonucleotides having a length of 16-23 linked subunits. In certain embodiments, the compounds described herein include oligonucleotides having a length of 17-30 linked subunits. In certain embodiments, the compounds described herein include oligonucleotides having a length of 17-23 linked subunits. In certain embodiments, the compounds described herein include oligonucleotides having a length of 18-30 linked subunits. In certain embodiments, the compounds described herein include oligonucleotides having a length of 18-23 linked subunits. In certain embodiments, the compounds described herein include oligonucleotides having a length of 19-30 linked subunits. In certain embodiments, the compounds described herein include oligonucleotides having a length of 19-23 linked subunits.In other words, each of these oligonucleotides may have between 12 and 30 subunits linked together, between 12 and 23 subunits linked together, between 14 and 30 subunits linked together, between 14 and 23 subunits linked together, between 15 and 30 subunits linked together, between 15 and 23 subunits linked together, between 16 and 30 subunits linked together, between 16 and 23 subunits linked together, between 17 and 30 subunits linked together, between 17 and 23 subunits linked together, between 18 and 30 subunits linked together, between 18 and 23 subunits linked together, between 19 and 30 subunits linked together, or between 19 and 23 subunits linked together. In certain embodiments, the compounds described herein include oligonucleotides that are 14 subunits linked in length. In certain embodiments, the compounds described herein include oligonucleotides that are 16 subunits linked in length. In certain embodiments, the compounds described herein include oligonucleotides that are 17 subunits linked in length. In certain embodiments, the compounds described herein include oligonucleotides with a length of 18 linked subunits. In certain embodiments, the compounds described herein include oligonucleotides with a length of 19 linked subunits. In certain embodiments, the compounds described herein include oligonucleotides with a length of 20 linked subunits. In certain embodiments, the compounds described herein include oligonucleotides with a length of 21 linked subunits. In certain embodiments, the compounds described herein include oligonucleotides with a length of 22 linked subunits. In certain embodiments, the compounds described herein include oligonucleotides with a length of 23 linked subunits.In another embodiment, the compounds described herein include oligonucleotides having 8-80, 12-50, 13-30, 13-50, 14-30, 14-50, 15-30, 15-50, 16-30, 16-50, 17-30, 17-50, 18-23, 18-24, 18-25, 18-50, 19-23, 19-30, 19-50, 20-23, or 20-30 linked subunits. In certain such embodiments, the compounds described herein include oligonucleotides that are 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 linked subunits in length, or a range defined by any two of the above values.

[0174] In certain embodiments, the compound may further comprise an additional moiety, such as a conjugate group or a delivery moiety. In certain embodiments, such a compound is an oligomeric compound, and the additional moiety is attached to the oligonucleotide. In certain embodiments, the conjugate group is attached to the nucleoside of the oligonucleotide.

[0175] In certain embodiments, the compound may be shortened or truncated, for example, one or more subunits may be deleted from the 5' end of the oligonucleotide (5' truncation) or from the 3' end (3' truncation).

[0176] In certain embodiments, the compound may be extended. For example, one or more subunits may be attached to the 3'-end or 5'-end of the oligonucleotide. In certain embodiments, at least one subunit (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or more subunits) is attached to the 5'-end of the oligonucleotide. In certain embodiments, at least one subunit (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or more subunits) is attached to the 3' end of the oligonucleotide. In certain embodiments, at least one subunit may be attached to the 3' or 5' end of an oligonucleotide of a double-stranded compound to form a 3' overhang and / or a 5' overhang. In certain embodiments, at least one subunit (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or more subunits) is attached to both 5' ends of the oligonucleotide of the double stranded compound.In certain embodiments, at least one subunit (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or more subunits) is attached to both 3' ends of the oligonucleotide of the double stranded compound. In certain embodiments, the subunits are attached to both oligonucleotides of a double-stranded compound at the same end (e.g., the subunit is attached to the 3' end of one oligonucleotide and the subunit is attached to the 5' end of the other oligonucleotide). In certain embodiments, when the subunits are attached to both oligonucleotides of a double-stranded compound at the same end, the number of subunits attached to each oligonucleotide may be the same or different. In certain embodiments, when the subunits are attached to both oligonucleotides of a double-stranded compound at the same end, the number of subunits attached to each oligonucleotide is the same. In certain embodiments, when the subunits are attached to both oligonucleotides of a double-stranded compound at the same end, the number of subunits attached to each oligonucleotide is different. This scenario, where the subunits are attached to both oligonucleotides of a double-stranded compound at the same end, may be found at one or both ends of the double-stranded compound. In certain embodiments, the subunits attached to the 3' end and / or the 5' end are modified.

[0177] 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.

[0178] In certain embodiments, the compounds described herein are oligonucleotide sequences that target CFB and can include any of the sequences described herein. In certain embodiments, the compounds can be double-stranded.

[0179] In certain embodiments, the compound comprises an oligonucleotide having a nucleobase sequence that comprises 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: 11-44 or 96-102. In certain embodiments, the compound comprises an oligonucleotide that comprises 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 an 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleobase portion of SEQ ID NO:96 and a second oligonucleotide comprising at least an 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleobase portion of SEQ ID NO:93. In certain embodiments, the compound comprises a first oligonucleotide comprising at least an 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleobase portion of SEQ ID NO:97 and a second oligonucleotide comprising at least an 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleobase portion 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.

[0180] In certain embodiments, the compound comprises a ribonucleotide in which the oligonucleotide has a uracil (U) in place of a thymine (T) in any of the sequences shown herein. In certain embodiments, the compound comprises a deoxyribonucleotide in which the oligonucleotide has a thymine (T) in place of a uracil (U) in any of the sequences shown herein.

[0181] A specific mechanism In certain embodiments, the compounds described herein comprise or consist of modified oligonucleotides. In certain embodiments, the compounds described herein comprise or consist of antisense oligonucleotides. In certain embodiments, the compounds comprise or consist of oligomeric compounds. In certain embodiments, the compounds described herein can hybridize to target nucleic acids. In certain embodiments, the compounds described herein selectively act on one or more target nucleic acids. Such compounds comprise nucleobase sequences that hybridize to one or more target nucleic acids to provide one or more desired activities, and do not hybridize to one or more non-target nucleic acids or do not hybridize to one or more non-target nucleic acids in a manner that provides less desirable activities.

[0182] In certain embodiments, the hybridization of the compound described herein to the target nucleic acid recruits one or more proteins that cleave the target nucleic acid. For example, certain compounds described herein or parts of the compounds are incorporated into the RNA-induced silencing complex (RISC), which ultimately cleaves the target nucleic acid. For example, certain compounds described herein cause the target nucleic acid to be cleaved by Argonaute. The compound that is incorporated into RISC is an RNAi compound. The RNAi compound can be double-stranded (siRNA) or single-stranded (ssRNA).

[0183] In certain embodiments, the hybridization of the compounds described herein to a target nucleic acid does not recruit a protein that cleaves the target nucleic acid. In certain such embodiments, the hybridization of the compounds to a target nucleic acid alters the splicing of the target nucleic acid. In certain embodiments, the hybridization of the compounds to a target nucleic acid inhibits the binding interaction of the target nucleic acid with a protein or other nucleic acid. In certain such embodiments, the hybridization of the compounds to a target nucleic acid alters RNA processing. In certain such embodiments, the hybridization of the compounds to a target nucleic acid alters the translation of the target nucleic acid.

[0184] The activity of a compound hybridized to a target nucleic acid may be observed directly or indirectly. In certain embodiments, observing or detecting an 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 splice variants of a nucleic acid or protein, and / or a change in a phenotype in a cell or animal.

[0185] Certain modifications In certain aspects, the present disclosure relates to a compound that comprises or consists of an oligonucleotide. The oligonucleotide is composed of linked nucleosides. In certain embodiments, the oligonucleotide may be unmodified RNA or DNA or may be modified. In certain embodiments, the oligonucleotide is a modified oligonucleotide. In certain embodiments, the modified oligonucleotide comprises at least one modified sugar, modified nucleobase, or modified internucleoside linkage compared to unmodified RNA or DNA. 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 comprise terminal modifications, such as 5'-terminal modifications and 3'-terminal modifications.

[0186] Sugar modifications and motifs 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 substitute. The sugar substitute may include one or more substitutions described herein.

[0187] 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.

[0188] In certain embodiments, the 2'-position substituent includes, but is not limited to, F and OCH3 ("OMe", "O-methyl" or "methoxy"). In certain embodiments, suitable 2'-position substituents for non-bicyclic modified sugars include, but are not limited to, halo, allyl, amino, azido, SH, CN, OCN, CF3, OCF3, F, Cl, Br, SCH3, SOCH3, SO2CH3, ONO2, NO2, N3, and NH2. In certain embodiments, the 2'-position substituent includes, but is not limited to, O-(C1-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, but are not limited thereto, wherein the alkyl, alkenyl and alkynyl can be substituted or unsubstituted C1-C 10 Alkyl or C2-C 10It can also be alkenyl and alkynyl. In certain embodiments, the substituents at the 2' position include, but are not limited to, alkaryl, aralkyl, O-alkaryl and O-aralkyl. In certain embodiments, these 2' substituents can be further substituted with one or more substituents independently selected from hydroxyl, alkoxy, carboxy, benzyl, phenyl, nitro(NO2), 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[(CH2) n O] m CH3, O(CH2) n OCH3, O(CH2) n CH3, O(CH2) n ONH2, O(CH2) n NH2, O(CH2) n SCH3 and O(CH2) n ON [(CH2) n CH3)]2, where n and m are independently 1 to about 10. In certain embodiments, the substituent at the 2' position includes, but is not limited to, OCH2CH2OCH3 ("MOE"), O(CH2)2ON(CH3)2 ("DMAOE"), O(CH2)2O(CH2)2N(CH3)2 ("DMAEOE"), and OCH2C(=O)-N(H)CH3 ("NMA").

[0189] In certain embodiments, suitable 4'-position substituents for non-bicyclic modified sugars include, but are not limited to, alkoxy (e.g., methoxy), alkyl, and those described in WO 2015 / 106128 to Manoharan et al. In certain embodiments, suitable 5'-position substituents for non-bicyclic modified sugars include, but are not limited to, methyl ("Me") (R or S), vinyl, and methoxy. In certain embodiments, the 2', 4', and 5'-position substituents described herein can also be attached to other specific positions on the sugar. In certain embodiments, such substituents can be attached to the 3'-position of the sugar of the 3'-terminal nucleoside, or the 5'-position of the 5'-terminal nucleoside. In certain embodiments, non-bicyclic modified sugars can include more than one non-bridged 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 the R and S isomers). In certain embodiments, modified sugar substituents include those described in WO 2008 / 101157 by Migawa et al. and US 2013 / 0203836 by Rajeev et al.

[0190] In certain embodiments, the modified sugar is a bicyclic sugar. A bicyclic sugar is a modified sugar that includes two rings, with the bicyclic structure being formed by a bridge connecting two of the atoms in the first ring to form the second ring. In certain embodiments, the bicyclic sugar includes a bridge substituent that bridges two of the atoms of the furanosyl ring to form the second ring. In certain embodiments, the bicyclic sugar does not include a furanosyl moiety. A "bicyclic nucleoside" ("BNA") is a nucleoside that has a bicyclic sugar. In certain embodiments, the bicyclic sugar includes a bridge between the 4' and 2' furanose ring atoms. In certain embodiments, the bicyclic sugar includes a bridge between the 5' and 3' furanose ring atoms. In certain such embodiments, the furanose ring is a ribose ring. In certain embodiments, the substituents bridging 4' and 2' include 4'-CH2-2', 4'-(CH2)2-2', 4'-(CH2)3-2', 4'-CH2-O-2' ("LNA"), 4'-CH2-S-2', 4'-(CH2)2-O-2' ("ENA"), 4'-CH(CH3)-O-2' ("constrained ethyl" or "cEt" when in the S configuration), 4'-CH2-O-CH2-2', 4'-CH2-N(R)-2', 4'-CH(CHOCH3)-O-2' ("constrained MOE" or "cMOE") and analogs thereof (e.g., U.S. Pat. No. 7,399,845), 4'-C(CH3)(CH3)-O-2' and analogs thereof (e.g., U.S. Pat. No. 8,278,283), 4'-CH2-N(OCH3)-2' and analogs thereof (e.g., U.S. Pat. No. 8,278,425), 4'-CH2-ON(CH3)-2' (e.g., U.S. Patent Application Publication No. 2004 / 0171570), 4'-CH2-N(R)-O-2' (wherein R is H, C1-C 12alkyl or a protecting group) (e.g., U.S. Pat. No. 7,427,672), 4'-CH2-C(H)(CH3)-2' (e.g., Chattopadhyaya el al., J. Org. Chem., 2009, 74, 118-134), and 4'-CH2-C(=CH2)-2' and analogs thereof (e.g., U.S. Pat. No. 8,278,426). The entire contents of each of the above are incorporated herein by reference. Additional representative U.S. patents and published U.S. patent applications that teach the preparation of bicyclic nucleonucleotides include, but are not limited to, U.S. Pat. Nos. 6,268,490, 6,525,191, 6,670,461, 6,770,748, 6,794,499, 6,998,484, 7,053,207, 7,034,133, 7,084,125, 7,399,845, 7,427,672, Nos. 7,569,686, 7,741,457, 8,022,193, 8,030,467, 8,278,425, 8,278,426, 8,278,283, US2008 / 0039618, US2009 / 0012281, US2013 / 0190383, and WO2013 / 036868, the entire contents of each of which are incorporated herein by reference. Any of the above bicyclic nucleosides can be prepared with one or more stereochemical sugar configurations, including, for example, α-L-ribofuranose and β-D-ribofuranose (see, e.g., WO99 / 14226). Certain bicyclic nucleosides herein are in the β-D configuration, unless otherwise indicated.

[0191] In certain embodiments, the modified sugar is a sugar substitute. In certain embodiments, the sugar substitute has an oxygen atom replaced with, for example, a sulfur atom, a carbon atom, or a nitrogen atom. In certain such embodiments, the sugar substitute may also include bridged and / or non-bridged substituents as described herein. In certain such embodiments, the sugar substitute includes a ring having more than five atoms. In certain such embodiments, the sugar substitute includes a cyclobutyl moiety in place of the pentofuranosyl sugar. In certain embodiments, the sugar substitute includes a six-membered ring in place of the pentofuranosyl sugar. In certain embodiments, the sugar substitute includes a tetrahydropyran ("THP") in place of the pentofuranosyl sugar. In certain embodiments, the sugar substitute includes a morpholino in place of the pentofuranosyl sugar. Representative United States patents which teach the preparation of such modified sugar structures include, but are not limited to, U.S. Pat. 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, and 5,591,722. Nos. 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, the entire contents of each of which are incorporated herein by reference.

[0192] In some embodiments, the surrogate sugar comprises an acyclic moiety. In certain embodiments, the surrogate sugar is an unlocked nucleic acid ("UNA"). A UNA is an acyclic unlocked nucleic acid in which any of the sugar bonds are removed to form an unlocked "sugar" residue. In one example, a UNA also includes a monomer in which the C1'-C4' bond (i.e., the carbon-oxygen-carbon covalent bond between the C1' and C4' carbons) is removed. In another example, the C2' and C3' bond (i.e., the carbon-carbon covalent bond between the C2' and C3' carbons) of the sugar is removed. Representative U.S. publications teaching the preparation of UNAs include, but are not limited to, U.S. Patent No. 8,314,227, and U.S. Patent Application Publication Nos. 2013 / 0096289, 2013 / 0011922, and 2011 / 0313020, the entire contents of each of which are incorporated herein by reference. In certain embodiments, sugar surrogates include peptide nucleic acids ("PNAs"), acyclic butyl nucleic acids (see, e.g., Kumar et al., Org. Biomol. Chem., 2013, 11, 5853-5865), and the nucleosides and oligonucleotides described in Manoharan et al., US 2013 / 130378, the entire contents of which are incorporated herein by reference. Many other bicyclic sugars, tricyclic sugars, and sugar surrogate ring systems are known in the art that can be used in modified nucleosides.

[0193] In certain aspects, the present disclosure relates to compounds comprising at least one oligonucleotide, the nucleosides of which contain one or more modified and / or unmodified sugars arranged in a predetermined pattern or "sugar motif" along the oligonucleotide or region thereof. In certain instances, such sugar motifs include, but are not limited to, any of the sugar modification patterns described herein.

[0194] In certain embodiments, the oligonucleotide comprises a gapmer sugar motif. A gapmer oligonucleotide comprises or consists of a region having two outer "wing" regions and a central or internal "gap" region. The gap and wing regions form a contiguous sequence of nucleosides, with the majority of nucleoside sugars of each wing being different from the majority of nucleoside sugars of the gap. In certain embodiments, the wing regions comprise a majority of modified sugars and the gap comprises a majority of unmodified sugars. In certain embodiments, the nucleosides of the gap are deoxynucleosides. Compounds having gapmer sugar motifs are described, for example, in U.S. Pat. No. 8,790,919, the entire contents of which are incorporated herein by reference.

[0195] In certain embodiments, one or both of the oligonucleotides of the double-stranded compound contain a triplex sugar motif. An oligonucleotide with a triplex sugar motif contains three identical sugar modifications on three consecutive nucleosides. In certain embodiments, the triplex is located at or near the cleavage site of the oligonucleotide. In certain embodiments, the oligonucleotide of the double-stranded compound may contain two or more triplex sugar motifs. In certain embodiments, the identical sugar modification of the triplex sugar motif is a 2'-F modification. Compounds with triplex sugar motifs are disclosed, for example, in U.S. Pat. No. 10,668,170, the entire contents of which are incorporated herein by reference.

[0196] In certain embodiments, one or both of the oligonucleotides of the double-stranded compound contain a quadruplex sugar motif. An oligonucleotide having a quadruplex sugar motif contains four identical sugar modifications on four consecutive nucleosides. In certain embodiments, the quadruplex is located at or near the cleavage site. In certain embodiments, the oligonucleotide of the double-stranded compound may contain two or more quadruplex sugar motifs. In certain embodiments, the identical sugar modification of the quadruplex sugar motif is a 2'-F modification. In a double-stranded compound having a double-stranded region that is 19-23 nucleotides in length, the cleavage site of the antisense oligonucleotide is typically around the 10th, 11th, and 12th positions from the 5' end. In certain embodiments, the quadruplex sugar motif is at the 8th, 9th, 10th, 11th position, 9th, 10th, 11th, 12th position, 10th, 11th, 12th position, 11th, 12th, 13th position, 11th, 12th, 13th, 14th position, or 12th, 13th, 14th, 15th positions of the sense oligonucleotide, counting from the first nucleoside at the 5' end of the sense oligonucleotide or from the first paired nucleotide in the double-stranded region toward the 5' end of the sense oligonucleotide. In certain embodiments, the quadruplex sugar motif is at the 8th, 9th, 10th, 11th position, 9th, 10th, 11th, 12th position, 10th, 11th, 12th position, 11th, 12th, 13th position, 11th, 12th, 13th, 14th position, or 12th, 13th, 14th, 15th position of the antisense oligonucleotide, counting from the first nucleoside at the 5' end of the antisense oligonucleotide or from the first paired nucleotide in the double-stranded region toward the 5' end of the antisense oligonucleotide. The cleavage site may vary depending on the length of the double-stranded region of the double-stranded compound and the position of the quadruplex may vary accordingly.

[0197] In certain embodiments, the oligonucleotide comprises an alternating sugar motif. In certain embodiments, one or both of the oligonucleotides of a double-stranded compound comprise an alternating sugar motif. An oligonucleotide with an alternating sugar motif comprises at least two different sugar modifications, where 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, etc. For example, the alternating motif can be "ABABABABABAB...", "AABBAABBAABB...", "AABAABAABAAB", "AAABAAABAAAB...", "AAABBBAAABBB..." or "ABCABCABCABC...", etc., where A, β, and C each represent one type of modification for that nucleoside. In certain embodiments, the alternating sugar motif is repeated 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 a 2'-OMe and a 2'-F sugar modification.

[0198] In certain embodiments, each nucleoside of an oligonucleotide is independently modified with one or more sugar modifications as described herein.In certain embodiments, each oligonucleotide of a double-stranded compound independently has one or more sugar motifs as described herein.In certain embodiments, the oligonucleotide that includes a sugar motif is fully modified, in that each nucleoside other than the nucleoside that includes the sugar motif includes a sugar modification.

[0199] Nucleobase modifications and motifs In certain embodiments, the compound described herein comprises modified oligonucleotide.In certain embodiments, modified oligonucleotide comprises one or more nucleosides that comprise modified nucleobase.In certain embodiments, modified oligonucleotide comprises one or more nucleosides that do not comprise nucleobase, and this nucleoside is called abasic nucleoside.

[0200] In certain embodiments, the modified nucleobase is selected from 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 nucleobases are 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—CH3) uracil, 5-propynylcytosine, 6-azo uracil, 6-azo cytosine, 6-azo thymine, 5-ribosyluracil (pseudouracil), 4-thiouracil, 8-halopurine, 8-aminopurine, 8-thiolpurine, 8-thioalkylpurine, 8-hydroxylpurine, 8-aza Selected from purine and other 8-substituted purines, 5-halo, particularly 5-bromo, 5-trifluoromethyl, 5-halouracil and 5-halocytosine, 7-methylguanine, 7-methyladenine, 2-F-adenine, 2-aminoadenine, 7-deazaguanine, 7-deazaadenine, 3-deazaguanine, 3-deazaadenine, 6-N-benzoyladenine, 2-N-isobutyrylguanine, 4-N-benzoylcytosine, 4-N-benzoyluracil, 5-methyl 4-N-benzoylcytosine, 5-methyl 4-N-benzoyluracil, universal bases, hydrophobic bases, promiscuous bases, size-extended bases, and fluorinated bases. Further modified nucleobases include tricyclic pyrimidines, such as 1,3-diazaphenoxazin-2-one, 1,3-diazaphenothiazin-2-one, and 9-(2-aminoethoxy)-1,3-diazaphenoxazin-2-one (G clamp).Modified nucleobases may also include bases in which the purine or pyrimidine base is replaced with other heterocycles, such as 7-deaza-adenine, 7-deazaguanosine, 2-aminopyridine, and 2-pyridone.

[0201] Further nucleobases include those described in U.S. Pat. No. 3,687,808, Modified Nucleosides in Biochemistry, Biotechnology and Medicine, Herdewijn, P. ed. Wiley-VCH, 2008, The Concise Encyclopedia Of Polymer Science And Engineering, pages 858-859, Kroschwitz, JL, Ed., John Wiley & Sons, 1990, 858-859, Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613, Sanghvi, YS, Chapter 15, dsRNA Research and Applications, pages 289-302, Antisense Research and Applications, Crooke, ST and Lebleu, β., Eds., CRC Press, 1993, 273-288, Antisense Drug Technology, Crooke ST, Ed., CRC Press, 2008, 163-166 and 442-443 (Chapters 6 and 15), each of which is incorporated herein by reference.

[0202] Publications which teach the preparation of certain of the above and other modified nucleobases include, but are not limited to, U.S. Patent Application Publication Nos. 2003 / 0158403 and 2003 / 0175906, U.S. Patent Nos. 4,845,205, 5,130,302, 5,134,066, 5,175,273, 5,367,066, 5,432,272, and 5,432,272. No. 5,434,257, No. 5,457,187, No. 5,459,255, No. 5,484,908, No. 5,502,177, No. 5,525,711, No. 5, No. 552,540, No. 5,587,469, No. 5,594,121, No. 5,596,091, No. 5,614,617, No. 5,645,985, No. 5,681,941 No. 5,811,534, No. 5,750,692, No. 5,948,903, No. 5,587,470, No. 5,457,191, No. 5,763,588, No. 5, No. 830,653, No. 5,808,027, No. 6,005,096, No. 6,015,886, No. 6,147,200, No. 6,166,197, No. 6,166,199 Nos. 6,222,025, 6,235,887, 6,380,368, 6,528,640, 6,639,062, 6,617,438, 7,045,610, 7,427,672, and 7,495,088, the contents of each of which are incorporated herein by reference in their entirety.

[0203] In certain embodiments, the compounds described herein comprise oligonucleotides. In certain embodiments, the oligonucleotides comprise modified and / or unmodified nucleobases arranged in a predetermined pattern or motif along the oligonucleotide or a region thereof. 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 oligonucleotide are 5-methylcytosine.

[0204] In certain embodiments, the modified oligonucleotide comprises a modified nucleobase block. In certain such embodiments, the block is at the 3' end of the oligonucleotide. In certain embodiments, the block is within 3 nucleosides from 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 from the 5' end of the oligonucleotide.

[0205] Internucleoside linkage modifications and motifs The 3'→5' phosphodiester bond is the natural internucleoside bond of RNA and DNA. In certain embodiments, the compounds described herein have one or more modified internucleoside linkages, i.e., non-natural internucleoside linkages. Certain non-natural internucleoside linkages can provide desirable properties, such as enhanced cellular uptake, enhanced affinity for target nucleic acids, and increased stability in the presence of nucleases. Representative modified internucleoside linkages that contain phosphorus include, but are not limited to, phosphotriesters, alkylphosphonates (e.g., methylphosphonates), phosphoramidates, and phosphorothioates ("P=S") and phosphorodithioates ("HS-P=S"). Representative phosphorus-free internucleoside linkage groups include, but are not limited to, methylenemethylimino (-CH2-N(CH3)-O-CH2), thiodiester, thionocarbamate (-OC(=O)(NH)-S-), siloxane (-O-SiH2-O-) and N,N'-dimethylhydrazine (-CH2-N((CH3)-N((CH3)-). Methods for preparing phosphorus-containing and phosphorus-free internucleoside linkages are well known to those of skill in the art. Neutral internucleoside linkages include phosphotriester, methylphosphonate, MMI(3'- Examples of neutral internucleoside linkages include, but are not limited to, CH2-N(CH3)-O-5'), amide-3 (3'-CH2-C(=O)-N(H)-5'), amide-4 (3'-CH2-N(H)-C(=O)-5'), formacetal (3'-O-CH2-O-5'), methoxypropyl, and thioformacetal (3'-S-CH2-O-5'). Additional neutral internucleoside linkages include nonionic linkages including siloxanes (dialkylsiloxanes), carboxylates, carboxamides, sulfides, sulfonates, and amides (see, e.g., Carbohydrate Modifications in Antisense Research; YS Sanghvi and PD Cook, Eds., ACS Symposium Series 580; Chapters 3 and 4, 40-65).Additional neutral internucleoside linkages include non-ionic linkages containing a mixture of N, O, S and CH2 moieties.

[0206] In certain embodiments, the compound provided by the present invention comprises at least one modified internucleoside bond.Modified internucleoside bond can be located at any position of oligonucleotide.In double-stranded compounds, modified internucleoside bond can be located at the sense oligonucleotide, antisense oligonucleotide or both oligonucleotides of the double-stranded compound.

[0207] In certain embodiments, the internucleoside linkage modifications may be present at all of the nucleosides of the oligonucleotide. In certain embodiments, the internucleoside linkage modifications may be present in an alternating pattern along the oligonucleotide. In certain embodiments, essentially all of the internucleoside linkage groups are phosphate internucleoside linkages (P=O). In certain embodiments, each internucleoside linkage group of the modified oligonucleotide is phosphorothioate (P=S). In certain embodiments, each internucleoside linkage group of the modified oligonucleotide is independently selected from phosphorothioate internucleoside linkages and phosphate internucleoside linkages. In certain embodiments, the pattern of internucleoside linkage modifications of each oligonucleotide of the double-stranded compound is the same. In certain embodiments, the pattern of internucleoside linkage modifications of each oligonucleotide of the double-stranded compound is different. In certain embodiments, the double-stranded compound comprises 6-8 modified internucleoside linkages. In certain embodiments, the 6-8 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 either or both of the 5'-terminus and 3'-terminus. In certain such embodiments, the modified internucleoside linkages are phosphorothioate internucleoside linkages or alkylphosphonate internucleoside linkages. In certain such embodiments, the antisense oligonucleotide comprises at least two modified internucleoside linkages at either or both of the 5'-terminus and 3'-terminus. In certain such embodiments, the modified internucleoside linkages are phosphorothioate internucleoside linkages or alkylphosphonate internucleoside linkages.

[0208] In certain embodiments, the double-stranded compound comprises an overhang region. In certain embodiments, the double-stranded compound comprises a phosphorothioate internucleoside bond modification or an alkylphosphonate internucleoside bond modification in the overhang region. In certain embodiments, the double-stranded compound comprises a phosphorothioate internucleoside bond or an alkylphosphonate internucleoside bond that connects the overhang nucleotide to the paired nucleotide next to the overhang nucleotide. For example, there may be at least two phosphorothioate internucleoside bonds between the three terminal nucleosides, two of which are overhang nucleosides, and the third nucleoside is the paired nucleoside next to the overhang nucleoside. These three terminal nucleosides 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.

[0209] In certain embodiments, the modified oligonucleotide comprises one or more internucleoside linkages with a chiral center. Exemplary chiral internucleoside linkages include, but are not limited to, alkyl phosphonates and phosphorothioates. Modified oligonucleotides comprising internucleoside linkages with a chiral center can be prepared as a population of modified oligonucleotides comprising stereorandom internucleoside linkages or as a population of modified oligonucleotides comprising phosphorothioate linkages of a specific stereochemical configuration. In certain embodiments, the population of modified oligonucleotides comprises phosphorothioate internucleoside linkages, all of which are stereorandom. Such modified oligonucleotides can be produced using a synthesis method in which the stereochemical configuration of each phosphorothioate linkage is randomly selected. As will be appreciated by those skilled in the art, each individual phosphorothioate of each individual oligonucleotide molecule has a defined stereochemical configuration. In certain embodiments, the population of modified oligonucleotides is enriched for modified oligonucleotides that contain one or more specific phosphorothioate internucleoside linkages that are in a specific stereochemical arrangement that is selected independently. In certain embodiments, the specific phosphorothioate linkages in the specific arrangement are present in at least 65% of the molecules in the population. In certain embodiments, the specific phosphorothioate linkages in the specific arrangement are present in at least 70% of the molecules in the population. In certain embodiments, the specific phosphorothioate linkages in the specific arrangement are present in at least 80% of the molecules in the population. In certain embodiments, the specific phosphorothioate linkages in the specific arrangement are present in at least 90% of the molecules in the population. In certain embodiments, the specific phosphorothioate linkages in the specific arrangement are present in at least 99% of the molecules in the population.Such modified oligonucleotide enriched populations can be produced using synthetic methods known in the art, such as those described in Oka et al., JACS 125, 8307 (2003), Wan et al. Nuc. Acid. Res. 42, 13456 (2014) and WO2017 / 015555. In certain embodiments, the modified oligonucleotide population is enriched in modified oligonucleotides having at least one phosphorothioate in the (Sp) configuration among the phosphorothioates shown. In certain embodiments, the modified oligonucleotide population is enriched in modified oligonucleotides having at least one phosphorothioate in the (Rp) configuration.

[0210] Conjugate Group In certain embodiments, the compounds described herein comprise or consist of one or more oligonucleotides and, optionally, one or more conjugate groups. The conjugate groups may be attached to either or both ends of the oligonucleotide and / or to any internal position. In certain embodiments, the conjugate groups may be attached at the 3' end of the oligonucleotide. In certain embodiments, the conjugate groups may be attached at the 5' end of the oligonucleotide. In certain embodiments, the oligonucleotide may be covalently attached to one or more conjugate groups.

[0211] In certain embodiments, the conjugate group is a terminal group attached to either or both ends of the oligonucleotide.In certain such embodiments, the terminal group is attached at the 3' end of the oligonucleotide.In certain such embodiments, the terminal group is attached at the 5' end of the oligonucleotide.In certain embodiments, the terminal group includes, but is not limited to, a capping group, a phosphate moiety, a protecting group, a modified or unmodified nucleoside, and two or more nucleosides that are independently modified or unmodified, such as an overhang.

[0212] In certain embodiments, the conjugate group modifies one or more of the properties of the oligonucleotide to which it is attached, including but not limited to its pharmacodynamics, pharmacokinetics, stability, activity, half-life, binding, absorption, tissue distribution, cellular distribution, cellular uptake, charge and clearance.In certain embodiments, the conjugate group enhances the affinity of the compound to a certain target, for example, a molecule, a cell or cell type, a compartment, for example, a cellular or organ compartment, a tissue, an organ or an area of ​​the body, for example, compared to a compound that does not have such a conjugate group.In certain embodiments, the conjugate group provides the oligonucleotide to which it is attached with a new property, for example, a fluorophore group or a reporter group that makes the oligonucleotide detectable.

[0213] In certain embodiments, conjugate groups include, but are not limited to, intercalators, reporter molecules, polyamines, polyamides, peptides, glycans, vitamin moieties, polyethylene glycols, thioethers, polyethers, cholesterol, thiocholesterol, cholic acid moieties, folic acid, lipids, phospholipids, biotin, phenazine, phenanthridine, anthraquinone, adamantane, acridine, fluoresceins, rhodamines, coumarins, fluorophores, and dyes.

[0214] In certain embodiments, the conjugate group includes an active drug substance, such as aspirin, warfarin, phenylbutazone, ibuprofen, suprofen, fenbufen, ketoprofen, (S)-(+)-pranoprofen, carprofen, dansylsarcosine, 2,3,5-triiodobenzoic acid, fingolimod, flufenamic acid, folinic acid, benzothiadiazide, chlorothiazide, diazepines, indomethacin, barbiturates, cephalosporins, sulfa drugs, antidiabetics, antibacterial agents, or antibiotics.

[0215] In certain embodiments, the conjugate group is a targeting moiety.In certain embodiments, the targeting moiety includes, but is not limited to, lectin, glycoprotein, lipid, protein, peptide, peptidomimetic, receptor ligand, antibody, thyrotropin, melanotropin, surfactant protein A, glycan, glycan derivative, modified glycan, glycan cluster, polysaccharide, modified polysaccharide or polysaccharide derivative, mucin glycan, polyvalent lactose, polyvalent galactose, N-acetyl-galactosamine (GalNAc), N-acetylglucosamine, polyvalent mannose, polyvalent fucose, glycosylated polyamino acid, polyvalent galactose, transferrin, bisphosphonate, polyglutamic acid, polyaspartic acid, lipid, cholesterol, steroid, bile acid, folic acid, vitamin B12, vitamin A, biotin, or RGD peptide or RGD peptide mimic.

[0216] In certain embodiments, the conjugate group may be any of the conjugate groups described in the following references, e.g., 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, e.g., hexyl-S-tritylthiol (e.g., Manoharan et al., αnn. 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, 19 ...esters, e.g., thioesters, e.g., thioesters, e.g., thioesters, e.g., thioesters, e.g., thioesters, e.g., thioesters, e.g., thioesters, e.g., Res., 1992, 20:533-538), aliphatic chains such as dodecanediol or undecyl residues (e.g., Saison-Behmoaras et al., EMBO J, 1991, 10:1111-1118; Kabanov et al., FEBS Lett., 1990, 259:327-330; Svinarchuk et al., Biochimie, 1993, 75:49-54), phospholipids such as di-hexadecyl-rac-glycerol or triethyl-ammonium 1,2-di-O-hexadecyl-rac-glycero-3-H-phosphonate (e.g., Manoharan et al., Tetrahedron Lett., 1995, 36:3651-3654; Shea et al., Nucl. Acids, 1995, 36:3651-3654). Res., 1990,18:3777-3783), polyamine or polyethylene glycol chains (e.g., Manoharan et al., Nucleosides & Nucleotides, 1995,14:969-973), adamantane acetic 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 moieties (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 glycans (e.g., Maier et al., Bioconjugate Chemistry, 2003, 14, 18-29; Rensen et al. al., J. Med. Chem. 2004, 47, 5798-5808, WO2009 / 073809, U.S. Patent Nos. 8,106,022, 8,450,467 and 8,828,957, WO2014 / 179445, WO2014 / 179620, and U.S. Patent Nos. 9,127,276, 9,181,549 and 10,844,379), each of which is incorporated herein by reference in its entirety.

[0217] The conjugate group may be attached to the oligonucleotide via a conjugate linker. In certain embodiments, the conjugate linker comprises a chain structure, such as a hydrocarbyl chain, or an oligomer consisting of repeating units or a combination of such repeating units. In certain embodiments, the conjugate linker comprises one or more groups selected from alkyl, amino, oxo, amide, disulfide, polyethylene glycol, ether, thioether, and hydroxylamino. In certain embodiments, the conjugate linker comprises at least one phosphorus group. In certain embodiments, the conjugate linker comprises at least one phosphate group. In certain embodiments, the conjugate linker comprises at least one neutral linking group. In certain embodiments, the conjugate linker includes, but is not limited to, pyrrolidine, 8-amino-3,6-dioxaoctanoic acid (ADO), succinimidyl 4-(N-maleimidophenyl)cyclohexane-1-carboxylate (SMCC), and 6-aminohexanoic acid (AHEX or AHA). Other conjugate linkers include substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C2-C 10 Alkenyl, or substituted or unsubstituted C2-C 10A non-limiting list of preferred substituents in this case includes, but is not limited to, alkynyl, hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro, thiol, thioalkoxy, halogen, alkyl, aryl, alkenyl, and alkynyl. In certain embodiments, the conjugate linker comprises 1-10 linker nucleosides. In certain embodiments, such linker nucleosides may comprise modified or unmodified nucleosides. It is typically desirable for the linker nucleosides to be cleaved from the compound after the compound has reached the target tissue. Thus, the linker nucleosides of the present invention can be linked to each other and to the remainder of the compound via cleavable bonds. In the present invention, the linker nucleosides are not considered to be part of the oligonucleotide. Thus, in embodiments where a compound comprises an oligonucleotide that comprises a predetermined number or range of linked nucleosides and / or a predetermined percentage of complementarity to a reference nucleic acid, and the compound also comprises a conjugate group that comprises a conjugate linker that comprises linker nucleosides, these linker nucleosides are not counted toward the length of the oligonucleotide and are not used in determining the percentage of complementarity of the oligonucleotide to the reference nucleic acid.

[0218] In certain embodiments, conjugate groups and conjugate linkers, as well as other modifications, include those described in US5,994,517, US6,300,319, US6,660,720, US6,906,182, US7,262,177, US7,491,805, US8,106,022, US7,723,509, US9,127,276, US2006 / 0148740, US2011 / 0123520, WO2013 / 033230, WO2012 / 037254, Biessen et al., J. Med. Chem. 1995, 38, 1846-1852, Lee et al., Bioorganic & Medicinal Chemistry 2011,19,2494-2500, Rensen et al.,J.Biol.Chem.2001,276,37577-37584, Rensen et al.,J.Med.Chem.2004,47,5798-5808, Sliedregt et al. al., J.Med.Chem.1999,42,609-618, Valentijn et al.,Tetrahedron,1997,53,759-770, Lee,Carhohydr Res,1978,67,509-514, Connolly et al.,J Biol Chem,1982,257,939-945, Pavia et al. al., Int J Pep Protein Res, 1983, 22, 539-548, Lee et al. al.,Biochem,1984,23,4255-4261, Lee et al.,Glycoconjugate J,1987,4,317-328,Toyokuni et al.,Tetrahedron Lett,1990,31,2673-2676,Biessen et al.,J Med Chem,1995,38,1538-1546, Valentijn et al.,Tetrahedron,1997,53,759-770, Kim et al.,Tetrahedron Lett,1997,38,3487-3490, Lee et al.,Bioconjug Chem,1997,8,762-765, Kato et al. al., Glycohiol, 2001, 11, 821-829, Rensen et al. al., J Biol Chem,2001,276,37577-37584、Lee et al.,Methids Enzymol,2003,362,38-43、Westerlind et al.,Glycoconj J,2004,21,227-241、Lee Meorg Me et al.,Bio Lett,2006,16(19),5132-5135、Maierhofer et al.,Bioorg Med Chem,2007,15,7661-7676、Khorev et al.,Bioorg Med Chem,2008,16,5216-Meorg et.5231、 Chem,2011,19,2494-2500、Kornilova et al.,Analyt Biochem,2012,425,43-46、Pujol et al.,Angew Chemie Int Ed Engl,2012,51,7445-7448 et.al.,Biessen、 Chem,1995,38,1846-1852、Sliedregt et al.,J Med Chem,1999,42,609-618、Rensen et al.,J Med Chem,2004,47,5798-5808、Rensense et al.,Throm Varterios Biol,2006,26,169-175、van Rossenberg et al.,Gene Ther,2004,11,457-464、Sato et al.,Jam Chem Soc,2004,126,14013-14022、Lee et al.,J Org. Chem,2012,77,7564-7571、Biessen et al.,FASEB J,2000,14,1784-1792、Rajur et al.,Bioconjug Chem,1997,8,935-940、Duff et al.,Methods Enzymol,2000,313,297-321、Maier et al.,Bioconjug Chem,2003,14,18-29、Jayaprakash et al.,Org Lett,2010,12,5410-5413、Ac02se Nucleic Devic,Antisen12,103-128, Merwin et al., Bioconjug Chem, 1994, 5, 612-620, Tomiya et al., Bioorg Med Chem, 2013, 21, 5275-5281, International Publication No. 1998 / 013381, same as No. 2011 / 038356, same as No. 1997 / 046098, same as No. 2008 / 098788, same as No. 2004 / 101619, same as No. 2 No. 012 / 037254, same as No. 2011 / 120053, same as No. 2011 / 100131, same as No. 2011 / 163121, same as No. 2012 / 177947, same as No. 2013 / 033230, same as No. 2013 / 075035, same as No. 2 012 / 083185, 2012 / 083046, 2009 / 082607, 2009 / 134487, 2010 / 144740, 2010 / 148013, 1997 / 020563, 2010 / 088537, 2002 / 043771, 2010 / 129709, 2012 / 068187, 2009 / 126933, 2004 / 024757, 2010 / 054406, 2 No. 012 / 089352, same as No. 2012 / 089602, same as No. 2013 / 166121, same as No. 2013 / 165816, US Patent No. 4,751,219, same as No. 7,582,744, same as No. 8,552,163, same as No. 8,1 No. 37,695, same as No. 6,908,903, same as No. 6,383,812, same as No. 7,262,177, same as No. 6,525,031, same as No. 5,994,517, same as No. 6,660,720, same as No. 6,300,319, same as No. 7,72 No. 3,509, same as No. 8,106,022, same as No. 7,491,805, same as No. 7,491,805, same as No. 8,541,548, same as No. 8,344,125, same as No. 8,313,772, same as No. 8,349,308, same as No. 8,450,467, same as No. 8,501,930, same as No. 8,158,601, same as No. 7,262,177, same as No. 6,906,182, same as No. 6,620,916, same as No. 8,435,491, same as No. 8,404,862, same as No. 7,851,615, U.S. Patent Application Publication Nos. 2011 / 0097264, 2011 / 0097265, 2013 / 0004427, 2003 / 0119724, 2011 / 0207799, 2012 / 0035115, 2012 / 0230938, 2005 / 0164235, 2006 / 0183886, 2012 / 0136042, 2012 / 0095075, 2013 / 0109817, 2014 / 0109821, 2015 / 0109822, 2016 / 0109823, 2017 / 0109824, 2018 / 0109825, 2019 / 0109826, 2019 / 0109827, 2019 / 0109829, 2020 / 0109828, 2020 / 0109829, 2021 / 0109829, 2022 / 0109829, 2023 / 0109829, 2024 / 0109829, 2025 / 0109829, 2026 / 0109829, 2027 / 0109829, 2028 / 0109829, 2029 / 0119724, 2011 / 0207799, 2012 / 0035115, 2012 / 0230938, 2005 / 0164235, 2006 / These include, but are not limited to, those described in the following references: 2006 / 0148740, 2008 / 0206869, 2012 / 0165393, 2012 / 0101148, 2013 / 0121954, 2011 / 0123520, 2003 / 0077829, 2008 / 0108801, and 2009 / 0203132, each of which is incorporated herein by reference in its entirety.

[0219] A specific targeting part In certain embodiments, the compounds provided herein include a conjugate group. In certain embodiments, the oligonucleotides or modified oligonucleotides provided herein include a conjugate group. In certain embodiments, the conjugate group is a targeting moiety. In certain embodiments, the targeting moiety includes one or more GalNAcs. In certain embodiments, the one or more GalNAcs are attached to one or more positions of the furanose ring. In certain embodiments, the one or more GalNAcs are attached to the 2' or 3' positions of the furanose ring. In certain embodiments, the furanose ring is a subunit of the oligonucleotide or modified oligonucleotide. In certain embodiments, the furanose ring is the sugar of the 5' nucleoside of an oligonucleotide or modified oligonucleotide. In certain embodiments, the furanose ring is the sugar of the 5' nucleoside of a sense oligonucleotide or a sense modified oligonucleotide. In certain embodiments, the compounds, oligonucleotides or modified oligonucleotides include one or more subunits of the following formula, or a salt, solvate or hydrate thereof: [ka] During the ceremony, R 1 is H, adenine, guanine, thymine, cytosine, uracil, carbocyclyl, heterocyclyl, aryl, heteroaryl or a nucleobase analogue; R 2 is an oligonucleotide sequence, a modified oligonucleotide, or a compound, L 1 is alkyl or alkyl-C(=O)-NH-alkyl, L 2 is alkyl or alkyl-C(=O)-NH-alkyl, L 3is a bond, a phosphodiester bond, a phosphorothioate bond, a triazole, a tetrazole, an amide, a reverse amide, a carbamate, a carbonate, a urea, O, S, S(=O), S(=O), NH, a substituted N group, an alkyl, an alkenyl, a dienyl, an alkynyl, a heteroalkyl, or a phosphate; R 3 is H, -C=(O)-NH-(CH2CH2O) j -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 4 is H, -C=(O)-NH-(CH2CH2O) k -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 5 is -C=(O)-NH-(CH2CH2O) m -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 6 is -C=(O)-NH-(CH2CH2O) n -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; W and Q are each independently O, NH, CH2, or CH2O; S 1 and S 2 are each independently C(R 7 ) or N, wherein R 7 each instance of is independently H, alkyl, heteroalkyl, or halogen; j is an integer between 1 and 10, inclusive; k is an integer between 1 and 10, inclusive; m is an integer from 1 to 10, inclusive; n is an integer from 1 to 10 (inclusive).

[0220] In certain embodiments, R 3 , R 4 , R5 and R 6 are the same. In certain embodiments, R 3 , R 5 and R 6 are the same. In certain embodiments, R 3 or R 4 is H.

[0221] In certain embodiments, L 1 and L 2 is the same.

[0222] In certain embodiments, L 1 and L 2 are each independently alkyl; R 3 is H, -C=(O)-NH-(CH2CH2O) j -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 4 is H, -C=(O)-NH-(CH2CH2O) k -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 5 is -C=(O)-NH-(CH2CH2O) m -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 6 is -C=(O)-NH-(CH2CH2O) n -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc.

[0223] In certain embodiments, L 1 and L 2 are each independently alkyl-C(=O)-NH-alkyl; R 3 is H, -C=(O)-NH-(CH2CH2O) j -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 4 is H, -C=(O)-NH-(CH2CH2O) k-GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 5 is -C=(O)-NH-(CH2CH2O) m -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 6 is -C=(O)-NH-(CH2CH2O) n -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc.

[0224] In certain embodiments, R 4 is H.

[0225] In certain embodiments, L 1 and L 2 are each independently alkyl; R 3 is -C=(O)-NH-(CH2CH2O) j -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 4 is H and R 5 is -C=(O)-NH-(CH2CH2O) m -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 6 is -C=(O)-NH-(CH2CH2O) n -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc.

[0226] In certain embodiments, L 1 and L 2 are each independently alkyl-C(=O)-NH-alkyl; R 3 is -C=(O)-NH-(CH2CH2O) j -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 4 is H and R 5is -C=(O)-NH-(CH2CH2O) m -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 6 is -C=(O)-NH-(CH2CH2O) n -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc.

[0227] In certain embodiments, R 3 is -C=(O)-NH-(CH2CH2O) j -GalNAc, R 4 is H and R 5 is -C=(O)-NH-(CH2CH2O) m -GalNAc, R 6 is -C=(O)-NH-(CH2CH2O) n -GalNAc.

[0228] In certain embodiments, R 3 is -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc, R 4 is H and R 5 is -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc, R 6 is -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc.

[0229] In certain embodiments, the compound, modified oligonucleotide, or oligonucleotide comprises one or more subunits of the following formula, or a salt, solvate, or hydrate thereof: [ka] During the ceremony, R 9is H, adenine, guanine, thymine, cytosine or uracil, or adenine, guanine, thymine, cytosine or uracil, respectively, containing 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 analog; L is a bond, a phosphodiester bond, a phosphorothioate bond, a triazole, a tetrazole, an amide, a reverse amide, a carbamate, a carbonate, a urea, an alkyl, or a heteroalkyl; R 2 is an oligonucleotide sequence, a modified oligonucleotide, or a compound, 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; Each of n1, n3, n4, and n5 is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0230] In certain embodiments, the compound, modified oligonucleotide, or oligonucleotide comprises one or more subunits of the following formula, or a salt, solvate, or hydrate thereof: [ka] During the ceremony, each n is independently 1, 2, 3, 4, or 5; each m is independently 0, 1, 2, 3, 4, 5, or 6; each o is independently 0, 1, 2, 3, 4, 5, or 6; each of L1, L2, and L3 is independently absent, C(=O), or C(=O)NH; Each Y1 is independently O, CH(R a ), S, S(=O), S(=O)2, NH, substituted N group, 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-, Each Y2 is independently O, CH(R b ), S, S(=O), S(=O)2, NH, substituted N group, 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-, Each of Het1, Het2 and Het3 is independently optionally substituted heteroaryl or optionally substituted heterocyclyl; R 1 is an oligonucleotide sequence, modified oligonucleotide or compound linked by a bond, a phosphodiester bond, a phosphorothioate bond, a triazole, a tetrazole, an amide, a reverse amide, a carbamate, a carbonate, a urea, an alkyl or a heteroalkyl; Each of R5, R6 and R7 is independently [ka] and R9 is optionally substituted heterocyclyl; Each R a are independently H, alkyl, halo, OR c or S.R. c and Each R b are independently H, alkyl, halo, OR c or S.R. c and Each Rc is independently H or alkyl.

[0231] In certain embodiments, R' is OH. In certain embodiments, R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula I and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula I and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula II and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula II and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula III and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula III and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula IV and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula IV and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula V and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula V and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VI and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VI and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VII and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VII and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VIII and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VIII and R' is SH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula XII and R' is OH. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula XII, where R' is SH.

[0232] In certain embodiments, the subunits are selected from Formulae I-VIII and XII, or salts, solvates or hydrates thereof, where 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 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 of formula IV and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula V and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula V and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VI and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VI and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VII and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VII and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VIII and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VIII and R' is S. In certain embodiments, the subunit is of formula XII, or a salt, solvate, or hydrate thereof, where R is a modified oligonucleotide other than the 5' nucleoside.In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula XII and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula XII and R' is S.

[0233] Target Nucleic Acids and Target Regions In certain embodiments, the compounds described herein comprise or consist of an oligonucleotide comprising a region complementary to a target nucleic acid. In certain embodiments, the target nucleic acid is an endogenous RNA molecule. In certain embodiments, the target nucleic acid encodes a protein. In certain embodiments, the target nucleic acid is a non-coding nucleic acid. In certain such embodiments, the target nucleic acid is selected from an mRNA and a pre-mRNA comprising an intron region, an exon region, and an untranslated region. In certain embodiments, the target RNA is an mRNA. In certain embodiments, the target nucleic acid is a pre-mRNA. In certain such embodiments, the target region is entirely within an exon. In certain such embodiments, the target region is entirely within an intron. In certain embodiments, the target region spans an intron / exon junction. In certain embodiments, the target region is at least 50% within an intron.

[0234] In certain embodiments, the compounds disclosed herein hybridize with CFB nucleic acid. The most common mechanism of hybridization involves hydrogen bonding between complementary nucleobases of nucleic acid molecules. Hybridization can occur under various conditions. Hybridization conditions are sequence-dependent and depend on the nature and composition of the hybridizing nucleic acid molecule. Methods for determining whether a sequence specifically hybridizes to a target nucleic acid are well known in the art. In certain embodiments, the compounds provided herein specifically hybridize with CFB nucleic acid.

[0235] Nucleotide sequences encoding CFB include, but are not limited to, 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).

[0236] Complementarity The oligonucleotides provided by the present invention may have a defined degree of complementarity to a particular nucleic acid, target region, oligonucleotide, or portion thereof. Non-complementary nucleobases may be permitted as long as the oligonucleotide can still specifically hybridize to the nucleic acid, oligonucleotide, or portion thereof. In certain embodiments, the oligonucleotides provided by the present invention, or a predetermined portion thereof, are at least or at most 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% complementary to the target nucleic acid, target region, oligonucleotide, or a predetermined portion thereof. In certain embodiments, the oligonucleotides provided by the present invention, or a predetermined portion thereof, are 70%-75%, 75%-80%, 80%-85%, 85%-90%, 90%-95%, 95%-100%, or any value between these ranges, to the target nucleic acid, target region, oligonucleotide, or a predetermined portion thereof. The complementarity of an oligonucleotide with a target nucleic acid, a target region, an oligonucleotide or a specified portion thereof can be determined by a conventional method. For example, an oligonucleotide in which 18 of the 20 nucleobases of the oligonucleotide are complementary to the target region, i.e., hybridize specifically, has a complementarity of 90%. In this example, the remaining non-complementary nucleobases can be clustered together or interspersed with complementary nucleobases, and do not have to be contiguous with each other or with complementary nucleobases. That is, an oligonucleotide that is 18 nucleobases long and has 4 non-complementary nucleobases flanked by two regions that are completely complementary to the target nucleic acid has an overall complementarity of 77.8% with the target nucleic acid. The complementarity of an oligonucleotide with a target nucleic acid, a target region, an oligonucleotide or a specified portion thereof can be determined by a conventional method using the BLAST program (basic local alignment search tool) known in the art.In certain embodiments, the oligonucleotides described herein or a given portion thereof are fully complementary (i.e., 100% complementary) to a target nucleic acid, target region, oligonucleotide, or a given portion thereof. For example, an oligonucleotide may be fully complementary to a target nucleic acid, target region, oligonucleotide, or a given portion thereof. As used herein, "fully complementary" means that each nucleobase of an oligonucleotide is complementary to a corresponding nucleobase of a target nucleic acid, target region, oligonucleotide, or a given portion thereof. For example, a 20 nucleobase oligonucleotide is fully complementary to its target sequence as long as a corresponding 20 nucleobase portion of a target nucleic acid that is 400 nucleobases long is fully complementary to the compound. "Fully complementary" can also be used in reference to a given portion of a first and / or second nucleic acid. For example, a 20 nucleobase portion of a 30 nucleobase oligonucleotide can be "fully complementary" to a 20 nucleobase region of a target sequence that is 400 nucleobases long. A 20 nucleobase portion of a 30 nucleobase compound is fully complementary to a target sequence if the target sequence has a corresponding 20 nucleobase portion to which each nucleobase is complementary to the 20 nucleobase portion of the compound. 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.

[0237] In certain embodiments, the oligonucleotides described herein comprise one or more nucleobases that are mismatched with target nucleic acid, target region, oligonucleotide or a predetermined portion thereof.In certain embodiments, the oligonucleotides described herein comprise 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 nucleobases in length or up to this nucleobase length, comprise 4 or less, 3 or less, 2 or less, or 1 or less nucleobases that are non-complementary with target nucleic acid or a predetermined portion thereof. In certain embodiments, oligonucleotides described herein that are, or are up to, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleobases in length contain 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 nucleobase that is non-complementary to a target nucleic acid, target region, oligonucleotide, or a given portion thereof. In certain embodiments, the mismatch is at the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, or 14th position from the 5' end of the oligonucleotide. In certain embodiments, the mismatch is at the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th or 14th position from the 3' end of the oligonucleotide. In certain embodiments, the mismatch forms a wobble base pair with the corresponding nucleobase on the target nucleic acid. For example, in certain embodiments, the mismatch forms a wobble base pair selected from hypoxanthine (nucleobase of inosine) and uracil (I:U base pair), guanine and uracil (G:U base pair), hypoxanthine and adenine (I:A base pair), and hypoxanthine and cytosine (I:C base pair). Thus, in certain embodiments, the mismatched nucleobase on the oligonucleotide comprises hypoxanthine, guanine or uracil.

[0238] In certain embodiments, the oligonucleotides described herein may be complementary to a portion of a nucleic acid. As used herein, a "portion" refers to a predetermined number of consecutive nucleobases within a region of a nucleic acid. A "portion" can also refer to a predetermined number of consecutive nucleobases of an oligonucleotide. In certain embodiments, the oligonucleotide is complementary to at least an 8 nucleobase portion of a nucleic acid. In certain embodiments, the oligonucleotide is complementary to at least an 9 nucleobase portion of a nucleic acid. In certain embodiments, the oligonucleotide is complementary to at least an 10 nucleobase portion of a nucleic acid. In certain embodiments, the oligonucleotide is complementary to at least an 11 nucleobase portion of a nucleic acid. In certain embodiments, the oligonucleotide is complementary to at least an 12 nucleobase portion of a nucleic acid. In certain embodiments, the oligonucleotide is complementary to at least an 13 nucleobase portion of a nucleic acid. In certain embodiments, the oligonucleotide is complementary to at least an 14 nucleobase portion of a nucleic acid. In certain embodiments, the oligonucleotide is complementary to at least an 15 nucleobase portion of a nucleic acid. In certain embodiments, the oligonucleotide is complementary to at least an 16 nucleobase portion of a nucleic acid. Also contemplated is an oligonucleotide that is complementary to at least 9 nucleobases, 10 nucleobases, 17 nucleobases, 18 nucleobases, 19 nucleobases, 20 nucleobases, 21 nucleobases, 22 nucleobases or 23 nucleobases or more of nucleic acid, or a range defined by any two of these values.In certain embodiments, the oligonucleotide is an antisense oligonucleotide.In certain embodiments, a portion of the antisense oligonucleotide is compared with an equal length portion of target nucleic acid.In certain embodiments, a portion of 8 nucleobases, 9 nucleobases, 10 nucleobases, 11 nucleobases, 12 nucleobases, 13 nucleobases, 14 nucleobases, 15 nucleobases, 16 nucleobases, 17 nucleobases, 18 nucleobases, 19 nucleobases, 20 nucleobases, 21 nucleobases, 22 nucleobases, 23 nucleobases, 24 nucleobases or 25 nucleobases is compared with an equal length portion of target nucleic acid.In certain embodiments, the oligonucleotide is a sense oligonucleotide.In certain embodiments, a portion of the sense oligonucleotide is compared with the same length portion of antisense oligonucleotide.In certain embodiments, 8 nucleobases, 9 nucleobases, 10 nucleobases, 11 nucleobases, 12 nucleobases, 13 nucleobases, 14 nucleobases, 15 nucleobases, 16 nucleobases, 17 nucleobases, 18 nucleobases, 19 nucleobases, 20 nucleobases, 21 nucleobases, 22 nucleobases, 23 nucleobases, 24 nucleobases or 25 nucleobases of the sense oligonucleotide are compared with the same length portion of antisense oligonucleotide.

[0239] identity The oligonucleotides provided herein may also be specified with a percent identity with a particular nucleic acid, target region, oligonucleotide or a given portion thereof.As used herein, an oligonucleotide is identical to a sequence disclosed herein if it has the same nucleic acid base pairing ability.For example, since both uracil and thymidine pair with adenine, a DNA containing thymidine instead of uracil in a disclosed RNA sequence will be considered identical to the RNA sequence.Shortened and extended forms of the compounds described herein are also contemplated, as well as compounds with non-identical bases to the compounds provided herein.The non-identical bases may be adjacent to each other or distributed throughout the compound.The percent identity of an oligonucleotide is calculated according to the number of bases that are identical base pairing compared to the sequence to which it is compared. In certain embodiments, the oligonucleotides or portions thereof described herein are 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or at least 100% identical to one or more of the nucleic acids, oligonucleotides or portions thereof disclosed herein. In certain embodiments, the oligonucleotides described herein are about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% or about 99% identical to a particular nucleic acid or oligonucleotide or portion thereof, or any percentage between such values.

[0240] In certain embodiments, oligonucleotide may have one or more mismatched nucleobases.In certain such embodiments, the mismatch is at the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th or 14th position from the 5' end of the oligonucleotide.In certain such embodiments, the mismatch is at the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th or 14th position from the 3' end of the oligonucleotide.In certain embodiments, a portion of the oligonucleotide is compared with a portion of the target nucleic acid of equal length. In certain embodiments, 8 nucleobases, 9 nucleobases, 10 nucleobases, 11 nucleobases, 12 nucleobases, 13 nucleobases, 14 nucleobases, 15 nucleobases, 16 nucleobases, 17 nucleobases, 18 nucleobases, 19 nucleobases, 20 nucleobases, 21 nucleobases, 22 nucleobases, 23 nucleobases, 24 nucleobases or 25 nucleobases are compared with the part of the target nucleic acid of equal length.In certain embodiments, the oligonucleotide is a sense oligonucleotide.In certain embodiments, the part of the sense oligonucleotide is compared with the part of the target nucleic acid of equal length.In certain embodiments, 8 nucleobases, 9 nucleobases, 10 nucleobases, 11 nucleobases, 12 nucleobases, 13 nucleobases, 14 nucleobases, 15 nucleobases, 16 nucleobases, 17 nucleobases, 18 nucleobases, 19 nucleobases, 20 nucleobases, 21 nucleobases, 22 nucleobases, 23 nucleobases, 24 nucleobases or 25 nucleobases are compared with the part of the target nucleic acid of equal length.

[0241] Pharmaceutical Compositions and Formulations The compounds described herein may be mixed with pharma- ceutically acceptable active or inactive 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 dosage administered. Certain embodiments provide pharmaceutical compositions comprising one or more compounds or salts thereof. In certain embodiments, the compounds are antisense oligonucleotides. In certain embodiments, the compounds are oligomeric compounds. In certain embodiments, the compounds comprise or consist of one or more modified oligonucleotides. In certain such embodiments, the pharmaceutical compositions comprise one or more compounds and a suitable pharma- ceutically acceptable diluent or carrier. In certain embodiments, the pharmaceutical compositions comprise one or more compounds and sterile saline. In certain embodiments, such pharmaceutical compositions consist of a compound and sterile saline. In certain embodiments, the sterile saline is pharmaceutical grade saline. In certain embodiments, the pharmaceutical compositions comprise one or more compounds and sterile water. In certain embodiments, the pharmaceutical compositions consist of a compound and sterile water. In certain embodiments, the 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 pharmaceutical grade PBS.

[0242] The compound described herein that targets the CFB can be used in a pharmaceutical composition by combining the compound with a suitable pharma- ceutically acceptable diluent or carrier. In certain embodiments, the pharma-ceutically acceptable diluent is water, for example, sterile water suitable for injection. Thus, in one embodiment, the method described herein uses a pharmaceutical composition that includes a compound that targets the CFB and a pharma-ceutically acceptable diluent. In certain embodiments, the pharma-ceutically acceptable diluent is water. In certain embodiments, the compound comprises or consists of one or more modified oligonucleotides provided by the present invention.

[0243] Pharmaceutical compositions containing the compounds provided herein include any pharma- ceutically acceptable salts, esters, salts of such esters, or any other oligonucleotides that, when administered to an animal, including a human, can result (directly or indirectly) in a biologically active metabolite or residue thereof. In certain embodiments, the compound is an antisense oligonucleotide. In certain embodiments, the compound is an oligomeric compound. In certain embodiments, the compound comprises or consists of one or more modified oligonucleotides. Thus, for example, the disclosure is also directed to pharma- ceutically acceptable salts of the compounds, prodrugs, pharma- ceutically acceptable salts of such prodrugs, and other bioequivalents. Suitable pharma- ceutically acceptable salts include, but are not limited to, sodium and potassium salts. Prodrugs can include those that incorporate additional nucleosides at one or both ends of the compound, which are cleaved by endogenous nucleases in the body to form the active compound. In certain embodiments, the compound or composition further comprises a pharma- ceutically acceptable carrier or diluent.

[0244] It is understood that the examples and embodiments described herein are for illustrative purposes and that various modifications or changes in light thereof will be suggested to those skilled in the art and are to be included within the spirit and scope of this application and the scope of the appended claims. All publications, patents, and patent applications cited herein are incorporated herein by reference in their entirety for all purposes.

[0245] Additional Embodiments Certain specific embodiments include the following embodiments 1 to 97.

[0246] Embodiment 1: A compound comprising a modified oligonucleotide having a length of 14 to 23 nucleosides linked together, said modified oligonucleotide having a nucleobase sequence that includes 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: 11-44 or 96-102.

[0247] Embodiment 2: A compound comprising a modified oligonucleotide having a length of 14 to 23 nucleosides linked together, said modified oligonucleotide having a nucleic acid base sequence comprising any one of the nucleic acid base sequences of SEQ ID NOs: 11 to 44 or 96 to 102.

[0248] Embodiment 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.

[0249] 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.

[0250] Embodiment 5: The compound of any one of embodiments 1 to 4, wherein the modified oligonucleotide comprises at least one modification selected from a modified internucleoside linkage, a modified sugar, and a modified nucleobase.

[0251] Embodiment 6: The compound of any one of embodiments 1 to 5, which is double-stranded.

[0252] Embodiment 7: A compound comprising a first modified oligonucleotide having a length of 14 to 23 nucleosides linked together, the first modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 consecutive nucleobases of any of the nucleobase sequences of SEQ ID NOs: 11 to 110, and a second modified oligonucleotide having a length of 14 to 23 nucleosides linked together, the second modified oligonucleotide having a region complementary to the first modified oligonucleotide.

[0253] Embodiment 8: A compound comprising a first modified oligonucleotide having a length of 14 to 23 nucleosides linked together, the first modified oligonucleotide having a nucleic acid base sequence including any one of the nucleic acid base sequences of SEQ ID NOs: 11 to 110, and a second modified oligonucleotide having a length of 14 to 23 nucleosides linked together, the second modified oligonucleotide having a region complementary to the first modified oligonucleotide.

[0254] Embodiment 9: A compound comprising a first modified oligonucleotide having a nucleic acid base sequence selected from any one of SEQ ID NOs: 11 to 110, and a second modified oligonucleotide having a length of 19 to 23 nucleosides linked together, the second modified oligonucleotide having a region complementary to the first modified oligonucleotide.

[0255] Embodiment 10. The compound of any one of embodiments 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 over its length with the nucleobase sequence of SEQ ID NO: 1 or 3.

[0256] Embodiment 11. The compound of any one of embodiments 7 to 10, wherein the nucleobase sequence of the first modified oligonucleotide has at least one, at least two, or at least three mismatches with a region of the nucleobase sequence of SEQ ID NO: 1 or 3 that is the same length as the first modified oligonucleotide.

[0257] Embodiment 12. The compound of any one of embodiments 7 to 11, wherein the complementary region between the first modified oligonucleotide and the second modified oligonucleotide is 14 to 23 nucleosides in length.

[0258] Embodiment 13. The compound of any one of embodiments 7 to 11, wherein the complementary region between the first modified oligonucleotide and the second modified oligonucleotide is 19 to 23 nucleosides in length.

[0259] Embodiment 14. The compound of any one of embodiments 7 to 11, wherein the complementary region between the first modified oligonucleotide and the second modified oligonucleotide is 21 to 23 nucleosides in length.

[0260] 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.

[0261] Embodiment 16. The compound of any one of embodiments 7 to 15, wherein the first modified oligonucleotide comprises at least one modification selected from a modified internucleoside linkage, a modified sugar, and a modified nucleobase.

[0262] Embodiment 17. The compound of any one of embodiments 7 to 16, wherein the second modified oligonucleotide comprises at least one modification selected from a modified internucleoside linkage, a modified sugar, and a modified nucleobase.

[0263] Embodiment 18. The compound of any one of embodiments 5, 16 or 17, wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage or a methylphosphonate internucleoside linkage.

[0264] Embodiment 19. The compound of embodiment 18, wherein the phosphorothioate internucleoside linkage or methylphosphonate internucleoside linkage is at the 3' end of the first or second modified oligonucleotide, or at the 5' end of the first modified oligonucleotide.

[0265] Embodiment 20. The compound of any one of embodiments 5, 16, or 17, wherein the modified sugar comprises a modification selected from a halogen, an alkoxy group, and a bicyclic sugar.

[0266] Embodiment 21 The compound of embodiment 20, wherein the modified sugar comprises a 2'-F modification.

[0267] Embodiment 22 The compound of embodiment 20, wherein the modified sugar comprises a 2'-OMe modification.

[0268] Embodiment 23. The compound of any one of embodiments 7-15, wherein each nucleoside of the first modified oligonucleotide comprises a modified sugar.

[0269] Embodiment 24. The compound of any one of embodiments 7-15, wherein each nucleoside of the second modified oligonucleotide comprises a modified sugar.

[0270] Embodiment 25. The compound of embodiment 23 or 24, wherein the modified sugar comprises a modification selected from a halogen, an alkoxy group, and a bicyclic sugar, or a combination thereof.

[0271] Embodiment 26. The compound of embodiment 25, wherein the modified sugar comprises a modification selected from LNA, cEt, 2'-MOE, 2'-F, 2'-OMe and 2'-deoxy, or a combination thereof.

[0272] Embodiment 27 The compound of embodiment 23, wherein the first modified oligonucleotide comprises 10 or fewer 2'-F sugar modifications.

[0273] Embodiment 28. The compound of embodiment 24, wherein the second modified oligonucleotide comprises five or fewer 2'-F sugar modifications.

[0274] Embodiment 29. A compound according to any one of the above embodiments, comprising a conjugate group.

[0275] Embodiment 30 The compound of embodiment 29, wherein the conjugate group is attached to the 5' end of the modified oligonucleotide.

[0276] Embodiment 31 The compound of embodiment 29 or 30, wherein the conjugate group comprises a targeting moiety.

[0277] Embodiment 32 The compound of embodiment 31, wherein the targeting moiety comprises one or more GalNAc.

[0278] Embodiment 33 The compound of embodiment 32, wherein the modified oligonucleotide is the second modified oligonucleotide.

[0279] Embodiment 34 The compound of embodiment 32 or 33, wherein the one or more GalNAc are attached to the 2' or 3' position of the ribosyl ring of a 5' nucleoside of the modified oligonucleotide.

[0280] Embodiment 35. The 5' nucleoside is of the formula: [ka] During the ceremony, R 9 is H, adenine, guanine, thymine, cytosine or uracil, or adenine, guanine, thymine, cytosine or uracil, respectively, containing a protecting group (PG), a modified nucleobase, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or a nucleobase analog; L is a bond, a phosphodiester bond, a phosphorothioate bond, a triazole, a tetrazole, an amide, a reverse amide, a carbamate, a carbonate, a urea, an alkyl, or a heteroalkyl; 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; The compound of embodiment 34, wherein each of n1, n3, n4, and n5 is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0281] Embodiment 36. The compound of embodiment 34, wherein the 5' nucleoside is selected from any one of formulas I-VIII, and XII, wherein R' is S or SH, and R is a portion of the modified oligonucleotide other than the 5' nucleoside.

[0282] Embodiment 37. The compound of embodiment 34, wherein the 5' nucleoside is selected from any one of formulas I-VIII and XII, wherein R' is O or OH, and R is a portion of the modified oligonucleotide other than the 5' nucleoside.

[0283] Embodiment 38. A compound comprising a first modified oligonucleotide having a nucleic acid base sequence selected from any one of the nucleic acid base sequences of SEQ ID NOs: 11 to 110, and a second modified oligonucleotide having a length of 14 to 21 nucleosides linked together, said second modified oligonucleotide being completely complementary to the first modified oligonucleotide.

[0284] Embodiment 39. A compound comprising a first modified oligonucleotide having a nucleobase sequence selected from any one of the nucleobase sequences of reference numbers IA0478-490, IA0840, IA0842-846, IA0852-862, IA0872-882, IA0887-890, IA1010-1012 and IA1015-1018, and a second modified oligonucleotide having a length of 14 to 21 nucleosides linked together, wherein the second modified oligonucleotide is completely complementary to the first modified oligonucleotide.

[0285] Embodiment 40. A first modified oligonucleotide having a nucleobase sequence selected from any one of the nucleobase sequences of Reference ID Nos. 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 the nucleobase sequences of Reference ID Nos. IS0570-587, IS0969, IS0972-977. and a second modified oligonucleotide having a nucleobase sequence selected from any one of the nucleobase sequences of IS1023-1027, IS1029, IS1031-1037, IS1042-1046, IS1082, IS1085, IS1086, IS1091-1095, IS1108-1111, IS1236-1239, IS1242, IS1249 and IS1251-1254.

[0286] Embodiment 41. A compound comprising a first modified oligonucleotide having a nucleobase sequence selected from any one of the nucleobase sequences of Reference ID Nos. IA0840, IA0842, IA0888, IA1010-1012, and IA1016, and a second modified oligonucleotide having a nucleobase sequence selected from any one of the nucleobase sequences of Reference ID Nos. IS0972, IS0974, IS1109, IS1236, IS1239, IS1242, and IS1252.

[0287] Embodiment 42. A compound according to any one of embodiments 1 to 41, in the form of a pharma- ceutically acceptable salt.

[0288] Embodiment 43. The compound of embodiment 42, wherein the pharma- ceutically acceptable salt is a sodium salt.

[0289] Embodiment 44. The compound of embodiment 42, wherein the pharma- ceutically acceptable salt is a potassium salt.

[0290] Embodiment 45. A modified oligonucleotide according to the following chemical structure: [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0291] Embodiment 46. A modified oligonucleotide according to the following chemical structure: [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0292] Embodiment 47. A modified oligonucleotide according to the following chemical structure: [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0293] Embodiment 48. A modified oligonucleotide according to the following chemical structure: [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0294] Embodiment 49. A modified oligonucleotide according to the following chemical structure: [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0295] Embodiment 50. A modified oligonucleotide according to the following chemical structure: [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0296] Embodiment 51. A modified oligonucleotide according to the following chemical structure: [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0297] Embodiment 52. A modified oligonucleotide according to the following chemical structure: [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0298] Embodiment 53. The modified oligonucleotide of any one of embodiments 45 to 52, wherein the pharma- ceutically acceptable salt is a sodium salt or a potassium salt.

[0299] Embodiment 54. A sodium salt according to the following chemical structure: [ka] or a stereoisomer thereof.

[0300] Embodiment 55. A sodium salt according to the following chemical structure: [ka] or a stereoisomer thereof.

[0301] Embodiment 56. A sodium salt according to the following chemical structure: [ka] or a stereoisomer thereof.

[0302] Embodiment 57. A sodium salt according to the following chemical structure: [ka] or a stereoisomer thereof.

[0303] Embodiment 58. A sodium salt according to the following chemical structure: [ka] or a stereoisomer thereof.

[0304] Embodiment 59. A sodium salt according to the following chemical structure: [ka] or a stereoisomer thereof.

[0305] Embodiment 60. A sodium salt according to the following chemical structure: [ka] or a stereoisomer thereof.

[0306] Embodiment 61. A sodium salt according to the following chemical structure: [ka] or a stereoisomer thereof.

[0307] Embodiment 62. A compound according to the following chemical structure: [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0308] Embodiment 63. A compound according to the following chemical structure: [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0309] Embodiment 64. A compound according to the following chemical structure: [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0310] Embodiment 65. A compound according to the following chemical structure: [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0311] Embodiment 66. A compound according to any one of embodiments 62 to 65, wherein the pharma- ceutically acceptable salt is a sodium or potassium salt.

[0312] Embodiment 67. A sodium salt according to the following chemical structure: [ka] or a stereoisomer thereof.

[0313] Embodiment 68. A sodium salt according to the following chemical structure: [ka] or a stereoisomer thereof.

[0314] Embodiment 69. A sodium salt according to the following chemical structure: [ka] or a stereoisomeric salt thereof.

[0315] Embodiment 70. A sodium salt according to the following chemical structure: [ka] or a stereoisomer thereof.

[0316] Embodiment 71. A composition comprising a compound or modified oligonucleotide according to any one of embodiments 1 to 70 and a pharma- ceutically acceptable carrier.

[0317] Embodiment 72. A composition comprising a compound or a modified oligonucleotide according to any one of the above embodiments, said composition for use in therapy.

[0318] Embodiment 73. A method of administering a compound or modified oligonucleotide according to any one of embodiments 1 to 70, or a composition according to embodiment 71 or 72 to a subject in need thereof.

[0319] Embodiment 74. A method of 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 that targets CFB, thereby treating, preventing or ameliorating said disease, disorder or condition.

[0320] Embodiment 75 The method of embodiment 74, wherein the disease, disorder or condition is a complement pathway disorder.

[0321] Embodiment 76. The method of any one of embodiments 73-75, wherein administering the compound inhibits, reduces and / or ameliorates the disease, disorder, condition or symptoms thereof.

[0322] Embodiment 77. A method for inhibiting expression of CFB in a cell, comprising inhibiting expression of CFB in the cell by contacting the cell with a compound or modified oligonucleotide that targets CFB.

[0323] Embodiment 78 The method of embodiment 77, wherein the cells are in the liver of the individual.

[0324] Embodiment 79. The method of embodiment 78, wherein the subject has or is at risk of having a disease, disorder, condition, or symptom thereof.

[0325] Embodiment 80. A method for alleviating 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 that targets CFB.

[0326] Embodiment 81. The method of embodiment 80, wherein the subject has or is at risk of having a complement pathway disease, disorder, condition, or symptom thereof.

[0327] Embodiment 82. The method of any one of embodiments 74-81, 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).

[0328] Embodiment 83. The method of any one of embodiments 74 to 82, wherein the disease, disorder or condition is lupus nephritis.

[0329] Embodiment 84 The method of any one of embodiments 74 to 83, wherein the compound is a compound that targets the CFB.

[0330] Embodiment 85. The method of any one of embodiments 74 to 84, wherein the compound is a compound or modified oligonucleotide described in any one of embodiments 1 to 70, or a composition described in embodiment 71 or 72.

[0331] Embodiment 86 The method of embodiment 85, wherein the compound, modified oligonucleotide or composition is administered parenterally.

[0332] Embodiment 87. Use of a compound that targets CFB to treat, prevent or ameliorate a disease, disorder or condition associated with CFB, comprising administering to a subject in need thereof a compound or modified oligonucleotide that targets CFB.

[0333] Embodiment 88. The use of embodiment 87, wherein the disease is a complement pathway disease, disorder, condition or symptom thereof.

[0334] Embodiment 89. The use according to embodiment 87 or 88, wherein the compound is a compound that targets the CFB.

[0335] Embodiment 90. The method of any one of embodiments 87-89, wherein the compound is a compound or modified oligonucleotide described in any one of embodiments 1-70, or a composition described in embodiment 71 or 72.

[0336] Embodiment 91. Use of a compound that targets CFB in the manufacture of a medicament for treating, preventing, or ameliorating a disease, disorder, or condition associated with CFB.

[0337] Embodiment 92. The use according to any one of embodiments 87 to 91, wherein the disease is a disease, disorder or condition of the complement pathway, 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).

[0338] Embodiment 93. The use of any one of embodiments 87 to 92, wherein the disease, disorder or condition is lupus nephritis.

[0339] Embodiment 94. The use according to any one of embodiments 87 to 93, wherein the compound is a compound that targets the CFB.

[0340] Embodiment 95. The use according to any one of embodiments 87 to 94, wherein the compound is a compound or modified oligonucleotide according to any one of embodiments 1 to 70, or a composition according to embodiment 71 or 72.

[0341] Embodiment 96. The method or use of any one of embodiments 73 to 95, wherein the compound or composition is administered to the subject about once every three months to about once a year.

[0342] 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. EXAMPLES

[0343] The Examples below describe the process of identifying lead compounds that target CFB. Certain compounds stand out as being highly potent and well tolerated.

[0344] The following examples merely serve to illustrate the compounds described herein and are not intended to limit the compounds. The following examples and the associated sequence listing attached to this application may define sequences as either "RNA" or "DNA", however, as disclosed herein, these sequences may be modified with any combination of chemical modifications. Those skilled in the art will readily recognize that the definition of a sequence as "RNA" or "DNA" is optional in certain cases. For example, an oligonucleotide containing a nucleoside containing a 2'-OH sugar moiety and a thymine base may be described as a DNA with a modified sugar (2'-OH instead of the natural 2'-H of DNA) or an RNA with a modified base (methylated uracil instead of the natural uracil of RNA). Thus, the nucleic acid sequences provided herein, including but not limited to those in the sequence listing, are intended to include nucleic acids that contain any combination of natural or modified RNA and / or DNA, including but not limited to those nucleic acids with modified nucleobases.

[0345] Each of the references cited in this application is incorporated herein by reference in its entirety. [Table 1]

[0346] The newly designed double-stranded compounds in Tables 2 and 3 below were designed as unmodified (Table 2) and modified (Table 3) compounds. The chemical modification abbreviations used in Table 3 are shown in Table 1 above. In the Reference ID numbers, IA is defined as the antisense strand of the compound, and IS is defined as the sense strand of the compound. It is understood that the sequence shown in each SEQ ID NO: contained herein is independent of any modifications to the sugar moiety, internucleoside linkage, or nucleobase, even when shown in terms of modified compounds. The oligomeric compounds referenced by Compound Number or Reference ID number indicate a combination of nucleobase sequence and chemical modification. "Start site" indicates the 5'-most nucleotide (opposite the 3'-most nucleoside of the antisense oligonucleotide) to which the compound is directed in the human gene sequence. "Stop site" indicates the 3'-most nucleotide (opposite the 5'-most nucleoside of the antisense oligonucleotide) to which the compound is directed in the human gene sequence. Each of the compounds listed in Tables 2 and 3 targets human CFB mRNA, which is referred to herein as SEQ ID NO:1 (GenBank Accession No. NM_001710.6). [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8]

[0347] Example 1 - Inhibition of CFB in HepG2 cells In 96-well plates, HepG2 cells (ATCC catalog number HB-8065) ​​or Hepa1-6 cells (ATCC CRL-1830) were seeded at 10,000 cells / well in antibiotic-free medium. The next day, the CFB compounds to be tested were diluted to 1.0 μM (stock solutions are 10 μM). The transfection mix was prepared as described for the transfection reagent Dharmafect4 (Dharmacon catalog number T-2004-0). The prepared transfection mix was incubated for 20 min at room temperature. During this incubation, the medium was replaced with 80 μl of antibiotic-free medium in the 96-well plate. Then, 20 μl of the transfection mix was added to each well at a final concentration of 10 nM to 1 nM (tested in triplicate). CFB siRNA SMARTpool (Dharmacon Catalog No. 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, 5% CO2 for 24 hours.

[0348] Cells were lysed as described in the Cells-To-CT1 Step TaqMan Kit. After cell lysis, the 96-well plate was placed on ice while the qRT-PCR reaction was prepared. 2 μl of cell lysate was added to a reaction mixture containing 5 μl TaqMan 1-Step qRT-PCR Mix, 1 μl CFB(FAM) TaqMan Gene Expression Assay (Hs00156060_m1 or Mm00433909_m1), 1 μl GAPDH(VIC) TaqMan Gene Expression Assay (Hs02786624_g1 or Mm99999915_g1), and 11 μl RT-PCR grade nuclease-free water in a MicroAmp Optical 96-well plate (0.2 mL). qPCR was performed using a QuantStudio3 qPCR machine with cycles of 1 min at 50° C., 20 sec at 95° C., and 40 cycles of 15 sec at 95° C. and 1 min at 60° C. Results are shown in the table below as percent CFB inhibition compared to untreated control cells (Table 4). [Table 4]

[0349] Example 2: Effects of compounds targeting human CFB in mice Compounds RD1706, RD1707, RD1727, RD1708, RD1705 and RD1726 modified as in Table 3 were evaluated in C57Bl / 6 mice. Mice were housed in a vivarium under IACUC approved housing conditions prior to testing. On study day 0, mice were injected with a single subcutaneous dose of 5 mg / kg of oligonucleotide. The mice were observed daily for signs of disease or distress during the study. Mice were bled on days 0, 8, 15, 22, 29 and 35.

[0350] Immunoblotting was used to assess the levels of complement factor B (CFB) in mouse (C57Bl / 6) serum. After serum collection, the serum was diluted with 1x PBS buffer and mixed with SDS-PAGE compatible loading buffer and reducing reagent. Samples were heated to 70°C for 10 min and separated by SDS-PAGE. After the samples were run by PAGE, the proteins were transferred to nitrocellulose or other compatible membranes. The membranes were stained with Revert700 and the total protein of each sample was quantified using the detection system Odyssey CLx.

[0351] The membranes were blocked with Intercept® Blocking Buffer (P / N: 927-60001) and then probed with a primary antibody specific for CFB (Invitrogen #27924). The antibody was diluted in Intercept® Antibody Diluent (P / N: 927-75001). After incubating the membranes with the primary antibody, the membranes were washed and then probed with a secondary antibody (IgG P / N: 926-32211). The antibody was diluted in Intercept® Antibody Diluent (P / N: 927-75001). The membranes were then analyzed with the detection system Odyssey CLx to determine the levels of CFB in each sample. The data for each sample was normalized to the total protein loaded in each lane, and the CFB levels were quantified using Image Studio Lite. The CFB inhibition data in Table 5 are presented as percent change from pre-treatment levels. [Table 5]

[0352] Example 3: Effects of compounds targeting human CFB in mice Compounds RD2401, RD2402, RD2403, RD2404, RD2405, RD2406, RD2407, RD2408 and RD2409, modified as in Table 3, were evaluated in C57Bl / 6 mice. Mice were housed in a vivarium under IACUC approved housing conditions prior to testing. On study day 0, mice were injected with a single subcutaneous dose of 5 mg / kg of oligonucleotide. The mice were observed daily for signs of disease or distress during the study. Mice were bled on days 0, 8, 15, 22, 29 and 36. Complement factor B (CFB) levels were assessed in mouse (C57Bl / 6) serum using immunoblotting as described in Example 2. CFB inhibition data in Table 6 are expressed as percent change from pre-dose levels. [Table 6]

[0353] Example 4: Effects of compounds targeting human CFB in mice Compounds RD2392, RD2393, RD2394, RD2395 and RD2396, modified as in Table 3, were evaluated in C57Bl / 6 mice. Mice were housed in a vivarium under IACUC approved housing conditions prior to testing. On study day 0, mice were injected with a single subcutaneous dose of 5 mg / kg of oligonucleotide. The mice were observed daily for signs of disease or distress during the study. Mice were bled on days 0, 7, 14, 21, 28 and 35. Complement factor B (CFB) levels were assessed in mouse (C57Bl / 6) serum using immunoblotting as described in Example 2. CFB inhibition data in Table 7 are expressed as percent change from pre-dose levels. [Table 7]

[0354] Example 5: Effects of compounds targeting human CFB in mice Compounds RD1701, RD2501, RD2502, RD2503, RD2504, RD2505, RD2506, RD2507, RD2508, RD2509, RD2512, RD2518 and RD2519, modified as in Table 3, were evaluated in C57Bl / 6 mice. Mice were housed in a vivarium under IACUC approved housing conditions prior to testing. On study day 0, mice were injected with a single subcutaneous dose of 5 mg / kg of oligonucleotide. The mice were observed daily for signs of disease or distress during the study. Mice were bled on days 0, 7, 15, 22, 28 and 35. Data for days 7, 15 and 22 are shown below. Complement factor B (CFB) levels were assessed in serum of mice (C57Bl / 6) using immunoblotting as described in Example 2. CFB inhibition data in Table 8 are expressed as percent change from pre-dose levels. [Table 8]

[0355] Example 6: Effects of compounds targeting human CFB in rats Compounds RD1709, RD1710, RD1711, RD1712 and RD1713, modified as in Table 3, were evaluated in Sprague-Dawley or Lewis rats. Rats were housed in a vivarium under IACUC approved housing conditions prior to testing. On study day 0, rats were injected with a single subcutaneous dose of 5 mg / kg of oligonucleotide. The rats were observed daily for signs of disease or distress during the study. Rats were bled on days 0, 8, 15, 22, 29 and 35. Data for days 8, 15 and 22 are shown below.

[0356] Immunoblotting was used to assess the levels of complement factor B (CFB) in rat (Sprague-Dawley and Lewis) serum. After serum collection, the serum was diluted with 1x PBS buffer and mixed with SDS-PAGE compatible loading buffer and reducing reagent. Samples were heated to 70°C for 10 min and separated by SDS-PAGE. After the samples were run by PAGE, the proteins were transferred to nitrocellulose or other compatible membranes. The membranes were stained with Revert700 and the total protein of each sample was quantified using the detection system Odyssey CLx.

[0357] The membranes were blocked with Intercept® Blocking Buffer (P / N: 927-60001) and then probed with a primary antibody specific for CFB (Invitrogen #27924). The antibody was diluted in Intercept® Antibody Diluent (P / N: 927-75001). After incubating the membranes with the primary antibody, the membranes were washed and then probed with a secondary antibody (IgG P / N: 926-32211). The antibody was diluted in Intercept® Antibody Diluent (P / N: 927-75001). The membranes were then analyzed with the detection system Odyssey CLx to determine the levels of CFB in each sample. The data for each sample was normalized to the total protein loaded in each lane, and the CFB levels were quantified using Image Studio Lite. The CFB inhibition data in Table 9 are presented as percent change from pre-treatment levels. [Table 9]

[0358] Example 7: Effects of compounds targeting human CFB in rats Compounds RD1709, RD1710, RD1711, RD1712 and RD1713, modified as in Table 3, were evaluated in Sprague-Dawley or Lewis rats. Rats were housed in a vivarium under IACUC-approved housing conditions prior to testing. On study day 0, rats were injected with a single subcutaneous dose of 5 mg / kg of oligonucleotide. The rats were observed daily for signs of disease or psychological distress during the study. Rats were bled on days 0 and 12. Data from day 12 are shown below. Complement factor B (CFB) levels were assessed in serum from rats (Sprague-Dawley and Lewis) using immunoblotting as described in Example 6. CFB inhibition data in Table 10 are expressed as percent change from pre-dose levels. [Table 10]

[0359] Example 8: Effects of compounds targeting human CFB in rats Compounds RD2380, RD2381, RD2382, RD2383, RD2384 and RD2385, modified as in Table 3, were evaluated in Sprague-Dawley or Lewis rats. Rats were housed in a vivarium under IACUC-approved housing conditions prior to testing. On study day 0, rats were injected with a single subcutaneous dose of 5 mg / kg of oligonucleotide. The rats were observed daily for signs of disease or psychological distress during the study. Separate groups of rats were bled on days 0, 4, 8, 15, 22, 29 and 36. Levels of complement factor B (CFB) were evaluated in serum of rats (Sprague-Dawley and Lewis) using immunoblotting as described in Example 6. CFB inhibition data in Table 11 are expressed as percent change from pre-dose levels. [Table 11]

[0360] Example 9: Effects of compounds targeting human CFB in rats Compounds RD1709, RD1711, RD2386, RD2388, RD2390, RD2391, RD2513 and RD2520, modified as in Table 3, were evaluated in Sprague-Dawley or Lewis rats. Rats were housed in a vivarium under IACUC approved housing conditions prior to testing. On study day 0, rats were injected with a single subcutaneous dose of 5 mg / kg of oligonucleotide. The rats were observed daily for signs of disease or psychological distress during the study. Rats were bled on days 0, 4, 8, 15, 22, 29 and 36. Complement factor B (CFB) levels were assessed in serum of rats (Sprague-Dawley and Lewis) using immunoblotting as described in Example 6. CFB inhibition data in Table 12 are expressed as percent change from pre-dose levels. [Table 12]

[0361] Example 10: Effects of compounds targeting human CFB in cynomolgus monkeys Compounds RD2273, RD2275, RD2276, RD2277, RD2278, RD2279, RD2533 and RD2534 were evaluated in cynomolgus monkeys with modifications as shown in Table 3. Prior to testing, the monkeys were kept in an isolation facility during which their general health was observed daily. On day 1 of the study, eight groups of two cynomolgus monkeys each were injected with a single subcutaneous dose of 6 mg / kg of oligonucleotide. The monkeys were observed daily for signs of illness or mental distress during the study. Blood was collected from the cynomolgus monkeys on days -6 and 1 (pre-dose), 8, 15, 22, 29, 36, 43, 50, 57 and 64.

[0362] CFB levels in cynomolgus monkey serum were determined using an Abcam (ab137973) ELISA kit. Abcam's antibody has less than 5% cross-reactivity with monkey CFB. The protocol used was that described by the manufacturer. All reagents, standards and samples were prepared as instructed in the manual. The 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. Chromogen substrate was added to each well and incubated with the samples at room temperature. Stop solution was added to each well and the plate was read immediately using a Biotek® plate reader. CFB inhibition data is expressed as percent change from pre-dose levels. Data for days 8, 15, 22, 29, 36 and 43 are shown in Table 13 below. [Table 13]

[0363] Immunoblotting was also used to assess the levels of complement factor B (CFB) in cynomolgus monkey serum. After serum collection, the serum was diluted with 1x PBS buffer and mixed with SDS-PAGE compatible loading buffer and reducing reagent. Samples were heated to 70°C for 10 min and separated by SDS-PAGE. After the samples were run by PAGE, the proteins were transferred to nitrocellulose or other compatible membranes. The membranes were stained with Revert700 and the total protein of each sample was quantified using the detection system Odyssey CLx.

[0364] The membranes were blocked with Intercept® Blocking Buffer (P / N: 927-60001) and then probed with a primary antibody specific for CFB (ProteinTech, Cat. No. 10170-1-AP). The antibody was diluted in Intercept® Antibody Diluent (P / N: 927-75001). After incubating the membranes with the primary antibody, the membranes were washed and then probed with a secondary antibody (IgG P / N: 926-32211). The antibody was diluted in Intercept® Antibody Diluent (P / N: 927-75001). The membranes were then analyzed with the detection system Odyssey CLx to determine the levels of CFB in each sample. Data for each sample were normalized to the total protein loaded in each lane, and CFB levels were quantified using Image Studio Lite. CFB inhibition data are expressed as percent change from pre-treatment levels. Data for days 8, 15, 22, 29, 36, 43, 50, 57, and 64 are shown below in Table 14. In a second set of experiments, certain cynomolgus monkeys were bled on days -6 and 1 (pre-dose), 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, 85, and 92 for serum collection and analysis, and the data are shown below in Table 15. [Table 14] [Table 15]

[0365] Example 11: Effects of compounds targeting human CFB in cynomolgus monkeys Compounds RD2557, RD2558, RD2559 and RD2560, modified as in Table 3, were evaluated in cynomolgus monkeys. Prior to testing, the monkeys were kept in an isolated facility, during which their general health was observed daily. On day 1 of the study, each group of two cynomolgus monkeys was injected with a single subcutaneous dose of 6 mg / kg of oligonucleotide. During the study, the monkeys were observed daily for signs of illness or mental distress. Blood was collected from the cynomolgus monkeys on days -6 and 1 (pre-dose), 4, 8, 15, 22, 29, 36, 43, 50, 57 and 64.

[0366] Complement factor B (CFB) levels were assessed in serum of cynomolgus monkeys using ELISA as described in Example 10. CFB inhibition data are expressed as percent change from pre-dose levels. Data for days 8, 15, 22 and 29 are shown in Table 16 below. [Table 16]

[0367] Immunoblotting was also used to assess levels of Complement Factor B (CFB) in serum of cynomolgus monkeys as described in Example 10. CFB inhibition data is expressed as percent change from 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 drawn from certain cynomolgus monkeys on days -6 and 1 (pre-dose), 4, 8, 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. [Table 17] [Table 18]

[0368] Example 12: Effects of compounds targeting human CFB in cynomolgus monkeys Compounds RD1714, RD1715 and RD2262, modified as in Table 3, were evaluated in cynomolgus monkeys. Prior to testing, the monkeys were kept in an isolation facility, during which their general health was observed daily. On day 1 of the study, each group of two cynomolgus monkeys was injected once with a subcutaneous dose of 3 mg / kg or 6 mg / kg of oligonucleotide. The monkeys were observed daily for signs of illness or mental distress during the study. For serum analysis, the monkeys were bled on days -6 and 1 (pre-dose), 8, 15, 22, 29, 36, 43, 50, 57 and 64. Complement factor B (CFB) levels were evaluated in serum of cynomolgus monkeys using ELISA, as described in Example 10. CFB inhibition data are expressed as percent change from pre-dose levels. Immunoblotting was also used to assess levels of Complement Factor B (CFB) in serum from cynomolgus monkeys, as described in Example 10. ELISA data for days 8, 15, 22, 29 and 36 are shown in Table 19 below. [Table 19]

[0369] Example 13: Effect of compounds targeting human CFB in complement pathway assays The Wieslab Complement Alternative Pathway Assay (COMPL AP330 RUO, SVAR) and Wieslab Complement Classical Pathway Assay (COMPL CL310 RUO, SVAR) were used according to the manufacturer's instructions to determine the level of active C5b-9 formation to assess alternative and classical complement pathway activity. From Example 10, sera from monkeys administered RD2273, RD2275, and RD2276 were tested, and data from the Wieslab Complement Alternative Pathway Assay is shown in Table 20 below. As expected, no effect was observed in the Wieslab Complement Classical Pathway Assay. From Example 11, sera from monkeys administered RD2558 and RD2560 were also tested, and data from the Wieslab Complement Alternative Pathway Assay is shown in Table 21 below. As expected, no effect was observed in the Wieslab Complement Classical Pathway Assay. In a separate study, serum from monkeys administered RD2558 and RD2560 from Example 11 was tested in a Wieslab Complement Alternative Pathway assay, and the data from the Wieslab Complement Classical Pathway assay is shown below in Table 22. As expected, no effect was seen in the Wieslab Complement Classical Pathway assay. Serum from monkeys administered RD2558 and RD2560 from Example 11 was also tested in a hemolytic assay to determine alternative pathway hemolytic activity, and the data are shown in Table 23.

[0370] Alternative pathway hemolytic activity was determined as follows: NHP serum (5.6%) was added to GVB° (Complement Technology, Tyler, Texas) and 5 mM EGTA containing 25% rabbit red blood cells (Er, Complement Technology, Tyler, Texas). Samples were incubated for 1 hour at 37°C with intermittent shaking. Hemolysis was stopped by adding GVBE (Complement Technology, Tyler, Texas) to the samples at a 1:1 ratio. Samples were then centrifuged and the supernatants transferred to a new 96-well plate. Absorbance was measured at 412 nm. Alternative pathway hemolytic activity was measured by subtracting the OD value from the negative control sample (buffer and Er only) and normalizing each sample to the positive control sample (water and Er only). Each time point sample was then normalized to the average of the pre-dose samples. [Table 20] [Table 21] [Table 22] [Table 23]

[0371] Example 14: Effects of compounds targeting human CFB in cynomolgus monkeys Using the parent compound RD2558 as a starting point, compounds RD2794, RD2795 and RD2796 were designed as shown in Tables 24 and 25 below. The modified compounds shown in Table 25 are evaluated in cynomolgus monkeys. Dosing to the monkeys is performed according to the protocol of Example 10 on day 1 of the study using a subcutaneous dose of 4 mg / kg oligonucleotide. Complement factor B (CFB) levels are evaluated in serum of cynomolgus monkeys using ELISA as described in Example 10. Complement factor B (CFB) levels are also evaluated in serum of cynomolgus monkeys using immunoblotting as described in Example 10. CFB inhibition data are expressed as percent change from pre-dosing 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 was collected on days 4, 8, 15, 22, 29, 36, 43, 50, 57, and 64 for RD2795 and RD2796, plus days 71, 78, 85, and 96 for RD2794, as shown in Table 27 below. Inhibition of alternative complement pathway activity was assessed using the WIESLAB assay (COMPL AP330) following the manufacturer's recommended protocol, as described above. The data are shown in Table 28 below. Inhibition of alternative pathway 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 Classical Pathway assay did not show the expected effect (not shown). [Table 24] [Table 25] [Table 26] [Table 27] [Table 28] [Table 29]

[0372] Example 15: Effects of compounds targeting human CFB in cynomolgus monkeys Compounds RD2797, RD2829, RD2798, RD2801, RD2830, RD2821, RD2831 and RD2832 were designed using parent compounds RD2273, RD2275, RD2558, RD2560 and RD2276 as starting points, as shown in Tables 30 and 31 below. The modified compounds shown in Table 31 are evaluated in cynomolgus monkeys. Administration to the monkeys is performed according to the protocol of Example 10 on day 1 of the study, using a subcutaneous dose of 4 mg / kg oligonucleotide. Complement factor B (CFB) levels are evaluated in serum of cynomolgus monkeys using ELISA, as described in Example 10. Complement factor B (CFB) levels are also evaluated in serum of cynomolgus monkeys using immunoblotting, as described in Example 10. CFB inhibition data is expressed as percent change from pre-administration levels. Data for days 8, 15, 22 and 29 for RD2798, RD2801, RD2821, RD2830 and RD2832 are shown in Table 32 below. In a second set of experiments, CFB inhibition data was collected on days 8, 15, 22, 29, 36, 43, 50, 57 and 64 for RD2821 and RD2832, plus days 71, 78 and 85 for RD2798 and RD2801, plus day 96 for RD2830, as shown in Table 33 below. In a third set of experiments, CFB inhibition data was collected on days 8, 15, 22, 29, 36, 43, 50, 57, 64, and 71 for RD2797, RD2829, and RD2831, as shown in Table 34 below. Inhibition of alternative complement pathway activity was assessed using the WIESLAB assay (COMPL AP330) following the manufacturer's recommended protocol, as described above. The data are shown in Table 35 below. Inhibition of alternative pathway 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 36 below. [Table 30] [Table 31] [Table 32] [Table 33] [Table 34] [Table 35] [Table 36]

[0373] Example 16: Effects of compounds targeting human CFB in Sprague Dawley rats Sprague Dawley rats (3 per sex per main group (Groups 1-5), 1 per sex per toxicokinetic group (Groups 6-9)), 8-9 weeks of age) were administered vehicle control (Group 1) or 30 mg (Groups 2 and 6), 60 mg (Groups 3 and 7), 150 mg (Groups 4 and 8), or 300 mg (Groups 9) of RD2830 per kg per dose by SC injection on days 1 and 21 in a dosing volume of 5 mL / kg.

[0374] Observations included cageside observations (general signs of toxicity, including fecal and urine volume), physical examination (pre-dose), body weights (days 1, 5, 8, 12, 15, 19, 21 (toxicokinetics group), and 26 (main group)), and food consumption (once a week). Blood samples were taken on day 26 for clinical chemistry, hematology, and coagulation data. Sacrifice was on day 26. Necropsy included visual inspection for external, abdominal, thoracic, and cranial abnormalities. Organ weights were recorded (heart, kidneys, liver, spleen, and thymus). Histology and microscopic pathology were performed (heart, kidneys, lesions, liver, lungs, lymph nodes, injection site, skin, spleen, and thymus).

[0375] RD2830 administered SC in single doses of 30 mg, 60 mg, 150 mg, and 300 mg / kg on days 1 and 21 was considered to be generally well tolerated in male and female rats.

[0376] SEQ ID NO:1 [ka]

[0377] Although the disclosure has been described with reference to the above examples, it will be understood that modifications and variations are encompassed within the spirit and scope of the disclosure and the following claims.

Claims

1. A compound, A first modified oligonucleotide having a length of 14 to 23 linked nucleosides, wherein the first modified oligonucleotide has a nucleic acid base sequence containing at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 consecutive nucleic acid bases from the nucleic acid base sequence of SEQ ID NO: 109, A second modified oligonucleotide having a length of 14 to 23 linked nucleosides, wherein the second modified oligonucleotide has a complementary region to the first modified oligonucleotide. Includes, One or more GalNAcs are bound to the first modified oligonucleotide, The 5' nucleoside of the first modified oligonucleotide is given by the following formula: 【Chemistry 61】 It is, and in the formula, R9 is H, adenine, guanine, thymine, cytosine, uracil, adenine containing a protecting group (PG), guanine containing PG, thymine containing PG, cytosine containing PG, uracil containing PG, modified nucleic acid base, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or nucleic acid base isostea. L is a bond, phosphodiester bond, phosphorothioate bond, triazole, tetrazole, amide, reverse amide, carbamate, carbonate, urea, alkyl, or heteroalkyl. R2 is an oligonucleotide sequence or modified oligonucleotide. Y1 is O, CH2, CH2O, or any substituted NH. Y2 is O, CH2, CH2O, or any substituted NH. Y3 is CO, SO₂, P(O)O, CH₂-O-C(O), CH₂-NH-C(O), CH₂-NH-SO₂, or CH₂. Y4 is CO, SO₂, P(O)O, CH₂-O-C(O), CH₂-NH-C(O), CH₂-NH-SO₂, or CH₂. n² is 0, 1, 2, 3, 4, 5, or 6. A compound in which each of n1, n3, n4, and n5 is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

2. The compound according to claim 1, wherein the first modified oligonucleotide has a length consisting of 23 linked nucleosides and has a nucleic acid base sequence including the nucleic acid base sequence of Sequence ID No.

109.

3. The compound according to claim 2, wherein the complementary region between the first modified oligonucleotide and the second modified oligonucleotide has a length of 19 to 23 linked nucleosides.

4. The compound according to claim 1, wherein at least one nucleoside bond of the first or second modified oligonucleotide is a phosphorothioate nucleoside bond or a methylphosphonate nucleoside bond.

5. The compound according to claim 4, wherein the phosphorothioate nucleoside bond or methylphosphonate nucleoside bond is located at the 3' end of the first or second modified oligonucleotide, or at the 5' end of the first or second modified oligonucleotide.

6. The compound according to claim 1, wherein the first or second modified oligonucleotide comprises a modification selected from the group consisting of LNA, cEt, 2'-MOE, 2'-F, 2'-OMe, and 2'-deoxy, or combinations thereof.

7. The compound according to claim 1, wherein the first modified oligonucleotide contains five or fewer 2'-F sugar modifications.

8. The compound according to claim 1, wherein the second modified oligonucleotide has a length consisting of 14 to 22 linked nucleosides and has a nucleic acid base sequence containing at least 14 consecutive nucleic acid bases from the nucleic acid base sequence of Sequence ID No.

100.

9. The first modified oligonucleotide is of formula: 【Chemical 86】 It consists of reference ID number IS1252, which has During the ceremony, "A" is a nucleoside having an adenine nucleic acid base, "G" is a nucleoside having a guanine nucleic acid base, "C" is a nucleoside having a cytosine nucleic acid base, and "U" is a nucleoside having a uracil nucleic acid base. "m" is a sugar modification called 2'-O-methyl. "f" is a sugar modification called 2'-F. "*" represents a phosphorothioate nucleoside bond, "." represents a phosphate nucleoside bond, "dQ" is the inverted debase deoxyribose, "H4 *" is the formula: 【Transformation 87】 The compound according to claim 1, wherein the compound is as described above.

10. The second modified oligonucleotide is of formula: 【Chemical 88】 It consists of reference ID number IA1016, which has the following characteristics: During the ceremony, "A" is a nucleoside having an adenine nucleic acid base, "G" is a nucleoside having a guanine nucleic acid base, "C" is a nucleoside having a cytosine nucleic acid base, and "U" is a nucleoside having a uracil nucleic acid base. "m" is a sugar modification called 2'-O-methyl. "f" is a sugar modification called 2'-F. "*" represents a phosphorothioate nucleoside bond, The compound according to claim 1, wherein "." represents an inter-nucleoside bond of phosphate.

11. The compound has the following chemical structure: 【Transformation 78】 The compound according to claim 8, which is the compound or a pharmaceutically acceptable salt or stereoisomer thereof.

12. The compound according to claim 11, wherein the pharmaceutically acceptable salt is a sodium salt or a potassium salt.

13. The following chemical structure: 【Chemistry 82】 The compound according to claim 12, which is a sodium salt or a stereoisomer thereof.

14. A composition comprising the compound according to claim 11 and a pharmaceutically acceptable carrier.

15. A composition comprising the compound described in Claim 1 and a pharmaceutically acceptable carrier.

16. A composition comprising the compound described in Claim 1, wherein the composition is administered to a subject that requires it.

17. The composition according to claim 16, wherein administration of the composition suppresses, alleviates, and / or improves a disease, disorder, condition, or symptoms associated with complement factor B (CFB).

18. A composition comprising the compound according to claim 1 for use in a method for inhibiting intracellular expression of CFB, wherein the method comprises contacting the cell with the compound.

19. The composition according to claim 18, wherein the cells are located in the liver of an individual.

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